Cytotoxic imidazo[1,2-a]pyridine compounds and their use in therapy

Abstract

The present invention relates to compounds of formula (I) and related embodiments. [Formula 1] TIFF2025531807000203.tif31170

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel cytotoxic compounds that are or are believed to be inhibitors of human N-myristoyltransferase (human NMT). The present invention also relates to such compounds for use as pharmaceuticals, particularly in the treatment or prevention of hyperproliferative disorders, such as cancer, or other diseases or disorders in which inhibition of human NMT provides a therapeutic or prophylactic effect. [Background technology]

[0002] BACKGROUND OF THE INVENTION N-myristoyltransferase (NMT) is a monomeric enzyme ubiquitous in eukaryotes that catalyzes the irreversible cotranslational transfer of myristate (a saturated 14-carbon fatty acid) from myristoyl-coenzyme A (myr-CoA) to protein substrates containing N-terminal glycines, accompanied by the formation of an amide bond (Farazi, T.A., G. Waksman, and J.I. Gordon, J. Biol. Chem., 2001, 276(43): 39501-39504).

[0003] There are two human NMTs: human NMT1 (HsNMT1) and human NMT2 (HsNMT2).Inhibition of human NMTs has been shown to be effective in treating a variety of diseases or disorders, such as hyperproliferative disorders (e.g., cancers, e.g., human colorectal cancer, gallbladder cancer, brain tumors, and lymphomas, e.g., B-cell lymphomas) (Resh MD, 1993. Biochern. Biophys. Acta 1115, 307-22; Bertiaume LG, Beuachamp E, WO2017011907), as well as viral infections, e.g., HIV (Gottlinger HG, Sodroski JG, Haseltine WA, 1989. Proc. Nat. Acad. Sci. USA 86:5781-85; Bryant ML, Ratner L, 1990. Proc. Natl. Acad. Sci. USA 87:523-27) and human rhinovirus (HRV) (Davis MP, Bottley G, Beales RD, 1994. Proc. Natl. Acad. Sci. USA 87:523-27). References LP, Killington, RA, Rowlands DJ, Tuthill, TJ, 2008 Journal of Virology 82 4169-4174; Mousnier A, Bell AS, Swieboda DP, Morales-Sanfrutos J, Perez-Dorado I, Brannigan JA, Newman J, Ritzefeld M, Hutton, JA, Guedan A, Asfor AS, Robinson, SW, References Hopkins-Navratilova I, Wilkinson AJ, Johnston SL, Leatherbarrow RJ, Tuthill TJ, Solari R, Tate EW, 2018 Nature Chemistry 10(6) 599-606), Corbic Ramljak I, Stanger J, Real-Hohn A. Dreier D, Wimmer L., Redlberger-Fritz M, Fischl W, Klingel K, Mihovilovic MD, Blaas D, Kowalski H, PLOS Pathogens 14(8): e1007203) have been proposed as targets for treating or preventing cancer.Because NMTs play important roles in protein trafficking, mediating protein-protein interactions, stabilizing protein structure, and signal transduction in biological systems, inhibition of HsNMT1 and / or HsNMT2 enzymes has the potential to disrupt multiprotein pathways. While inhibition of human NMTs is thought to inhibit both HsNMT1 and HsNMT2, its therapeutic and / or prophylactic activity is thought to derive primarily from inhibition of HsNMT1. The above characteristics are thought to be desirable, for example, to reduce the risk of resistance development in the treatment or prevention of microbial infections and hyperproliferative disorders.

[0004] NMT has two binding pockets: one is the myr-CoA binding pocket and the other is the peptide binding pocket. Most NMT inhibitors reported to date target the peptide binding pocket.

[0005] Compounds active as inhibitors of NMT have been previously disclosed, see, for example, WO00 / 37464 (Roche), WO2010 / 026365 (University of Dundee), WO2013 / 083991 (Imperial Innovations Limited), WO2017 / 001812 (Imperial Innovations Limited), WO2020 / 128473 (Imperial College Innovations Limited), WO2020 / 128475 (Imperial College Innovations Limited), and WO2022 / 058745 (Imperial College Innovations Limited et al.). Certain uses of NMT inhibitors have been disclosed, see for example WO2022 / 090746 (Imperial College Innovations Limited et al.) and WO2022 / 082306 (Pacylex Pharmaceuticals).

[0006] However, there remains a need for additional compounds with cytotoxic activity and inhibitors of human NMT, particularly those that combine cytotoxic activity and highly potent inhibition of human NMT with favorable pharmacokinetic properties, such as cell permeability and / or metabolic stability, and an improved therapeutic window.

[0007] Surprisingly, the present inventors have now discovered that alcohol-substituted imidazo[1,2-a]pyridine compounds exhibit particularly potent cytotoxic activity and / or are potent inhibitors of human NMT and may desirably exhibit other properties, such as cell permeability and metabolic stability profiles, that are suited to particular therapeutic purposes. These properties are believed to make the compounds of the invention particularly suitable for use as pharmaceuticals for the treatment or prevention of hyperproliferative diseases such as cancer. Summary of the Invention

[0008] (Summary of the Invention) In a first aspect, the present invention provides a compound of formula (I): or a salt and / or solvate thereof [ka] (In the formula: R 1 is a group of formula OLA; L is -(CHR 12 ) m - and; Each R 12 are independently H or C 1-4 is alkyl; m is 1, 2, or 3; A is, [ka] : and v is 0, 1, or 2; R 9a is H, C 1-4 Alkyl, or C 1-4 is haloalkyl; R 9b is H, C 1-4Alkyl or C 1-4 is haloalkyl; R 9c is C 1-4 Alkyl or C 1-4 is haloalkyl; R 9d is H, C 1-4 Alkyl or C 1-4 is haloalkyl; R 10 is H, C 1-4 Alkyl or C 1-4 is haloalkyl; R 11 H, halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; s is 0, 1, 2, or 3; Each R 2 are independently F, Cl, Br, OCH3, OCF3, or C optionally substituted by up to three halogen groups. 1-4 is alkyl; Y is CH or C 1-4 is alkyl; R 3 is H or C 1-4 is alkyl; R 4 is H or C 1-4 is alkyl; R 5 is H or C 1-4 is alkyl; R 6 is H or C 1-4 is alkyl; q is 0 or 1; R 7 is H or methyl; R 8 is H or methyl; or R 3 and R 5 and an intervening atom, the intervening atom and a bond, or the intervening atom and -(CHR a ) r-, or R 7 group and the R 5 The group and the intervening atom are separated by a -(CHR a ) r -, forming a 3- to 7-membered non-aromatic heterocycle; r is 1, 2, 3, 4, or 5; and R a is hydrogen or methyl).

[0009] The compound of formula (I) may be provided in the form of a salt and / or solvate. Preferably, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and / or solvate. Preferably, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt. Preferably, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt. Preferably, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable solvate. Preferably, the compound of formula (I) may be provided.

[0010] The present invention further provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier.

[0011] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use as a pharmaceutical.

[0012] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a hyperproliferative disorder (e.g., cancer).

[0013] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the treatment or prevention of a hyperproliferative disorder (e.g. cancer).

[0014] The present invention also provides a method for treating or preventing a hyperproliferative disorder (e.g., cancer) in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0015] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a disease or disorder in which inhibition of human NMT provides a therapeutic or prophylactic effect.

[0016] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of human NMT provides a therapeutic or prophylactic effect.

[0017] The present invention also provides a method for treating or preventing a disease or disorder in which inhibition of human NMT provides a therapeutic or preventive effect in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0018] The present invention also provides a kit of parts comprising: (a) a first pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier; and (b) a second pharmaceutical composition comprising a further therapeutic agent, preferably a further compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier. [Brief explanation of the drawings]

[0019] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]Figure 1A shows the effect of treatment with Examples 5 and 14 compared to Comparative Compound 1 and cis-platin on the viability of CA46 cancer cells in vitro. Figure 1B shows the effect of treatment with Examples 5 and 14 compared to Comparative Compound 1 and cis-platin on the viability of Panc-1 cancer cells in vitro. Figure 1C shows the effect of treatment with Examples 5 and 14 compared to Comparative Compound 1 and cis-platin on the viability of RKO cancer cells in vitro. Figure 1D shows the effect of treatment with Examples 5 and 14 compared to Comparative Compound 1 and cis-platin on the viability of MCF-7 cancer cells in vitro. Figure 1E shows the effect of treatment with Examples 5 and 14 compared to Comparative Compound 1 and cis-platin on the viability of NCI-H1703 cancer cells in vitro. Figure 1F shows the effect of treatment with Examples 5 and 14 compared to Comparative Compound 1 and cis-platin on the viability of SW480 cancer cells in vitro. Figure 1G: shows the effect of treatment with Examples 5 and 14 compared to Comparative Compound 1 and cis-platin on the viability of MX-1 cancer cells in vitro. Figure 1H: shows the effect of treatment with Examples 5 and 14 compared to Comparative Compound 1 and cis-platin on the viability of DU4475 cancer cells in vitro. Figure 1I: shows the effect of treatment with Examples 5 and 14 compared to Comparative Compound 1 and cis-platin on the viability of HCC1806 cancer cells in vitro. [Figure 2] Figure 2A shows the effect of treatment with Example 12 compared to Comparative Compound 1 and cis-platin on the viability of LU2511 cancer cells in vitro. Figure 2B shows the effect of treatment with Example 12 compared to Comparative Compound 1 and cis-platin on the viability of LU0884 cancer cells in vitro. [Figure 3] FIG. 3: Shows the effect of treatment of Example 21 compared to vehicle on tumor volume in a DOHH2 xenograft model. [Figure 4] FIG. 4: Shows the effect of treatment of Example 5 compared to vehicle on tumor volume in a DOHH2 xenograft model. [Figure 5]FIG. 5: Shows the effect of treatment of Example 12 compared to vehicle on tumor volume in a DOHH2 xenograft model. [Figure 6] FIG. 6: Shows the effect of treatment of Example 12 compared to vehicle on tumor volume in a DOHH2 xenograft model. [Figure 7] FIG. 7: Shows the effect of treatment with trastuzumab (2.5 mg / lg), ADC Example 1 (2.5 mg / kg), or Example 12 (2 mg / kg) on ​​tumor volume in a mouse xenograft study. [Figure 8] FIG. 8: Shows the effect of treatment with trastuzumab (5 mg / kg), ADC Example 1 (5 mg / kg), or Example 12 (2 mg / kg) on ​​tumor volume in a mouse xenograft study. [Figure 9] FIG. 9: Shows the effect of treatment with trastuzumab (2.5 mg / kg), ADC Example 1 (2.5 mg / kg), or Example 12 (2 mg / kg) on ​​mouse body weight in a mouse xenograft study. [Figure 10] FIG. 10: Shows the effect of treatment with trastuzumab (5 mg / kg), ADC Example 1 (5 mg / kg), or Example 12 (2 mg / kg) on ​​mouse body weight in a mouse xenograft study. [Figure 11] Figure 11: Shows the effect of treatment with trastuzumab (2.5 mg / kg), ADC Example 1 (2.5 mg / kg), trastuzumab deruxtecan (2.5 mg / kg), and an isotype control antibody (5 mg / kg) on ​​tumor volume in a mouse gastric cancer xenograft model. [Figure 12] Figure 12: Shows the effect of treatment with trastuzumab (5 mg / kg), ADC Example 1 (5 mg / kg), trastuzumab deruxtecan (5 mg / kg), and isotype control antibody (5 mg / kg) on ​​tumor volume in a mouse gastric cancer xenograft model. [Figure 13]Figure 13A: Shows the % weight change in mice following the experiment described in Biological Example 8 (and Figure 11, 2.5 mg / kg (mpk)). Figure 13B: Shows the % weight change in mice following the experiment described in Biological Example 8 (and Figure 12, 5 mg / kg (mpk)). [Figure 14] Figure 14: Shows the effect of treatment with ifinatamab (5 mg / kg and 10 mg / kg), ifinatamab-DXd (5 mg / kg and 10 mg / kg), ADC Example 4 (5 mg / kg and 10 mg / kg), and vehicle control on tumor volume in a murine LNCaP prostate cancer xenograft model. [Figure 15] Figure 15: Shows the effect of treatment with ifinatamab (5 mg / kg and 10 mg / kg), ifinatamab-DXd (5 mg / kg and 10 mg / kg), ADC Example 4 (5 mg / kg and 10 mg / kg), and vehicle control on body weight in a mouse LNCaP prostate cancer xenograft model. [Figure 16] Figure 16: Shows the effect of treatment with ifinatamab (5 mg / kg), ifinatamab-DXd (5 mg / kg), ADC Example 4 (2.5 mg / kg, 5 mg / kg, and 10 mg / kg), and vehicle control on tumor volume in a murine VCaP prostate cancer xenograft model. [Figure 17] Figure 17: Shows the effect of treatment with ifinatamab (5 mg / kg), ifinatamab-DXd (5 mg / kg), ADC Example 4 (2.5 mg / kg, 5 mg / kg, and 10 mg / kg), and vehicle control on body weight in a murine VCaP prostate cancer xenograft model. [Figure 18] Figure 18: Shows the effect of treatment with sacituzumab (5 mg / kg), sacituzumab govitecan (5 mg / kg) (plus 5 mg / kg of ADC Example 3 added on study days 27 and 34), and ADC Example 3 (5 mg / kg), and vehicle control on tumor volume in a murine JIMT-1 breast cancer xenograft model. [Figure 19]Figure 19: Shows the effect of treatment with sacituzumab (2.5 mg / kg), sacituzumab govitecan (2.5 mg / kg plus 5 mg / kg of ADC Example 3 added on study day 27), and ADC Example 3 (2.5 mg / kg), and vehicle control on tumor volume in a murine JIMT-1 breast cancer xenograft model. [Figure 20] Figure 20: Shows the effect of treatment with sacituzumab (5 mg / kg), sacituzumab govitecan (5 mg / kg) (plus 5 mg / kg of ADC Example 3 added on study days 27 and 34), and ADC Example 3 (5 mg / kg and 10 mg / kg), and vehicle control on body weight in a murine JIMT-1 breast cancer xenograft model. [Figure 21] Figure 21: Shows the effect of treatment with sacituzumab (2.5 mg / kg), sacituzumab govitecan (2.5 mg / kg plus 5 mg / kg of ADC Example 3 added on study day 27), and ADC Example 3 (2.5 mg / kg), and vehicle control on body weight in a murine JIMT-1 breast cancer xenograft model. DETAILED DESCRIPTION OF THE INVENTION

[0020] (Sequence Listing) SEQ ID NO: 1 - Amino acid sequence of the light chain of trastuzumab SEQ ID NO:2 - Amino acid sequence of the heavy chain of trastuzumab SEQ ID NO: 3 - Amino acid sequence of the light chain of rituximab SEQ ID NO: 4 - Amino acid sequence of the heavy chain of rituximab SEQ ID NO: 5 - Amino acid sequence of the light chain of ifinatamab SEQ ID NO: 6 - Amino acid sequence of the heavy chain of ifinatamab SEQ ID NO: 7 - Amino acid sequence of the light chain of sacituzumab SEQ ID NO: 8 - Amino acid sequence of the heavy chain of sacituzumab

[0021] (Detailed Description of the Invention) As used herein, "C 1-4 The term "alkyl" may be used alone or as a larger group, e.g., C 1-4It refers to a straight or branched alkyl chain, whether or not it forms part of an alkoxy group. 1-4 Examples of alkyl are methyl, ethyl, propyl, and butyl. Reference to "propyl" includes n-propyl and iso-propyl, and reference to "butyl" includes n-butyl, iso-butyl, tert-butyl, and sec-butyl. Exemplary C 1-4 Particular groups of alkyl groups are methyl, isopropyl, and tert-butyl. 1-4 An example of an alkoxy is methoxy.

[0022] As used herein, "C 1-4 The term "haloalkyl" includes straight or branched chain alkyl groups containing 1 to 4 carbon atoms substituted with one or more halo atoms, for example, fluoromethyl, difluoromethyl, and trifluoromethyl. 1-4 A particular example of haloalkyl is trifluoromethyl.

[0023] As used herein, "C 1-4 The term "haloalkoxy" includes straight or branched chain alkoxy groups containing 1 to 4 carbon atoms substituted with one or more halo atoms, such as fluoromethyl, difluoromethyl, and trifluoromethyl. 1-4 Examples of haloalkoxy are trifluoromethoxy and trifluoroethoxy.

[0024] The term heterocycle as used herein, for example, in 3-7 ring non-aromatic heterocycle, refers to a fully or partially saturated hydrocarbon ring containing the specified number of carbon atoms, which may include the carbon atom to which a cycloalkyl group is attached, where at least one of the carbon atoms in the ring is replaced by a heteroatom such as N, S, or O. Heterocycloalkyl may optionally be C 1-4 Alkyl (e.g., Me), C 1-4 Haloalkyl (e.g., CF3), C 1-4 Alkoxy (e.g., Ome), C 1-4It may be substituted with up to three substituents, e.g., one or two, e.g., one, independently selected from the group consisting of haloalkoxy (e.g., OCF), halo (e.g., Cl or F), and CN. In some embodiments, the heterocycloalkyl is unsubstituted.

[0025] Examples of the 3-7 ring non-aromatic heterocyclic group include pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, piperidine, tetrahydropyran, thiane, diazinane, morpholine, thiomorpholine, dioxane, triazinane, trioxane, trithiane, azepane, oxepane, and diazepane. An example of a substituted 3-7 ring non-aromatic heterocyclic group is N-methylpiperazine.

[0026] The term "prevention" is used herein to mean to prepare in advance, and thus can include preventing symptoms of a disease or disorder in a subject, or preventing the recurrence of symptoms of a disease or disorder in an affected subject, and is not limited to complete prevention of illness.

[0027] The term "treatment" or "treating" as used herein includes controlling, alleviating, reducing or modulating a disease state or its symptoms.

[0028] In one embodiment, at least one R 12 is H. Preferably, each R 12 is H. In a second embodiment, at least one R 12 is C 1-4 Preferably, each R 12 is C 1-4 It is alkyl.

[0029] In one embodiment, m is 1. In a second embodiment, m is 2. In a third embodiment, m is 3. In one embodiment, v is 0. In one embodiment, v is 1. In one embodiment, v is 2.

[0030] In one embodiment, R 9a is H. In a second embodiment, R 9a is C 1-4 In a third embodiment, R 9a is C 1-4 In one embodiment, R 9b is H. In a second embodiment, R 9b is C 1-4 In a third embodiment, R 9b is C 1-4 In one embodiment, R 9c is C 1-4 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl, for example methyl, isopropyl, or tert-butyl. 9c is methyl. Preferably, R 9c is isopropyl. Preferably, R 9c is tert-butyl. In a second embodiment, R 9c is C 1-4 In one embodiment, R 9d is H. In a second embodiment, R 9d is C 1-4 alkyl, for example, methyl. In a third embodiment, R 9d is C 1-4 In one embodiment, R 9c is tert-butyl, and R 9d is H. In a second embodiment, R 9c is methyl and R 9d is methyl.

[0031] In one embodiment, R 10is H. In a second embodiment, R 10 is C 1-4 alkyl, for example, methyl. In a third embodiment, R 10 is C 1-4 In one embodiment, R 11 is H. In a second embodiment, R 11 is halo. In a third embodiment, R 11 is CN. In a fourth embodiment, R 11 is C 1-4 In a fifth embodiment, R 11 is C 1-4 In a sixth embodiment, R 11 is C 1-4 In a seventh embodiment, R 11 is C 1-4 It is haloalkoxy.

[0032] In one embodiment, s is 0. In a second embodiment, s is 1. In a third embodiment, s is 2. In a fourth embodiment, s is 3.

[0033] In one embodiment, at least one R 2 is F, Cl, or Br, for example Cl or F, especially F. Preferably, each R 2 is F, Cl, or Br, e.g., Cl or F, in particular, F. In a second embodiment, at least one R 2 is C 1-4 alkyl, and preferably each R 2 is C 1-4 In a third embodiment, at least one R 2 is OCH3, and preferably each R 2 is OCH3. In a fifth embodiment, at least one R 2 is OCF3, and preferably each R 2 is OCF3.

[0034] In one embodiment, s is 1 and R2 is F. In a second embodiment, s is 2 and each R 2 is F.

[0035] In one embodiment, Y is CH. In a second embodiment, Y is C 1-4 In one embodiment, R 3 is H. In a second embodiment, R 3 is C 1-4 It is alkyl.

[0036] In one embodiment, R 4 is H. In a second embodiment, R 4 is C 1-4 It is alkyl.

[0037] In one embodiment, R 5 is H. In a second embodiment, R 5 is C 1-4 Alkyl, for example, methyl.

[0038] In one embodiment, R 6 is H. In a second embodiment, R 6 is C 1-4 alkyl, for example, methyl. In one embodiment, R 5 is methyl and R 6 is H. In one embodiment, R 5 and R 6 At least one of is H.

[0039] In one embodiment, q is 0. In a second embodiment, q is 1.

[0040] In one embodiment, R 7 is H. In a second embodiment, R 7 is methyl. In one embodiment, R 8 is H. In a second embodiment, R 8 is methyl.

[0041] In one embodiment, R 3 and R 5 and an intervening atom, the intervening atom and a bond, or the intervening atom and -(CHR a ) r In the second embodiment, R 7 Groups and R 5 The group and the intervening atom are a ) r -, forming a 3- to 7-membered non-aromatic heterocycle.

[0042] In one embodiment, r is 1. In a second embodiment, r is 2. In a third embodiment, r is 3. In a fourth embodiment, r is 4. In a fifth embodiment, r is 5.

[0043] In one embodiment, R a is hydrogen. In a second embodiment, R a is methyl.

[0044] In one embodiment, there is provided a compound of formula (IA): or a salt and / or solvate thereof [ka] (In the formula: R 2a is H or F; R 2b is F; R 5a is H or methyl; R 6a is H or methyl; R 9ca is methyl, iso-propyl, or tert-butyl; R 9cb is H or methyl; R 10a is methyl; and R 11a is methyl; However, R 2a When is H, R 9cbis H).

[0045] It will be understood that with respect to the aspects of pharmaceutical compositions, compounds for use, uses, and methods, the statements and preferences given with respect to compounds of formula (I) or salts and / or solvates thereof apply equally to compounds of formula (IA) or salts and / or solvates thereof.

[0046] In one embodiment, R 2a is H. In a second embodiment, R 2a is H. In one embodiment, R 5a is H. In a second embodiment, R 5a is methyl. In one embodiment, R 6a is H. In a second embodiment, R 6a is methyl. In one embodiment, R 9ca is methyl. In a second embodiment, R 9ca is isopropyl. In a third embodiment, R 9ca is tert-butyl. In one embodiment, R 9cb is H. In a second embodiment, R 9cb is methyl. In one embodiment, R 9ca is tert-butyl, and R 9cb is H. In a second embodiment, R 9ca is methyl and R 9cb is methyl.

[0047] In one embodiment, the compound of formula (I) is 1-{4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}ethan-1-ol; 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol; (Isomer 1) 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol; (Isomer 2) 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol; 1-{4-[2-(2,3-difluoro-6-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}ethan-1-ol; 1-(4-(2-(6-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol; 1-(4-(2-(2-(3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol; 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 1) 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 2) 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 1) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 2) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 1) 1-(4-(2-(6-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 2) 1-(4-(2-(6-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; 1-(4-(2-(6-(3-(aminomethyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; 2-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol; 2-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol; 2-[4-(2-{6-[3-(aminomethyl)imidazo[1,2-a]pyridin-6-yl]-2,3-difluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]propan-2-ol; 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol; 2-{4-[2-(2-{3-[(ethylamino)methyl]imidazo[1,2-a]pyridin-6-yl}-5-fluorophenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}propan-2-ol; 2-(4-(2-(2-(3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol; 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol; and 1-{4-[2-(2,3-difluoro-6-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}-2-methylpropan-1-ol : selected from the group consisting of:

[0048] Salts and / or solvates thereof (eg, pharmaceutically acceptable salts thereof) are also provided.

[0049] In one embodiment, the present invention provides 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol, or a salt and / or solvate thereof. In one embodiment, the present invention provides a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol. In one embodiment, the present invention provides a pharmaceutically acceptable salt of 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol. In one embodiment, the present invention provides a pharmaceutically acceptable solvate of 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol. In one embodiment, the invention provides 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol.

[0050] In one embodiment, the present invention provides (Isomer 1) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol, or a salt and / or solvate thereof. In one embodiment, the present invention provides a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of (Isomer 1) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol. In one embodiment, the present invention provides a pharmaceutically acceptable salt of (Isomer 1) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol. In one embodiment, the present invention provides a pharmaceutically acceptable solvate of (Isomer 1) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol. In one embodiment, the present invention provides (Isomer 1) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol.

[0051] In one embodiment, the present invention provides (Isomer 2) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol, or a salt and / or solvate thereof. In one embodiment, the present invention provides a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of (Isomer 2) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol. In one embodiment, the present invention provides a pharmaceutically acceptable salt of (Isomer 2) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol. In one embodiment, the present invention provides a pharmaceutically acceptable solvate of (Isomer 2) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol. In one embodiment, the present invention provides (isomer 2) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol.

[0052] In one embodiment, the present invention provides 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol, or a salt and / or solvate thereof. In one embodiment, the present invention provides a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol. In one embodiment, the present invention provides a pharmaceutically acceptable salt of 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol. In one embodiment, the present invention provides a pharmaceutically acceptable solvate of 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol. In one embodiment, the invention provides 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol.

[0053] In one embodiment, R 9d is H and R 9c and the alcohol has the following stereochemical configuration: [ka] It has.

[0054] In one embodiment, R 9d is H and R 9c and the alcohol has the following stereochemical configuration: [ka] It has.

[0055] It is understood that for use in medicine, salts of compounds of formula (I) should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of compounds of formula (I) may be useful in other contexts, for example, during the preparation of compounds of formula (I). Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described in Berge et al. (1977). Such pharmaceutically acceptable salts include acid and base addition salts. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, and organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid. Other salts, such as oxalates or formates, may be used, for example, in the isolation of compounds of formula (I), and are within the scope of the present invention.

[0056] Some compounds of formula (I) can form acid addition salts with one or more equivalents of acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. Compounds of formula (I) can be prepared in crystalline or non-crystalline form, and, if crystalline, can be optionally solvated, for example, as hydrates. The present invention includes within its scope stoichiometric solvates (e.g., hydrates) and compounds containing variable amounts of solvent (e.g., water). It should be understood that the present invention encompasses all isomers of formula (I), including all geometric, tautomeric, and optical forms, and mixtures thereof (e.g., racemic mixtures). If additional chiral centers are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0057] The present disclosure includes all isotopic forms of the compounds of formula (I) or salts and / or solvates thereof provided herein, whether (i) in a form in which all atoms of a given atomic number have the mass number (or mixture of mass numbers) that is predominant in nature (referred to herein as "natural isotopic forms"), or (ii) in a form in which one or more atoms are replaced by an atom having the same atomic number but a mass number different from the mass number of the atom that is predominant in nature (referred to herein as "unnatural variant isotopic forms"). It is understood that atoms may exist in nature as a mixture of mass numbers. The term "unnatural variant isotopic form" also includes embodiments in which the proportion of atoms of a given atomic number having a mass number less commonly found in nature (referred to herein as "uncommon isotopes") is increased relative to the proportion occurring in nature, e.g., to a level of >20%, >50%, >75%, >90%, >95%, or >99% of the number of atoms of that atomic number (the latter embodiments being referred to as "isotopically enriched variant forms"). The term "unnatural variant isotopic form" also includes embodiments in which the proportion of uncommon isotopes is reduced relative to the proportion occurring in nature. Isotopic forms can include radioactive forms (i.e., those incorporating a radioactive isotope) and non-radioactive forms. Radioactive forms are typically isotopically enriched variant forms.

[0058] Non-naturally occurring isotopic forms of the compounds of formula (I) or salts and / or solvates thereof include deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-15( 15 N), oxygen-15( 15 O), oxygen-17( 17 O), oxygen-18( 18 O), phosphorus-32( 32 P), sulfur-35( 35 S), chlorine-36( 36 Cl), chlorine-37( 37 Cl), fluorine-18( 18 F), iodine-123( 123 I), iodine-125(125 It may contain one or more artificial or uncommon isotopes, such as I), in one or more atoms, or may contain an increased proportion of such isotopes compared to the proportion that predominates in nature.

[0059] Non-natural variant isotopic forms containing radioactive isotopes can be used, for example, for drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. 2 Non-naturally occurring variant isotopic forms incorporating H or D may confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some situations. 11 C. 18 F, 15 O, and 13 Non-natural variant isotopic forms can be prepared incorporating positron emitting isotopes such as N, which are useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. In one embodiment, the compound of formula (I) or salts and / or solvates thereof are provided in natural isotopic form.

[0060] In one embodiment, the compound of formula (I) or its salts and / or solvates is provided in a non-naturally occurring isotopic form. In a specific embodiment, the non-naturally occurring isotopic form is provided in which one or more atoms of the compound of formula (I) or its salts and / or solvates have deuterium (i.e., 2In one embodiment, the atoms of the compound of formula (I) or its salts and / or solvates are in isotopic form that is not radioactive. In one embodiment, one or more atoms of the compound of formula (I) or its salts and / or solvates are in isotopic form that is radioactive. Preferably, the radioisotope is a stable isotope. Preferably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

[0061] In one embodiment, compounds of formula (I) or salts and / or solvates thereof are provided, wherein a single atom of the compound exists in a non-naturally occurring variant isotopic form. In another embodiment, compounds of formula (I) or salts and / or solvates thereof are provided, wherein two or more atoms exist in a non-naturally occurring variant isotopic form.

[0062] Non-natural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described herein, for example, those described in the accompanying Examples for preparing natural isotopic forms. Thus, non-natural isotopic variant forms can be prepared by substituting appropriate isotopic variant (or labeling) reagents for the conventional reagents utilized in the Examples. Because the compounds of formula (I) are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, e.g., at least 60% pure, more suitably at least 75% pure, and preferably at least 85%, particularly at least 98% pure (percentages are on a weight-to-weight basis). Impure preparations of the compounds can be used to prepare more pure forms for use in pharmaceutical compositions.

[0063] In general, compounds of formula (I) or salts and / or solvates thereof can be prepared according to organic synthesis techniques known to those skilled in the art, as well as by the representative methods set out below, the methods in the Examples, and modifications thereof.

[0064] Patent applications WO2017 / 001812, WO2020 / 128473, and WO2020 / 128475, each of which is incorporated herein by reference in its entirety, provide methods for the synthesis of intermediates that may be useful in making the compounds of the present invention.

[0065] (General synthesis scheme) (Synthesis of the Compounds of the Present Invention) Many synthetic routes for the compounds of the present invention can be devised by those skilled in the art, and the synthetic routes exemplified below are not intended to limit the present invention. Many methods exist in the literature on the synthesis of heterocycles, for example, Joule, JA; Mills, K.: "Heterocyclic Chemistry", 2010, 5th Edition, Pub. Wiley. Some possible synthetic routes are exemplified below. Where appropriate, any initially prepared compound according to the present invention can be converted into another compound according to the present invention by known methods. In the following description, the groups L, A, R 1 , R 2 , s, q, v, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 9c , R 9d , R 10 , R 11 , and R 12 is as defined above for compounds of formula (I) unless otherwise specified.

[0066] (Scheme 1) [ka] A compound of formula (I) 4 and R 5 and R are both methyl) can be obtained by reductive amination. In this reaction, another compound of formula (I) (where R 5 and R 6where one is methyl and the other is H) is reacted with formaldehyde in the presence of a metal hydride reducing agent such as NaBH3CN (sodium cyanoborohydride) in a suitable solvent such as methanol at 0°C.

[0067] (Scheme 2) [ka] A compound of formula (I) 5 and R 6 one of which is H and the other is methyl, or R 5 and R 6 and (wherein both are H) can be obtained by reacting a compound of formula (II) with an acid such as 2M HCl in diethyl ether (Et2O).

[0068] (Scheme 3) [ka] A compound of formula (II) 9d is H) can be prepared by reacting a compound of formula (III) with a reducing agent such as NaBH4 in a solvent such as methanol.

[0069] (Scheme 4) [ka] A compound of formula (II) 9d is C 1-4 Alkyl or C 1-4 haloalkyl) can be prepared by reacting a compound of formula (IV) (wherein M is a metal ion, for example Mg or Li) with a compound of formula (III) (wherein P is C 1-4 Alkyl or C 1-4 It can be prepared by reacting with an alkyl group (an alkoxy group).

[0070] (Scheme 5a) [ka] A compound of formula (III) 1-4 The compounds of formula (V) (wherein the aryl group is alkyl) can be obtained by reacting a compound of formula (V) with an organometallic reagent such as an organomagnesium or organolithium compound, for example, methylmagnesium bromide, iso-propylmagnesium bromide, or tert-butyllithium, in a suitable solvent such as diethyl ether (EtO) or tetrahydrofuran (THF).

[0071] (Scheme 5b) [ka] Compounds of formula (III) 1-4 alkoxy) by reacting a compound of formula (VIII) with a compound of formula (IX) 1-4 The compound can be obtained by reacting the compound (which is an alkoxy group) with a phosphine reagent such as (tributylphosphoranylidene)acetonitrile in a suitable solvent such as toluene.

[0072] (Scheme 6) [ka] Compounds of formula (V) can be prepared by reacting compounds of formula (VI) with an amine such as N,O-dimethylhydroxylamine hydrochloride, a base such as triethylamine (EtN), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC . HCl) and hydroxybenzotriazole (HOBt) in a suitable solvent such as tetrahydrofuran (THF).

[0073] (Scheme 7) [ka] The compound of formula (VI) can be prepared by reacting a compound of formula (VII) 1-4alkoxy) with lithium hydroxide monohydrate (LiOH . It can be obtained by reacting it with a metal hydroxide such as HCl (H2O) in a suitable solvent such as methanol.

[0074] (Scheme 8) [ka] Compounds of formula (VII) 1-4 alkoxy) by reacting a compound of formula (VIII) with a compound of formula (IX) 1-4 The compound can be obtained by reacting the compound (which is an alkoxy group) with a phosphine reagent such as (tributylphosphoranylidene)acetonitrile in a suitable solvent such as toluene.

[0075] The compound of formula (IX) can be prepared by reacting a compound of formula (IXA): [ka] (Wherein, P is C 1-4 alkoxy) may be.

[0076] Compounds of formula (IXA) can be prepared by the methods described in WO2017 / 001812.

[0077] (Intermediate of the present invention) The present invention also relates to novel intermediates in the synthesis of compounds of formula (I), for example, compounds of formulae (II) to (VII). Particular intermediates of interest are of the following general formula, where the variables and associated preferences are as defined above for compounds of formula (I): a compound of formula (II): [ka] ; a compound of formula (III): [ka] (Wherein, P is C 1-4 Alkyl or C 1-4 alkoxy); a compound of formula (V): [ka] ; a compound of formula (VI) [ka] ; a compound of formula (VII) [ka] (Wherein, P is C 1-4 alkoxy) is.

[0078] Included as an embodiment of the present invention is a salt, e.g., a pharmaceutically acceptable salt, of any one of the intermediates disclosed herein, e.g., any one of the compounds of formulas (II)-(VII).

[0079] Uses of the Compounds and ADCs of the Invention In any one of the following medical use embodiments, the ADC of the invention comprises a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, and therefore the same uses can be applied to an ADC of the invention or a pharmaceutically acceptable salt thereof.

[0080] (hyperproliferative disorders) Since the compound of formula (I) has cytotoxic activity, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is believed to be useful in the treatment or prevention of hyperproliferative disorders. Therefore, in one embodiment of the present invention, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is for use in the treatment or prevention of hyperproliferative disorders. In one particularly preferred embodiment, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is for use in the treatment of hyperproliferative disorders.

[0081] Since the ADC of the present invention has cytotoxic activity, the ADC of the present invention or a pharmaceutically acceptable salt thereof is believed to be useful in the treatment or prevention of hyperproliferative disorders.

[0082] Thus, the present invention provides an ADC of the invention or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a hyperproliferative disorder. In one particularly preferred embodiment, the ADC of the invention or a pharmaceutically acceptable salt thereof is for use in the treatment of a hyperproliferative disorder.

[0083] In one embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the treatment or prevention of a hyperproliferative disorder. In one particularly preferred embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the treatment of a hyperproliferative disorder.

[0084] In one embodiment, the present invention provides a method of treating or preventing a hyperproliferative disorder in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof. In one particularly preferred embodiment, the present invention provides a method of treating a hyperproliferative disorder in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0085] In one embodiment, the hyperproliferative disorder is cancer.

[0086] In one embodiment, the cancer is a hematological malignancy selected from the group consisting of lymphoma (e.g., B-cell lymphoma, particularly a lymphoma selected from the group consisting of high-grade mantle zone lymphoma, follicular lymphoma, plasmablastic lymphoma, diffuse large B-cell lymphoma, and Burkitt's lymphoma), myeloma (e.g., multiple myeloma), leukemia (e.g., a leukemia selected from the group consisting of chronic lymphocytic leukemia, AML, and B-acute lymphocytic leukemia), and melanoma (e.g., a melanoma selected from the group consisting of superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, amelanotic melanoma, and acral lentigo melanoma).

[0087] The cancer may also or alternatively be a solid tumor selected from the group consisting of brain cancer, lung cancer, breast cancer (e.g., triple-negative breast cancer or invasive breast cancer), prostate cancer, ovarian cancer, colorectal (e.g., colon) cancer, gallbladder cancer, kidney cancer, and liver cancer. For example, the cancer may be ovarian serous cystadenocarcinoma, esophageal cancer, lung squamous cell carcinoma, lung adenocarcinoma, bladder urothelial carcinoma, uterine carcinosarcoma, stomach cancer (herein referred to as "gastric cancer"), e.g., gastric adenocarcinoma, invasive breast cancer, or hepatocellular carcinoma of the liver. In a preferred embodiment, the cancer is breast cancer, e.g., triple-negative breast cancer or invasive breast cancer. In a preferred embodiment, the cancer is brain cancer, breast cancer, prostate cancer, colon cancer, gallbladder cancer, or kidney cancer. In some embodiments, the cancer is breast cancer, colon cancer, or gallbladder cancer. In another embodiment, the cancer is gastric cancer.

[0088] The cancer may also or alternatively be a blastoma, particularly a neuroblastoma, such as a retinoblastoma, a glioblastoma, a small cell lung cancer, or an astrocytoma.

[0089] In particularly preferred embodiments, the cancer is a hematological malignancy (e.g., lymphoma, particularly B-cell lymphoma (e.g., high-grade mantle zone lymphoma, follicular lymphoma, plasmablastic lymphoma, diffuse large B-cell lymphoma, and Burkitt's lymphoma), myeloma (e.g., multiple myeloma), or leukemia (e.g., chronic lymphocytic leukemia, AML, and B-acute lymphocytic leukemia)), solid tumor (e.g., brain cancer, The cancer may be selected from the group consisting of lung cancer, breast cancer (e.g., triple-negative breast cancer or invasive breast cancer), prostate cancer, ovarian cancer, colorectal (e.g., colon) cancer, gallbladder cancer, kidney cancer, or liver cancer, or neuroblastoma (e.g., retinoblastoma, glioblastoma, small cell lung carcinoma, or astrocytoma)), and melanoma (e.g., superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, amelanotic melanoma, or acral lentigo melanoma).

[0090] In a preferred embodiment, the cancer can be selected from the group consisting of diffuse large B-cell lymphoma, Burkitt's lymphoma, multiple myeloma, neuroblastoma, AML, and B-acute lymphocytic leukemia. In a preferred embodiment, the cancer can be selected from the group consisting of diffuse large B-cell lymphoma, Burkitt's lymphoma, neuroblastoma, AML, B-acute lymphocytic leukemia, and breast cancer. In a preferred embodiment, the cancer can be selected from the group consisting of diffuse large B-cell lymphoma, neuroblastoma, B-acute lymphocytic leukemia, and triple-negative breast cancer. In a preferred embodiment, the cancer can be selected from the group consisting of diffuse large B-cell lymphoma, Burkitt's lymphoma, multiple myeloma, neuroblastoma, AML, B-acute lymphocytic leukemia, and triple-negative breast cancer. In a preferred embodiment, the cancer can be selected from the group consisting of multiple myeloma, neuroblastoma, AML, B-acute lymphocytic leukemia, and triple-negative breast cancer. In a preferred embodiment, the cancer can be selected from the group consisting of multiple myeloma, neuroblastoma, and triple-negative breast cancer.

[0091] In one embodiment, the cancer is a MYC-dependent cancer described in WO2020 / 128475, the entire contents of which are incorporated by reference for purposes of defining MYC-dependent cancer.

[0092] (Inhibition of human NMT) Inhibition of human NMT has been proposed as a target for treating or preventing various diseases or disorders such as those described above. The present invention provides compounds that are or are believed to be human NMT inhibitors. The present invention also proposes ADCs comprising human NMT inhibitors. As used herein, the term "human NMT inhibitor" is intended to cover any moiety that binds to human NMT. ​​The human NMT is preferably HsNMT1. The inhibitor can act as a competitive inhibitor or a partially competitive inhibitor. The inhibitor can bind to human NMT at the myr-CoA binding pocket or the peptide-binding pocket (or inhibit human NMT via another mechanism). Because the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is or is believed to be a human NMT inhibitor, the compounds of the present invention are believed to bind to and inhibit human NMT preferably via the peptide-binding pocket. Furthermore, since the ADC of the present invention or a pharmaceutically acceptable salt thereof contains an NMT inhibitor that is a human NMT inhibitor, it is believed that after the NMT inhibitor is released intracellularly from the ADC of the present invention, the NMT inhibitor preferably binds to and inhibits human NMT via the peptide-binding pocket.

[0093] Because the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is or is believed to be a human NMT inhibitor, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is believed to be useful in the treatment or prevention of diseases or disorders associated with human NMT activity, or in the treatment or prevention of diseases or disorders by targeting human NMT activity, in addition to, for example, hyperproliferative diseases such as cancer, viral infections (e.g., picornavirus infections). Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use as a pharmaceutical. The present invention also provides an ADC of the present invention or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0094] Also provided are compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the treatment or prevention of diseases or disorders in which inhibition of human NMT provides a therapeutic or preventive effect. In one embodiment, provided are compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the treatment of diseases or disorders in which inhibition of human NMT provides a therapeutic effect. In one embodiment, provided are compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the prevention of diseases or disorders in which inhibition of human NMT provides a preventive effect.

[0095] The present invention also provides methods for the treatment or prevention of a disease or disorder in a subject (e.g., a mammal, e.g., a human) for which inhibition of human NMT results in a therapeutic or prophylactic effect in the subject, comprising administering to the subject a therapeutically effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier. The present invention also provides methods for the treatment of a disease or disorder in a subject (e.g., a mammal, e.g., a human) for which inhibition of human NMT results in a therapeutic effect in the subject, comprising administering to the subject a therapeutically effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier. The present invention also provides methods for the prevention of a disease or disorder in a subject (e.g., a mammal, e.g., a human) for which inhibition of human NMT results in a prophylactic effect in the subject, comprising administering to the subject a therapeutically effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier.

[0096] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of human NMT provides a therapeutic or preventive effect. The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the treatment of a disease or disorder in which inhibition of human NMT provides a therapeutic effect. The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the prevention of a disease or disorder in which inhibition of human NMT provides a preventive effect.

[0097] Diseases or disorders for which inhibition of human NMT provides therapeutic or prophylactic benefit include hyperproliferative disorders such as cancer, viral infections (e.g., human immunodeficiency virus (HIV) or human rhinovirus (HRV)), neurological diseases, ischemia, osteoporosis, diabetes, autoimmune diseases, and inflammatory diseases. Thus, in preferred embodiments, compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof find use in the treatment or prevention of these disorders / diseases.

[0098] In another particularly preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is for use in the treatment or prevention of viral infections, and in particular enterovirus infections, retrovirus infections, poxvirus infections, arenavirus infections, flavivirus infections, alphaherpesvirus infections, chickenpox infections, or betaherpesvirus infections. In another particularly preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is for use in the treatment or prevention of viral infections, and in particular enterovirus infections, retrovirus infections, poxvirus infections, arenavirus infections, flavivirus infections, alphaherpesvirus infections, chickenpox infections, or betaherpesvirus infections. In another particularly preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is for use in the prevention of viral infections, and in particular enterovirus infections, retrovirus infections, poxvirus infections, arenavirus infections, flavivirus infections, alphaherpesvirus infections, chickenpox infections, or betaherpesvirus infections. In an even more preferred embodiment, the enterovirus infection may be a picornavirus infection (e.g., a rhinovirus, poliovirus, foot and mouth disease virus, coxsackievirus, hepatitis A virus, or enterovirus 71 infection); and the retroviral infection may be a lentivirus infection (e.g., an HIV infection). In an even more preferred embodiment, the viral infection may be selected from the group consisting of a rhinovirus infection (HRV, also known as the common cold), a lentivirus infection (e.g., an HIV infection), a poliovirus infection, a foot and mouth disease virus infection, a coxsackievirus infection, a hepatitis A virus infection, and an enterovirus 71 infection. In one particularly preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is for use in the treatment or prophylaxis of a viral infection, wherein the viral infection is a picornavirus infection, and even more particularly, it is a rhinovirus infection (HRV, also known as the common cold).

[0099] The viral infections mentioned above cause many types of disease. For example: rhinovirus infections cause the common cold; various picornavirus infections, particularly coxsackieviruses and enterovirus 71, cause hand, foot, and mouth disease and polio-like syndromes; coxsackieviruses can also cause flaccid paralysis, herpangina, acute hemorrhagic conjunctivitis, nonspecific febrile illness, rash, and upper respiratory tract illness, and enterovirus 71 can also cause severe neurological illness in children; foot and mouth disease virus causes foot and mouth disease; hepatitis A virus causes hepatitis A; HIV infection can cause acquired immunodeficiency syndrome (AIDS); poxviruses can cause smallpox; arenaviruses can cause Lassa fever; flaviviruses can cause dengue fever; alphaherpesviruses can cause uncomplicated infection, chickenpox infection, Marek's disease, or laryngotracheitis; and betaherpesviruses can cause congenital CMV infection, HHV-6, and HHV-7.

[0100] Therefore, in a particularly preferred embodiment, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is for use in the treatment or prevention of the above-mentioned diseases caused by the above-mentioned viral infections. In a particularly preferred embodiment, the compound of formula (I) is for use in the treatment of the above-mentioned diseases caused by the above-mentioned viral infections. In a particularly preferred embodiment, the compound of formula (I) is for use in the prevention of the above-mentioned diseases caused by the above-mentioned viral infections. Suitably, the compound of formula (I) can be used in the treatment or prevention (e.g., treatment) of other diseases and illnesses caused by enterovirus infection, retrovirus infection, poxvirus infection, arenavirus infection, flavivirus infection, alphaherpesvirus infection, chickenpox infection, or betaherpesvirus infection.

[0101] (Combination Therapy) While a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof can be used as the sole active ingredient in a medicament, a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof can also be used in combination with one or more additional therapeutic agents. Accordingly, the present invention also provides a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof along with an additional therapeutic agent. The additional therapeutic components may be for simultaneous, sequential, or separate administration. The present invention also provides a kit of parts comprising: (a) a first pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier; and (b) a second pharmaceutical composition comprising an additional therapeutic agent and a pharmaceutically acceptable carrier. Such additional therapeutic agent may be an additional compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0102] The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates may be used in combination with one or more additional therapeutic agents useful for the treatment or prevention of hyperproliferative disorders, such as cancer, or another disease or disorder for which inhibition of human NMT provides a therapeutic or prophylactic benefit (e.g., agents useful for the treatment or prevention of hyperproliferative disorders, viral infections, neurological disorders, ischemia, osteoporosis, diabetes, autoimmune diseases, and inflammatory diseases, particularly hyperproliferative disorders (e.g., cancer) and viral infections (e.g., HRV or HIV infections)). The individual components of such combinations may be administered separately at different times during the course of treatment or simultaneously in divided or single combination forms. The present invention, therefore, should be understood as embracing all such regimens of simultaneous or alternating treatment, and the term "administering" should be interpreted accordingly. It will be understood that the scope of combinations of the compounds of the present invention with other therapeutic agents useful for the treatment or prevention of diseases or disorders for which inhibition of human NMT provides a therapeutic or prophylactic benefit includes, in principle, any combination with any pharmaceutical composition useful for the treatment or prevention of diseases or disorders for which inhibition of human NMT provides a therapeutic or prophylactic benefit.

[0103] When utilized in combination with a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, the additional therapeutic agent can be used, for example, in the amount set forth in the Physicians' Desk Reference (PDR) for that agent or as otherwise determined by one of skill in the art. When a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is utilized in combination with one or more additional therapeutic agents, either simultaneously or sequentially, the following combination ratios and dosage ranges are suitable: When combined with an additional therapeutic agent, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof can be utilized, for example, in a weight ratio within the range of about 10:1 to about 1:10 relative to the additional therapeutic agent.

[0104] In one embodiment, when the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is for the treatment or prevention of cancer, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate can be utilized in combination with one or more additional therapeutic agents, either simultaneously or sequentially, for the treatment or prevention of cancer. More preferably, when the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is for the treatment of cancer, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate can be utilized in combination with one or more additional therapeutic agents, either simultaneously or sequentially, for the treatment of cancer.

[0105] Such conjoint treatment may be achieved by simultaneous, sequential, or separate administration of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and one or more other therapeutic agents of treatment. Such combination products may utilize the NMT inhibitors of the present invention within any suitable dosage range, e.g., the dosage ranges described herein, and the other pharmaceutically active agent(s) may be within their approved dosage ranges.

[0106] Suitable, but non-limiting, examples of other therapeutic agents that may be administered in combination with an NMT inhibitor include one or more other chemotherapeutic agents.

[0107] In one embodiment, when the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is for the treatment or prevention of rhinovirus (HRV, also known as the common cold), the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof may be utilized in combination with one or more further therapeutic agents, either simultaneously or sequentially, for the treatment or prevention of HRV and / or for the treatment or prevention of asthma and / or for the treatment or prevention of chronic obstructive pulmonary disease (COPD). For example, the additional therapeutic agent(s) may be pleconaril, pirodavir, vapentavir BTA-798, V-073, rupintrivir, enviroxime, IFN-β (SNG001); corticosteroids (inhaled and oral, e.g., beclomethasone, fluticasone, budesonide, ciclesonide), beta agonists (e.g., salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, isoprenaline, salmeterol, formoterol, bambuterol, The therapeutic agent may be selected from the group consisting of anti-inflammatory drugs (e.g., benzodiazepine, benzocaine, benzodiazepine, benzocaine, benzodiazepine, benzocaine, benzodiazepine, benzocaine, benzocaine), benzocaine, ...

[0108] (ADC of the present invention) (payload) The compounds of formula (I) are believed to be useful as payloads for antibody-drug conjugates (ADCs). The payload is a drug that is linked to an antibody in the ADC and released at the site of action (the target of the antibody, usually a cancerous cell, e.g., a tumor cell that expresses an antigen to which the antibody can bind) after administration, as described, for example, in Coats et al., Clin Cancer Res 2019;25:5441-8. For example, the cancerous cells may express HER2 and the antibody may be trastuzumab, or the cancerous cells may express CD20 and the antibody may be rituximab. Alternatively, the cancerous cells may express CD276 / B7-H3 and the antibody may be ifinatamab. Alternatively, the cancerous cells may express Trop-2 and the antibody may be sacituzumab.

[0109] In one embodiment, the antibody binds to HER2. In one embodiment, the antibody is trastuzumab, pertuzumab, margetuximab, ertumaxomab, MM-111, HER2Bi-aATC, MCLA-128, ZW25, MDX-210, ado-trastuzumab, and fam-trastuzumab. Preferably, the antibody is trastuzumab. In one embodiment, the antibody has six CDRs of trastuzumab. Trastuzumab comprises a heavy chain of SEQ ID NO: 2 and a light chain of SEQ ID NO: 1.

[0110] In one embodiment, the antibody binds to CD20. Preferably, the antibody is rituximab. In one embodiment, the antibody has six CDRs of rituximab. Rituximab comprises a heavy chain of SEQ ID NO: 4 and a light chain of SEQ ID NO: 3.

[0111] In one embodiment, the antibody binds to Trop-2. ADCs comprising the antibody may be used in the treatment of metastatic triple-negative breast cancer and metastatic urothelial carcinoma. In this embodiment, the antibody is preferably sacituzumab. In one embodiment, the cancer expresses Trop-2. Sacituzumab comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 7.

[0112] In one embodiment, the antibody binds to CD276 (B7-H3). An ADC comprising the antibody may be used in the treatment of prostate cancer. In this embodiment, the antibody is preferably ifinatamab. In one embodiment, the cancer expresses CD276 (B7-H3). Ifinatamab comprises a heavy chain of SEQ ID NO: 6 and a light chain of SEQ ID NO: 5.

[0113] Means of linking drugs to antibodies in ADCs are described, for example, in WO2007 / 011968, WO2015 / 057699, WO2015 / 095755, WO20108 / 031690, WO2018 / 075600, WO2018 / 160683, WO2018 / 175994, WO2018 / 201087, and WO2019 / 923654, each of which is incorporated herein by reference.

[0114] The antibody can be linked to a payload such as a compound of formula (I), for example, via a linker (a bifunctional group capable of forming a covalent bond with the antibody and the compound of formula (I), for example, a glucuronide linker as described in WO 2007 / 011968.

[0115] For an antibody to be linked to a compound of Formula (I) via a linker, the antibody must have a functional group capable of forming a bond with a functional group on the linker, such as a functional group on the amino side chain of the antibody. Useful functional groups that may exist on an antibody naturally or through chemical manipulation include, but are not limited to, sulfhydryl (-SH), amino, hydroxyl, carboxy, anomeric hydroxyl groups of carbohydrates, and carboxyl. In some embodiments, the antibody functional group is sulfhydryl and / or amino, particularly sulfhydryl. Sulfhydryl groups can be generated by reduction of intramolecular disulfide bonds in an antibody. Sulfhydryl groups can also be generated by reaction of amino groups on lysine moieties of an antibody with 2-iminothiolane (Traut's reagent) or another sulfhydryl-generating reagent.

[0116] In one embodiment, the linker forms a bond with a sulfur atom of the antibody, which can be derived from a sulfhydryl group of the antibody.

[0117] The linker can be linked to the compound of formula (I) by forming a covalent bond with a functional group of the compound of formula (I). For example, the linker can be linked to an amino functional group of the compound of formula (I), such as the group NR 5 R 6 When the linker forms a covalent bond with a compound of formula (I), for example, between a carbonyl group in the linker and an amino functional group in the compound of formula (I), the compound of formula (I) must have a suitable functional group for reaction with a suitable functional group on the linker to form the covalent bond. For example, the amino group in the compound of formula (I) must have an available hydrogen atom (e.g., R 5 or R 6 is H), i.e., the amino group in the compound of formula (I) cannot be tertiary.

[0118] The linker, when cleaved, forms R 5 is H. 5 and R 6 The linker may be attached to the compound of formula (I) via a carbamate (derived from the nitrogen atom bearing the group and a carboxylic acid group on the linker).

[0119] Drug loading (referred to as the variable "p") is the average number of NMT inhibitors per antibody. When the compounds of the present invention are conjugated to cysteine ​​residues, drug loading can range from 1 to 10 NMT inhibitors per antibody, i.e., in this case, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 NMT inhibitors are covalently attached to the antibody. Conjugate compositions include collections of antibodies conjugated with 1 to 10 different NMT inhibitors. Preferably, p is 1 to 10, e.g., p is 2 to 6, 4 to 6, 8 to 10, or 6 to 8. Most preferably, p is about 5, e.g., 5.

[0120] Therefore, in one embodiment, the present invention provides the use of a compound of formula (I) or a salt and / or solvate thereof as a payload of an antibody-drug conjugate. In one embodiment, the present invention provides an antibody-drug conjugate comprising a compound of formula (I) or a salt and / or solvate thereof as a payload. In one embodiment, the antibody-drug conjugate or salt thereof further comprises a linker.

[0121] In one embodiment, the linker has the formula (LI): [ka] (In the formula, [ka] represents the point of attachment to the chain terminus (e.g., N-terminus) or functional group on an amino acid side chain of the antibody; and [ka] represents the point of attachment to the functional group of the compound of formula (I) It has.

[0122] In one embodiment, the linker has formula (LII): [ka] (In the formula, [ka] represents the point of attachment to the chain terminus (e.g., N-terminus) or functional group on an amino acid side chain of the antibody; and [ka] represents the point of attachment to the functional group of the compound of formula (I) It has.

[0123] In one embodiment, the linker has formula (LIII): [ka] (In the formula, [ka] represents the point of attachment to the chain terminus (e.g., N-terminus) or functional group on an amino acid side chain of the antibody; and [ka] represents the point of attachment to the functional group of the NMT inhibitor) It has.

[0124] In one embodiment, the linker has the formula (LIV): [ka] (In the formula, [ka] represents the point of attachment to the chain terminus (e.g., N-terminus) or functional group on an amino acid side chain of the antibody; and [ka] represents the point of attachment to the functional group of the NMT inhibitor) It has.

[0125] The ADCs of the invention can be prepared using a drug conjugate, or a salt and / or solvate thereof, which is then covalently bound to an antibody. Thus, in one embodiment, a drug conjugate, or a salt and / or solvate thereof, is provided that includes a group capable of forming a covalent bond with a chain terminus (e.g., N-terminus) or a functional group, e.g., a sulfhydryl group, on an amino acid side chain of an antibody.

[0126] In one embodiment, the drug conjugate has the formula (DC-1): [ka] or a salt and / or solvate thereof, wherein: [ka] is a compound of formula (I) or a salt and / or solvate thereof.

[0127] In one embodiment, the drug conjugate is a compound of formula (DC-2): [ka] or a salt and / or solvate thereof, wherein: [ka] is a compound of formula (I) or a salt and / or solvate thereof.

[0128] In one embodiment, the drug conjugate is a compound of formula (DC-3): [ka] or a salt and / or solvate thereof, wherein: [ka] is a compound of formula (I) or a salt and / or solvate thereof.

[0129] In one embodiment, the drug conjugate is a compound of formula (DC-4): [ka] or a salt and / or solvate thereof, wherein: [ka] is a compound of formula (I) or a salt and / or solvate thereof.

[0130] As used herein, " [ka] It will be understood by one of skill in the art that the phrase "is a compound of Formula (I)" refers to the moiety that remains after an NMT inhibitor, e.g., an NMT inhibitor that includes a suitable functional group for attachment to a linker, such as an amino group (which includes a hydrogen atom) or an alcohol (-OH), reacts with a suitable functional group on the linker, e.g., a carbonyl group, thereby forming a linker-compound of Formula (I) covalent bond.

[0131] Suitably, the drug conjugate is (1S,2R,3S,4R,5R)-5-(4-{[({[6-(3,4-difluoro-2-{2-[3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3yl]methyl}(methyl)carbamoyl)oxy]methyl}-2-[3-(3-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}propanamido)propanamido]phenoxy)-3,4-dihydroxy-2-methylcyclohexane-1-carboxylic acid: [ka] or a salt and / or solvate thereof.

[0132] In one embodiment, the ADC of the invention has the following formula: [ka] where Ab is an antibody as defined herein, and [ka] represents an NMT inhibitor, for example, a compound of Formula (I) or a pharmaceutically acceptable salt thereof). Preferably, the ADC of the present invention or a salt thereof is conjugated to the antibody via a sulfhydryl group on the side chain of a cysteine ​​amino acid on the antibody. Preferably, the antibody is trastuzumab or rituximab, particularly trastuzumab. Alternatively, the antibody is sacituzumab. Alternatively, the antibody is ifinatamab. Preferably, p is 1 to 10, for example, p is 2 to 6, 4 to 6, 8 to 10, or 6 to 8. Most preferably, p is about 5, for example, 5.

[0133] In one embodiment, the ADC of the invention has the following formula: [ka] (wherein Ab is an antibody as defined herein). Preferably, the ADC of the invention or a salt thereof is linked to the antibody via a sulfhydryl group on the side chain of a cysteine ​​amino acid on the antibody. Preferably, the antibody is trastuzumab or rituximab, particularly trastuzumab. Alternatively, the antibody is sacituzumab. Alternatively, the antibody is ifinatamab. Preferably, p is 1 to 10, for example, p is 2 to 6, 4 to 6, 8 to 10, or 6 to 8. Most preferably, p is about 5, for example, 5.

[0134] (Dosage and Formulation) The amount of active ingredient required to achieve a therapeutic effect will, of course, vary depending on the particular compound, the route of administration, the subject being treated or prevented (including the type, species, age, weight, sex, and medical condition of the subject), and the subject's renal and hepatic function, as well as the particular disorder or disease being treated or prevented, and its severity. An ordinarily skilled physician, veterinarian, or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the disease.

[0135] Oral dosages of the present invention, when used for the indicated effects, range from about 0.01 mg / kg body weight / day (mg / kg / day) to about 100 mg / kg / day for adults, preferably 0.01 mg / kg body weight / day (mg / kg / day) to 10 mg / kg / day, and most preferably 0.1 to 5.0 mg / kg / day. For oral administration, the compositions are preferably provided in the form of tablets or other presentations provided as discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of active ingredient for symptomatic adjustment of dosage to the patient being treated. Medicaments typically contain from about 0.01 mg to about 500 mg of active ingredient, preferably from about 1 mg to about 100 mg. Intravenously, the most suitable dose ranges from about 0.1 to about 10 mg / kg / min during a constant rate infusion. Advantageously, the compound of formula (I) or its pharmaceutically acceptable salts and / or solvates can be administered in a single daily dose, or the total daily dosage can be administered in divided doses two, three, or four times daily. Furthermore, the compound of formula (I) or its pharmaceutically acceptable salts and / or solvates can be preferably administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes using transdermal skin patch formulations well known to those skilled in the art. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0136] The dose provided to a subject is typically a safe and effective dose, i.e., an amount that provides an acceptable balance between desired benefits and unwanted side effects. A "safe and effective amount" is intended to include an amount of a compound that is effective to achieve a desired effect in the treatment and / or prevention of a disease state. The desired effect is typically clinically meaningful and / or measurable, for example, in the context of (a) preventing a disease state from occurring in a mammal, particularly when such a mammal is susceptible to the disease state but has not yet been diagnosed as having it; (b) inhibiting the disease state, i.e., slowing or halting its development; and / or (c) alleviating the disease state, i.e., causing regression of the disease state or relief of associated symptoms. A safe and effective amount may be an amount that is sufficient to achieve a desired effect when the compound is administered alone, or alternatively, when it is administered in combination with one or more additional APIs, which are either additional compounds for use in the present invention or different from the compounds for use in the present invention.

[0137] For the avoidance of doubt, the "safe and effective amounts" recited herein can be achieved by any suitable dosing regimen, including, but not limited to, the exemplary dosing regimens set forth elsewhere herein. Thus, for example, references herein to administering a safe and effective amount of a compound by a particular route of administration include, for example, achieving a safe and effective amount by a single dose or by multiple doses administered by the specified route of administration. For example, orally administering a safe and effective amount includes both orally administering a single dose and orally administering any multiple doses, provided that a safe and effective amount is thereby achieved by oral administration.

[0138] While it is possible for the active ingredient to be administered alone, it is preferable for it to be present in a pharmaceutical formulation or composition. Accordingly, the present invention provides a pharmaceutical formulation or composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable diluent, excipient, or carrier (collectively referred to herein as "carrier" materials). The pharmaceutical compositions of the present invention can take the form of pharmaceutical formulations as described below.

[0139] Thus, in one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an ADC of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The uses of pharmaceutical compositions below apply equally to pharmaceutical compositions comprising an ADC of the invention or a pharmaceutically acceptable salt thereof.

[0140] In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g., a pharmaceutically acceptable salt) for use in the treatment or prevention of a disease or disorder described herein. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g., a pharmaceutically acceptable salt) for use in the treatment of a disease or disorder described herein. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g., a pharmaceutically acceptable salt) for use in the prevention of a disease or disorder described herein.

[0141] In a further embodiment, methods are provided for the treatment or prevention of a disease or disorder described herein, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g., a pharmaceutically acceptable salt). In a further embodiment, methods are provided for the treatment of a disease or disorder described herein, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g., a pharmaceutically acceptable salt). In a further embodiment, methods are provided for the prevention of a disease or disorder described herein, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g., a pharmaceutically acceptable salt). The pharmaceutical compositions of the present invention can take the form of pharmaceutical formulations as described below.

[0142] The present invention also provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g., a pharmaceutically acceptable salt) in the manufacture of a medicament for the treatment or prevention of a disease or disorder described herein.The present invention also provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g., a pharmaceutically acceptable salt) in the manufacture of a medicament for the treatment of a disease or disorder described herein.The present invention also provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g., a pharmaceutically acceptable salt) in the manufacture of a medicament for the prevention of a disease or disorder described herein.

[0143] Pharmaceutical formulations according to the present invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion), and intraarticular), intranasal (also known as intranasal administration), inhalation (including fine particle dusts or mists which may be generated by various types of pressurized metered dose aerosols, nebulizers, or inhalers), insufflation, rectal, intraperitoneal, and topical (including cutaneous, buccal, sublingual, and intraocular) administration, although the most suitable route may depend, for example, on the disease and disorder of the recipient.

[0144] Preferred pharmaceutical formulations according to the present invention are those suitable for oral and parenteral administration; and more preferably those suitable for oral administration. Such embodiments are particularly suitable, for example, for the treatment or prevention of hyperproliferative disorders, and in particular, cancer.

[0145] In another preferred embodiment, the compound according to Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is administered intranasally, by inhalation (including fine particle dusts or mists that can be generated by various types of pressurized metered-dose aerosols, nebulizers, or inhalers), or by insufflation. Such embodiments are particularly suitable for the treatment or prevention of picornavirus infections, such as human rhinovirus infections. Such administration methods allow for lower doses of the compounds of the invention to be administered, which may lead to fewer side effects. For example, daily doses of 10 to 0.01 μg, preferably 1 to 0.01 μg, and more preferably as low as approximately 0.1 μg (100 ng) of the compounds of the invention can be used.

[0146] The formulations can be conveniently provided in unit dosage form and can be prepared by any method known in the art of pharmacy.All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients.In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.

[0147] Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets, pills, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid, for example, an elixir, tincture, suspension, or syrup; or as an oil-in-water or water-in-oil emulsion. The active ingredient can also be presented as a bolus, electuary, or paste.

[0148] Tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof can be administered, for example, in a form suitable for immediate release or sustained release. Immediate release or sustained release can be achieved by the use of a suitable pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, or, particularly in the case of sustained release, by the use of a device such as a subcutaneous implant or an osmotic pump. The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates may also be administered via liposomes.

[0149] Exemplary compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose to impart bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate-release tablets, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose, and / or lactose, and / or other excipients, binders, fillers, disintegrants, diluents, and lubricants such as those known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn syrup, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. The compound of formula (I) or its pharmaceutically acceptable salts and / or solvates can also be delivered through the oral cavity by sublingual and / or buccal administration. Molded tablets, compressed tablets, or freeze-dried tablets are exemplary forms that can be used. Exemplary compositions include those in which the compound of the present invention is formulated with a fast-dissolving diluent such as mannitol, lactose, sucrose, and / or cyclodextrin. Such formulations may also contain high molecular weight excipients such as cellulose (avicel) or polyethylene glycol (PEG). Such formulations may also contain excipients that aid adhesion to the mucosa, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez), and release-controlling agents such as polyacrylic acid copolymers (e.g., Carbopol 934). Lubricants, glidants, flavors, colors, and stabilizers can also be added for ease of manufacture and use.Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc.

[0150] The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (cephalin), or phosphatidylcholine (lecithin).

[0151] Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above. Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, suitable non-toxic parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

[0152] Exemplary compositions for intranasal, aerosol, or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0153] Formulations for rectal administration can be presented as suppositories using conventional carriers such as cocoa butter, synthetic glyceride esters, or polyethylene glycols. Such carriers are usually solid at room temperature but liquefy and / or melt in the rectal cavity to release the drug.

[0154] Formulations for topical administration in the mouth, e.g., buccal or sublingual, include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0155] Suitable unit dosage formulations are those containing an effective dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0156] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question, e.g., those suitable for oral administration may include flavoring agents.

[0157] The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates are believed to exhibit one or more of the following advantageous properties: - inhibition of human NMT, for example as shown in the HsNMT1-sensitive fluorescence-based assay of Biological Example 1; - cytotoxic activity, e.g., as shown in the cell line assays of Biological Examples 2 and 3; - In vivo cytotoxic activity, as shown, for example, in the mouse xenograft model of Biological Example 4.

[0158] The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates may also exhibit one or more of the following advantageous properties: - cell permeability, as shown, for example, in the Caco-2 cell permeability assay of Biological Example 5; - Relatively low metabolic stability, which is desirable for certain therapeutic applications (e.g., as a payload for antibody drug conjugates), as demonstrated in the mouse and rat hepatocyte assays of Biological Example 6 and the in vivo mouse xenograft study of Biological Example 7.

[0159] The ADC or its pharmaceutically acceptable salt and / or solvate may also exhibit one or more of the following advantageous properties: - in vivo cytotoxic activity, as demonstrated, for example, in the mouse xenograft models of Biological Examples 7, 8, 9, 10, and 11; and - in vivo tolerability, as shown, for example, in the mouse xenograft models of Biological Examples 7, 8, 9, 10, and 11;

[0160] Such properties are believed to make the compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof, or the ADCs of the invention or pharmaceutically acceptable salts thereof, suitable for use in the treatment or prevention (e.g., treatment) of hyperproliferative disorders such as cancer or other diseases or disorders in which inhibition of human NMT provides a therapeutic or prophylactic effect.

[0161] (abbreviation) [Table 1] TIFF2025531807000048.tif201170 [Example]

[0162] (Example) (Synthesis of Example Compounds) (General experimental details) (LCMS method, formic acid buffer, 3-minute run) Column: YMC Triart C18 (33 x 2.1 mm, 3 μm), (Mobile phase: 98% [0.05% HCOOH in water] and 2% [0.05% HCOOH in can:water (90:10)] held for 0.75 min, then 90% [0.05% HCOOH in water] and 10% [0.05% HCOOH in can:ACN:water (90:10)] at 1.0 min, then 2% [0.05% HCOOH in water] and 98% [0.05% HCOOH in can:ACN:water (90:10)] at 2.0 min, held at this mobile phase composition until 2.25 min, and finally returned to initial at 3.0 min). Flow rate = 1.0 ml / min.

[0163] (LCMS method, ammonium acetate buffer, 3-minute run) Column - Xbridge C18 (50 x 3.0 mm, 3.5 u), (Mobile phase: 95% [5 mM NHOac in water] and 5% [90:10 ACN:5 mM NcanAc in water] hold for 0.75 min, then 70% [5 mM NHOac in water] and 30% [90:10 ACN:5 mM NcanAc in water] at 1.00 min, then 2% [5 mM NHOac in water] and 90:10 ACN:98% NHOac in water] at 2.0 min, hold this mobile phase until 2.25 min, return to starting condition at 2.75 min, hold this mobile phase until 3.0 min). Flow rate = 1.2 ml / min.

[0164] (LCMS method, ammonium acetate buffer, 5-minute run) Column - Xbridge C18 (50 x 3.0 mm, 3.5 u), (Mobile phase: 95% [5 mM NHOac in water] and 5% [90:10 ACN:5 mM NHOac in water] held for 0.75 min, then 85% [5 mM NHOac in water] and 15% [90:10 ACN:5 mM NHOac in water] at 1.25 min, further 30% [5 mM NHOac in water] and 70% [90:10 ACN:5 mM NHOac in water] at 2.5 min, again 2% [0.05% HCOOH in water] and 98% [90:10 ACN:5 mM NHOac in water] at 3.75 min. NHClOac] and hold this mobile phase composition until 4.25 min, finally return to the initial condition at 4.50 min and hold this initial condition until 5.10 min). Flow rate = 1.2 ml / min.

[0165] (HPLC) The purity of certain examples was determined on a TyeEclipse Extend or XDB 5 μm C18 (150 × 4.6 mm), Xbridge 5 μm C18 (100 × 4.6 mm), Zorbax Extend 5 μm C18 (150 × 4.6 mm), or Shimadzu L Column 2 ODS 5 μm C18 (150 × 4.6 mm) column using a gradient elution of acetonitrile in water containing 10 mM ammonium acetate over 15 minutes (HPLC B), 17 minutes (B1), and 18 minutes (B3).

[0166] The purity of certain examples was determined by analytical HPLC using a Poroshell 120 2.7 μm EC18 (100 × 4.6 mm), a Luna Omega Polar 3 μm C18 (100 × 4.6 mm), an Xbridge 5 μm C18 (150 × 4.6 mm), or a Sunfire 5 μm C18 (100 × 4.6 mm) column, using a gradient elution of acetonitrile in water containing 0.05% trifluoroacetic acid over 12 min (HPLC A), 14 min (A1), or 17 min (A2), and 16 min (A4).

[0167] The purity of certain examples was determined by analytical HPLC using a Gemini NX 3 μm C18 (100×4.6 mm) column with gradient elution of acetonitrile in water containing 0.05% formic acid over 16 min (A6).

[0168] (NMR) 1 H NMR and 13 C spectra were recorded at room temperature on 400 MHz and 101 MHz instruments, respectively, and referenced to the residual solvent signal unless otherwise specified. Data are presented as follows: chemical shift in ppm, integral, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet), and coupling constants (in Hz).

[0169] (ADC test method) (SEC-HPLC) Column: TOSOH TSKgel G3000SWXL 7.8 mm x 30 cm 5 μm particles (MERCK 808541) coupled to a security guard column (MERCK 822858) with a GFC3000 4 x 3 mm cartridge (Phenomenex); buffer: 0.2 M phosphate, 0.25 M KCl, 10% IPA; gradient: isocratic at 0.5 ml / min at 25°C. Sample load was approximately 10 μg, and monomer and concentration were determined from the 214 nm signal. Monomer was reported based on peak integration, and [ADC] mg / mL was based on the antibody calibration curve.

[0170] (RP-HPLC for residual NMT inhibitors) Column: Kinetex® 2.6 μm C8 100 Å, LC column 50×4.6 mm (Phenomex 00B-4497-E0); Mobile phase A 0.05% TFA in water; Mobile phase B 0.05% TFA in CAN; Gradient, 2 ml / min at 60° C.: [Table 2]

[0171] 50 μl sample (ADC or PBS / PS20 matrix) + 2 μl 5 M NaCl + 150 μl cold MeOH (from -20°C freezer). Incubated at -20°C for 30 minutes. Centrifuged at 21,000 g for 30 minutes at 4°C. 125 μl of supernatant was extracted and mixed with 125 μl of WFI. 100 μl of this was injected onto the Kinetex column. Data were analyzed at 214 nm, and residual NMT inhibitor in the sample was estimated from an external calibration curve of the relevant NMT inhibitor-linker. Results are expressed as a percentage of free versus bound, using the ADC concentration and calculated DAR to determine the amount of bound NMT inhibitor.

[0172] (HIC-HPLC for calculating the average DAR (drug-antibody ratio)) This method can be used as an alternative to the PLRP-HPLC method for determining the mean DAR.

[0173] Column: TOSOH Butyl-NPR 4.6 mm x 3.5 cm, 2.5 μm particle size (Merck 822855); Mobile phase A: 1.5 M (NH4)2SO4, 25 mM NaPi, pH 6.95 ± 0.05; Mobile phase B: 25 mM NaH2PO4 pH 6.95 ± 0.05 + 25% IPA; Gradient, 0.8 ml / min at 25 °C: [Table 3] Cartridge load: 10 μg and reported results analyzed at 214 nm.

[0174] (RP-HPLC for average DAR calculation) Column—PLRP-S 2.1 mm × 5 cm, 5 μm (Agilent PL1912-1502); Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient, 1 mL / min at 80 °C: [Table 4]

[0175] Approximately 10 μg of sample (ADC) + 5 μl of 0.1 M DTT was adjusted to 50 μL with 0.5 M Tris, pH 8.0, and incubated at 37°C for 15 minutes. The sample was then diluted 1:1 with 49% water, 49% acetonitrile, 2% formic acid (+ 50 μL). 20 μL of this solution was then injected onto the RP-HPLC column. Data was analyzed at 214 nm, and the average DAR was calculated.

[0176] (Endotoxin dynamic chromogenic assay) Endotoxin was determined by a kinetic chromogenic LAL assay using the Endosafe PTS endotoxin system. ADC was diluted 10-fold in LAL reagent water. All samples were analyzed on 0.01-1 EU / mL cartridges. EU / mL values ​​were converted to EU / mg by dividing by ADC[P]mg / mL.

[0177] (Preparation of Comparative Compound 1) Comparative compound 1 is the compound 4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-chlorophenoxy}ethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide: [ka] and was prepared according to the method described in WO2020 / 128473.

[0178] (Preparation of Example Compounds 1 to 25) [ka] (Step 1 - Intermediate (2): 1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester) Procedure: To a stirred solution of sodium hydride (60% in mineral oil, 31.17 g, 779.221 mmol) in THF (700 ml) at 0° C., a solution of 5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (100 g, 649.351 mmol) in THF (300 ml) was slowly added. The reaction mixture was stirred at 0° C. for 30 min. Then, methyl iodide (48.19 ml, 779.221 mmol) was added dropwise at 0° C., and the reaction mixture was stirred at RT for 2 h. TLC showed complete consumption of the starting material and the formation of the product. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give 1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester (2) (109 g, 99.8%) as a brown gum. LC-MS MH + 169, FA:ACN, R t =1.35 min, 3 min driving; [ka]

[0179] (Step 2 - Intermediate (3): 4-Bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester) Procedure: To a stirred solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester (intermediate (2)) (109 g, 648.81 mmol) in acetonitrile (990 ml) was added N-bromosuccinimide (120.58 g, 681.25 mmol) portionwise at 0° C. The resulting mixture was stirred at RT for 16 h. TLC showed complete consumption of the starting material and product formation. The solvent was evaporated, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) eluting with 20% ethyl acetate and hexane to give 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester (3) (140 g, 87.33%) as a brown solid. LC-MS MH +247 & 249, NH4Oac:ACN, R t =3.32 min, 6 min driving; [ka]

[0180] (Step 3 - Intermediate (4): 1,5-dimethyl-4-vinyl-1H-pyrazole-3-carboxylic acid ethyl ester) Procedure: To a solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester (intermediate (3)) (50 g, 202.429 mmol) in DMF (250 ml) was added tributylvinyltin (118.286 ml, 404.858 mmol). The solution was degassed with argon for 20 minutes, and Pd(PPh3)4 (11.69 g, 10.121 mmol) was added under argon. The reaction mixture was stirred at 110°C for 16 hours. TLC showed the formation of product with complete consumption of starting material. The reaction mixture was cooled to RT, quenched with water, and extracted with ethyl acetate. The organic layer was washed with saturated KF solution, the precipitate was filtered through a Celite pad, and the filtrate was washed with water and finally with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. The crude product was purified by column chromatography (silica gel, 100-200 mesh) eluting with 20%-30% ethyl acetate and hexane to give 1,5-dimethyl-4-vinyl-1H-pyrazole-3-carboxylic acid ethyl ester (4) (30 g, 76.3%) as a brown gum. LC-MS MH + 195, FA:ACN, R t =1.59 min, 3 min driving; [ka]

[0181] (Step 4 - Intermediate (5): 1,5-dimethyl-4-(2-oxo-ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester) Procedure: To a stirred solution of 1,5-dimethyl-4-vinyl-1H-pyrazole-3-carboxylic acid ethyl ester (intermediate (4)) (35 g, 180.412 mmol) in acetonitrile (700 ml) was added (diacetoxyiodo)benzene (61 g, 189.433 mmol) at −10° C. Then, 5% sulfuric acid (70 ml) was added dropwise and stirred at RT for 1 h. The solvent was evaporated under reduced pressure, diluted with water, extracted with ethyl acetate, and finally extracted with 20% MeOH-DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give 1,5-dimethyl-4-(2-oxo-ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (5) (32 g, 84.37%) as a brown gum. The crude product was carried on to the next step without purification. LC-MS MH + 211, FA:ACN, R t =1.32 min, 3 min driving; [ka]

[0182] (Step 5 - Intermediate (6): 4-(2-hydroxy-ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester) Procedure: To a stirred solution of 1,5-dimethyl-4-(2-oxo-ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (intermediate (5)) (25 g, 119.048 mmol) in ethanol (450 ml) at 0 °C, NaBH4 (9.7 g, 261.905 mmol) was added portionwise. The reaction mixture was stirred at RT for 1 h. The solvent was then evaporated under reduced pressure, diluted with saturated sodium bicarbonate solution, extracted with ethyl acetate, and finally extracted with 20% MeOH-DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) eluting with 80% ethyl acetate and hexane to give 4-(2-hydroxy-ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester (6) (13 g, 51.45%) as a light brown gum. LC-MS MH +213, FA:ACN, R t =1.27 mins, 3 mins drive. [ka]

[0183] [ka] (Step 1 - Intermediate (8): 6-Bromoimidazo[1,2-a]pyridine-3-carbaldehyde) Procedure: Phosphorus oxychloride (6.102 ml, 65.469 mmol) was added dropwise to anhydrous DMF (50 ml) at 0°C and stirred at that temperature for 1 h. A solution of 6-bromoimidazo[1,2-a]pyridine (5 g, 25.376 mmol) in DMF (10 ml) was added at 0°C. The reaction mixture was heated to 100°C for 5 h and stirred at RT for 16 h. The reaction mixture was quenched with cold saturated sodium bicarbonate solution, extracted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (8) (3.2 g, 56.04%) as a brown solid. [ka] (Step 2 - Intermediate (9): 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)-N-methylmethanamine) Procedure: To a stirred solution of 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (intermediate (8)) (4.5 g, 20.089 mmol) in methanol (10 ml) was added methylamine solution (6.15 ml, 60.267 mmol) and stirred at RT for 16 h. To the reaction mixture was added NaBH4 (1.56 g, 40.179 mmol) at 0° C. and stirred for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM, washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography to give 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)-N-methylmethanamine (9) (1.6 g, 33.17%). LC-MS MH + 240, NH4Oac:ACN, R t =1.46 min, 5 min driving; [ka]

[0184] (Step 3 - Intermediate (10): tert-butyl((6-bromoimidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: To a stirred solution of 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)-N-methylmethanamine (intermediate (9)) (4.9 g, 20.248 mmol) in DCM (50 ml) was added triethylamine (5.644 ml, 40.496 mmol) and BOC anhydride (5.576 ml, 24.298 mmol) at 0° C. and stirred at RT for 16 h. The reaction mixture was diluted with water, extracted with DCM, washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography to give tert-butyl ((6-bromoimidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (10) (5.6 g, 81.29%). LC-MS MH + 340, NH4Oac:ACN, R t =3.36 mins, 5 mins drive. [ka]

[0185] [ka] (Step 1 - Intermediate (12): 4-fluoro-2-hydroxyphenyl)boronic acid) Procedure: To a stirred solution of (4-fluoro-2-methoxyphenyl)boronic acid (11.0 g, 64.706 mmol) in dichloromethane (130.0 ml) was added BBr3 (1 M DCM) (129.0 ml, 129.41 mmol) at 0 °C. The reaction mixture was stirred at RT for 1 h. After complete consumption of the starting material, the reaction mixture was cooled to 0 °C and quenched with ice water. The resulting reaction mixture was diluted with dichloromethane, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (4-fluoro-2-hydroxyphenyl)boronic acid (12) (10 g, 99.12%). LC-MS MH-155, NHOac:ACN, Rt = 2.73 min, run for 5 min.

[0186] (Step 2 - Intermediate (13): tert-butyl((6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: To a stirred solution of (4-fluoro-2-hydroxyphenyl)boronic acid (Intermediate (12)) (6.8 g, 20.0 mmol) in 1,4-dioxane (75.0 ml) was added tert-butyl ((6-bromoimidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate (10)) (6.2 g, 40.0 mmol), followed by a solution of potassium phosphate (12.72 g, 60.0 mmol) in water (15.0 ml). The reaction mixture was degassed under an argon balloon for 30 minutes, after which tetrakis(triphenylphosphine)palladium(0) (2.31 g, 2.0 mmol) was added and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, concentrated under reduced pressure, and the crude product was purified by flash column chromatography eluting with 3% MeOH in DCM to give tert-butyl ((6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (13) (5.0 g, 67.31%). [ka] LC-MS MH+ 372, NHClOac:ACN, Rt=1.48 min, 5 min run.

[0187] (Step 3 - Intermediate (14): Ethyl 4-(2-(2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate) Procedure: To a stirred solution of tert-butyl ((6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate (13)) (1.5 g, 4.041 mmol) and ethyl 4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Intermediate (6)) (1.714 g, 8.081 mmol) in toluene (15.0 ml) was added cyanomethyltributylphosphorane (CMBP) (2.118 ml, 8.081 mmol) at room temperature, and the reaction mixture was stirred at 110° C. for 16 hours. TLC and LCMS showed the formation of the product. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 100-200 mesh) using 5% MeOH-DCM to afford ethyl 4-(2-(2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (14) (1.5 g, 65.63%) as a brown solid. [ka] LC-MS MH+ 566, NHClOac:ACN, Rt=3.41 min, 5 min run.

[0188] (Step 4 - Intermediate (15): 4-(2-(2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid) Procedure: To a stirred solution of ethyl 4-(2-(2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (intermediate (14)) (1.5 g, 2.655 mmol) in THF:water (4:1) (15.0 ml) was added ethanol (0.2 ml), LiOH.HO (0.223 g, 5.31 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. LCMS was checked, which indicated the formation of the product. The reaction mixture was cooled to 0° C., acidified with citric acid solution (pH ∼2) and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 4-(2-(2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (15) (1.3 g, 91.19%). [ka] LC-MS MH+ 538, FA:ACN, Rt=1.53 min, 3 min run.

[0189] (Step 5 - Intermediate (16): tert-butyl((6-(4-fluoro-2-(2-(3-(methoxy(methyl)carbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: To a stirred solution of 4-(2-(2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-5-methyl-1H-pyrazole-3-carboxylic acid (Intermediate (15)) (1.3 g, 2.421 mmol) in tetrahydrofuran (15.0 mL) was added N,O-dimethylhydroxylamine hydrochloride (0.354 g, 3.631 mmol). To the reaction mixture were added triethylamine (1.687 mL, 12.104 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.696 g, 3.631 mmol), and 1-hydroxybenzotriazole (0.491 g, 3.631 mmol), and the reaction mixture was stirred at room temperature for 16 hours. TLC confirmed the formation of the product. The reaction was washed with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude was purified by combiflash using 5% MeOH in DCM to give tert-butyl ((6-(4-fluoro-2-(2-(3-(methoxy(methyl)carbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (16) (1.2 g, 85.37%). [ka] LC-MS MH+ 581, NHClOac:ACN, Rt=3.33 min, 5 min run.

[0190] Example 8: 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol [ka] (Step 1 - Intermediate (17): tert-butyl((6-(2-(2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)ethoxy)-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: A stirred solution of tert-butyl ((6-(4-fluoro-2-(2-(3-(methoxy(methyl)carbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate (16)) (500 mg, 0.862 mmol) in THF was cooled to −50° C., and t-butyllithium (1.26 ml, 2.155 mmol) was added at −50° C. The reaction mixture was then stirred at −50° C. for 2 hours. TLC showed the formation of the product, and the reaction mixture was quenched with saturated NH4Cl solution. The reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, and concentrated. The crude product was purified by combiflash column chromatography using MeOH in DCM to give tert-butyl ((6-(2-(2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)ethoxy)-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate intermediate (17) (200 mg, 40.18%). LC-MS MH + 578, NH4Oac:ACN, R t =4.14 min, 5 min driving; [ka]

[0191] (Step 2 - Intermediate (18): tert-butyl((6-(4-fluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: To a stirred solution of tert-butyl ((6-(2-(2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)ethoxy)-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (intermediate (17)) (250 mg, 0.433 mmol) in methanol (2 ml) was added sodium borohydride (50.602 mg, 1.3 mmol) at 0° C. The reaction mixture was then stirred at ambient temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo. The crude was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, then with water, then with brine. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The crude product was purified by combiflash with 3% MeOH in DCM to give tert-butyl ((6-(4-fluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (18) (190 mg, 75.65%). LC-MS MH + 580.4, NHClOac:ACN, R t =3.73 min, 5 min driving; [ka]

[0192] (Step 3—Example 8: 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol) Procedure: To a stirred solution of tert-butyl ((6-(4-fluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (intermediate (18)) (480 mg, 0.829 mmol) in diethyl ether (5 ml) was added 2 M HCl in diethyl ether (25 ml) at 0° C. The reaction mixture was stirred at RT for 2 h. After complete consumption of SM (starting material), the reaction mixture was evaporated in vacuo, triturated with diethyl ether, and lyophilized to give Example 8, 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (423 mg, 98.94%) as a light brown solid. LCMS (HCOOH:ACN): M+H=480.2, R t =1.52 min, 3 min driving; [ka] HPLC RT(A) 5.22 min.

[0193] Example 11: 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol [ka] Procedure: To a stirred solution of 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Example 8) (120 mg, 0.233 mmol) in MeOH (4 ml) was added HCHO solution (37%) (0.25 ml, 2.33 mmol) and stirred at RT for 1 h. Then NaCNBH (43 mg, 0.699 mmol) was added at 0° C. and continued at RT for 16 h. The reaction mixture was evaporated under reduced pressure, diluted with DCM, and washed with saturated NaHCO solution, water, and brine. The organic layer was separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude was purified by preparative TLC plate using 7% MeOH in DCM to give Example 11, 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (64 mg, 55.64%). LC-MS MH + 494.4, NH4Oac:ACN, R t =3.36 mins, 5 mins drive. [ka] HPLC RT(A6) 5.07 min.

[0194] Example 19: 2-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol [ka] (Step 1 - Intermediate (19): tert-butyl((6-(2-(2-(3-acetyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: A stirred solution of tert-butyl N-({6-[4-fluoro-2-(2-{3-[methoxy(methyl)carbamoyl]-1,5-dimethyl-1H-pyrazol-4-yl}ethoxy)phenyl]imidazo[1,2-a]pyridin-3-yl}methyl)-N-methylcarbamate (Intermediate (16)) (1.0 g, 1.723 mmol) in tetrahydrofuran (17.0 mmol) was cooled to 0° C., and methylmagnesium bromide (3 M in ether) (2.9 ml, 8.615 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 1 hour. TLC and LCMS showed the formation of the product, and the reaction mixture was quenched with a saturated solution of NH4Cl. The reaction mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by combiflash column chromatography using MeOH in DCM to give tert-butyl ((6-(2-(2-(3-acetyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (19) (700 g, 75.84 mmol). [ka] LC-MS MH+ 536, NHClOac:ACN, Rt=3.54 min, 5 min run.

[0195] (Step 2—Intermediate (20): 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-one) Procedure: To a stirred solution of tert-butyl ((6-(2-(2-(3-acetyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate (19) (850.0 mg, 1.588 mmol) in diethyl ether (5.0 ml) was added 2M HCl in diethyl ether (40.0 ml). HCl was added at 0° C. The reaction mixture was stirred at room temperature for 3 hours. TLC and LCMS showed the consumption of the starting material. The reaction mixture was evaporated under reduced pressure to give the crude product. The crude product was triturated with diethyl ether to give 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-one (20) (650.0 mg, 94.05%) as the HCl salt compound. [ka] LC-MS MH+ 436, NHClOac:ACN, Rt=2.76 min, 5 min run.

[0196] (Step 3 - Intermediate 274: 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-one) Procedure: To a stirred solution of 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-one (Intermediate (20)) (700.0 mg, 1.608 mmol) in methanol (10.0 ml) was added HCHO solution (ca. 37%) (801.24 ml, 8.042 mmol) and the mixture was stirred at room temperature for 1 hour. Then, NaCNBH3 (300.81 mg, 4.825 mmol) was added at 0°C and the reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by combiflash column chromatography (12 g silica column, 2% MeOH-DCM) to afford 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-one (274) (350.0 mg, 48.41%) as a white solid. [ka] LC-MS MH+ 450, HCOOH:ACN, Rt=1.31 min, 3 min run; HPLC RT(A1) 6.054 min.

[0197] (Step 4 - Example 19: 2-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol) Procedure: A solution of 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-one (274) (90.0 mg, 0.2 mmol) in tetrahydrofuran (5.0 ml) was cooled at 0° C., and methylmagnesium bromide (3 M in diethyl ether) (0.133 ml, 0.4 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 1 hour. TLC and LCMS showed the formation of the product, and the reaction mixture was quenched with a saturated solution of NH4Cl. The reaction mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by combiflash column chromatography using MeOH in DCM to give Example 19, 2-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol (25.0 mg, 26.82%). [ka] LC-MS MH+ 466, NHClOac:ACN, Rt=2.95 min, 5 min run; HPLC RT(B3) 8.587 min.

[0198] Example 2: 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol [ka] Procedure: To a stirred solution of 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-one (274) (200.0 mg, 0.445 mmol) in MeOH (4.0 ml) was added NaBH (34.554 mg, 0.89 mmol) at 0° C. and stirred at room temperature for 3 h. TLC showed approximately 50% unreacted starting material. Again, 18 mg of NaBH was added and stirred at RT for another 2 h. The reaction mixture was quenched with sodium bicarbonate solution and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified on preparative TLC (7% MeOH-DCM) to give Example 2, 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol (100.0 mg, 49.77%). [ka] LC-MS MH+ 452, NHClOac:ACN, Rt=3.13 min, 5 min run.

[0199] (Example 1: 1-{4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}ethan-1-ol) [ka]

[0200] (Step 1 - Intermediate (21): tert-butyl((6-(4-fluoro-2-(2-(3-(1-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: A stirred solution of tert-butyl ((6-(2-(2-(3-acetyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-12-azanecarboxylate (intermediate (19)) (50.0 mg, 0.093 mmol) in methanol (1.0 ml) was cooled at 0° C., and NaBH (5.447 mg, 0.14 mmol) was added at 0° C. The reaction mixture was then stirred at RT for 1 h. TLC showed the formation of the product. The reaction mixture was quenched with saturated sodium bicarbonate solution. The reaction mixture was then filtered through a bed of celite and washed with ethyl acetate. The filtrate was dried over sodium sulfate and concentrated. The crude material was purified by preparative TLC (5% MeOH in DCM) to give tert-butyl ((6-(4-fluoro-2-(2-(3-(1-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (21) (35.0 mg, 69.79%). [ka] LC-MS MH+ 538, NHClOac:ACN, Rt=3.13 min, 5 min run.

[0201] (Step 2—Example 1: 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol) Procedure: To a solution of tert-butyl ((6-(4-fluoro-2-(2-(3-(1-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (intermediate (21)) (35.0 mg, 0.065 mmol) in diethyl ether (2.0 ml) was added 2 M HCl in diethyl ether (5.0 ml) at 0° C. The reaction mixture was stirred at rt for 2 hours. After complete consumption of the starting material, the reaction mixture was evaporated under vacuum, triturated with diethyl ether, and lyophilized to give Example 1 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol (22.0 mg, 77.15%). [ka] LC-MS MH+ 438, NHClOac:ACN, Rt=2.98 min, 5 min run; HPLC RT(B3) 6.945 min.

[0202] Example 3 (Isomer 1) 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol [ka] and Example 4 (Isomer 2) 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol [ka] Chiral separation of racemic 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol to give Procedure: 100 mg of Example 2, racemic 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol was separated in chiral preparative HPLC [Column name: CHIRALPAK IC (21 x 250 mm, 5i) Flow rate: 21.0 ml / min Mobile phase: HEX / ETOH / EA / DEA: 70 / 15 / 15 / 0.1 Dissolving in MEOH] to give (Peak-1) Example 3 (Isomer 1, Rt 11.84 min). 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol (16.0 mg, 16.0%) and (Peak-2, Rt 13.60 min) Example 4 (Isomer 2) 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol (15.0 mg, 15.0%) were obtained. Example 3 (Isomer 1): LC-MS MH+ 452, NHOac:ACN, Rt=2.78 min, 5 min run; Example 4 (Isomer 2): LC-MS MH+ 452, NHOac:ACN, Rt=2.78 min, 5 min run.

[0203] (Examples 9 (Isomer 1) and 10 (Isomer 2): tert-butyl-((6-(4-fluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) [ka] (Step 1 - Chiral separation of tert-butyl((6-(4-fluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: Racemic tert-butyl ((6-(4-fluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (intermediate (18)) (190 mg, 0.328 mmol) was separated by chiral preparative SFC [Chiralpak IG, 0.3% Ip amine in MEOH, instrument method (M-2-25F), injection volume (10), column (IG), well position (21B), temperature (35.3), flow rate (2), % modifier (25), pressure (100)]. After evaporation of the preparative fractions, we obtained 45 mg of intermediate 18a (isomer 1) tert-butyl ((6-(4-fluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate and 28 mg of intermediate 18b (isomer 2) tert-butyl ((6-(4-fluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate.

[0204] Intermediate 18a (Isomer 1) tert-butyl-((6-(4-fluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate: LCMS (HCOOH:ACN): M+H=580.6, R t =2.41 min, 5 min driving; [ka]

[0205] Intermediate 18b (Isomer 2) tert-butyl-((6-(4-fluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate: LCMS (HCOOH:ACN): M+H=580.6, R t =2.39 min, 5 min drive; [ka]

[0206] Example 9 (Isomer 1)-1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol [ka] Procedure: To a stirred solution of intermediate 18a (45 mg, 0.078 mmol) in diethyl ether (2 ml) was added 2 M HCl in diethyl ether (8 ml) at 0° C. The reaction mixture was stirred at RT for 2 h. After complete consumption of SM, the reaction mixture was evaporated in vacuo, triturated with diethyl ether, and lyophilized to give Example 9 (Isomer 1) 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (31 mg, 77.36%) as the HCl salt. LC-MS MH + 480.5, NHClOac:ACN, R t =1.57 min, 3 min driving; [ka] HPLC RT(A6) 4.96 min.

[0207] Example 10 (Isomer 2)-1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol [ka] Procedure: To a stirred solution of intermediate 18b (isomer 2) (22_Peak 2) (28 mg, 0.048 mmol) in diethyl ether (2 ml) was added 2 M HCl in diethyl ether (6 ml) at 0° C. The reaction mixture was stirred at rt for 2 h. After complete consumption of SM, the reaction mixture was evaporated in vacuo, triturated with diethyl ether, and lyophilized to give Example 10 (isomer 2) 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (18.5 mg, 74.15%) as the HCl salt. LC-MS MH + 480.2, NHClOac:ACN, R t =1.37 min, 3 min driving; [ka] HPLC RT(A6) 4.96 min.

[0208] Example 18: 2-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol [ka] (Step 1 - Intermediate (23): tert-butyl((6-(4-fluoro-2-(2-(3-(2-hydroxypropan-2-yl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: A stirred solution of ethyl 4-(2-(2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (intermediate (14)) (2.0 g, 3.538 mmol) in THF (30.0 ml) was cooled at 0° C., and methylmagnesium bromide solution (3 M in diethyl ether) (4.717 ml, 14.152 mmol) was added at 0° C. The reaction mixture was then stirred at RT for 2 hours. TLC showed the formation of the product. The reaction mixture was quenched with saturated NH4Cl solution. The reaction mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by combiflash with MeOH in 5% DCM to give tert-butyl ((6-(4-fluoro-2-(2-(3-(2-hydroxypropan-2-yl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (23) (1.3 g, 66.6%) as an off-white sticky solid. [ka] LC-MS MH+ 552, NHClOac:ACN, Rt=1.32 min, 5 min run.

[0209] (Step 2 - Example 18: 2-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol) Procedure: To a solution of tert-butyl ((6-(4-fluoro-2-(2-(3-(2-hydroxypropan-2-yl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate (23)) (1.3 g, 2.358 mmol) in dichloromethane (25.0 ml) was added trifluoroacetic acid (1.804 ml, 23.581 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. After complete consumption of the starting material, the reaction mixture was quenched with sodium bicarbonate solution at 0° C., diluted with dichloromethane, and the organic layer was separated and evaporated to give the compound, which was purified by combiflash column chromatography using 5% MeOH in DCM to give Example 18 2-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol (650.0 mg, 61.05%). [ka] LC-MS MH+ 452, NHClOac:ACN, Rt=1.52 min, 3 min run; HPLC RT(A6) 5.247 min.

[0210] (Intermediate (28): (3,4-difluoro-2-hydroxyphenyl)boronic acid) [ka] Intermediate (28) was prepared according to the method disclosed in WO2017 / 001812.

[0211] (Intermediate (29): tert-butyl((6-(3,4-difluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) [ka] Procedure: Suzuki coupling of intermediates (28) and (10) using the procedure used for the synthesis of intermediate (13). LCMS (HCOOH:ACN): M+H=390.3, R t =1.54 min, 3 min driving; [ka]

[0212] Example 5: 1-{4-[2-(2,3-difluoro-6-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}ethan-1-ol [ka] (Step 1 - Intermediate (30): Ethyl 4-(2-(6-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate) Procedure: Coupling of intermediates (29) and (6) using the procedure used for the synthesis of intermediate (14). Yield—900 mg, 60.01%. [ka] LC-MS MH+ 584.1, NHClOac:ACN, Rt=3.63 min, 5 min run.

[0213] (Step 2 - Intermediate (31): 4-(2-(6-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid) Procedure: Hydrolysis of intermediate (30) used in the synthesis of intermediate (15). Yield—2.3 g, 92.87%. [ka] LC-MS MH+ 556, NHClOac:ACN, Rt=1.83 min, 3 min run.

[0214] (Step 3 - Intermediate (32): tert-butyl((6-(3,4-difluoro-2-(2-(3-(methoxy(methyl)carbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: Amidation of intermediate (31) used in the synthesis of intermediate (16). Yield - 2.0 g, 80.65%; [ka] LC-MS MH+ 599, NHClOac:ACN, Rt=3.38 min, 5 min run.

[0215] (Step 4 - Intermediate (33): tert-butyl((6-(2-(2-(3-acetyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: Addition of MeMgBr to intermediate (32) used in the synthesis of intermediate (19). Yield—600.0 mg, 64.84% [ka] LC-MS MH+ 554, NHClOac:ACN, Rt=3.69 min, 5 min run.

[0216] (Step 5 - Intermediate (34): tert-butyl((6-(3,4-difluoro-2-(2-(3-(1-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: Reduction of intermediate (33) using the procedure used for the synthesis of intermediate (274). Yield—430.0 mg, 71.41%; [ka] LC-MS MH+ 556, HCOOH:ACN, Rt=1.87 min, run for 3 min.

[0217] (Step 6 - Example 5, 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol) Procedure: Deprotection of intermediate (34) used in the synthesis of intermediate (20). Yield—205.0 mg, 85.79%. [ka] LC-MS MH+ 456, HCOOH:ACN, Rt=1.35 min, 3 min run; HPLC RT(A5) 4.68 min.

[0218] (Example 13: (Isomer 1): 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol) [ka] (Step 1 - Intermediate (35): tert-butyl((6-(2-(2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: Addition of tBu group to intermediate (32) used in the synthesis of intermediate (17). Yield: 270 mg, 27.12%; LC-MS MH+ 595.6, NHOac:ACN, Rt=4.48 min, 5 min run; [ka]

[0219] (Step 2 - Intermediate (36): tert-butyl((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: Reduction of intermediate 35 used in the synthesis of intermediate (18). Yield: 150 mg (49.8%). LC-MS MH+ 598.3, NHOac:ACN, Rt=3.77 min, run 5 min; [ka]

[0220] (Step 3 - Intermediate (37a) (Isomer 1), tert-butyl-((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) and Intermediate (37b) (Isomer 2), tert-butyl-((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate)

[0221] Procedure: Intermediate (36) (150 mg, 0.251 mmol) was subjected to chiral separation by chiral preparative HPLC [column name: CHIRALPAK IC (250 × 20 mm, 5i) flow rate: 18.0 ml / min mobile phase: HEX / ETOH / IP amine: 80 / 20 / 0.1 solvent: MEOH]. Evaporation of the preparative fractions gave 50 mg of intermediate 37a (isomer 1), tert-butyl-((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate and 45 mg of intermediate 37b (isomer 2), tert-butyl-((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (stereochemistry assigned arbitrarily). Intermediate (37a) (isomer 1): LCMS (HCOOH:ACN): M+H=598.3, R t =2.48 min, 5 min run; Intermediate (37b) (isomer 2): LCMS(HCOOH:ACN): M+H=598.3, R t =2.46 mins, 5 mins drive.

[0222] (Example 13 (Isomer 1): 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol) [ka] Procedure: Deprotection of intermediate (37a) (Isomer 1) using the procedure used in Example 9 (Isomer 1). Yield: 40 mg, 91.09%. LC-MS MH+ 498.4, NHOac:ACN, Rt=3.15 min, 5 min run; [ka] HPLC RT(A4) 6.47 min.

[0223] (Example 14 (Isomer 2): 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol) [ka] Procedure: Deprotection of intermediate (37b) (isomer 2) using a procedure similar to that in Example 10 (isomer 2). Yield: 394 mg, 95.93%; LCMS (HCOOH:ACN): M+H=498.33, R t =1.53 min, 3 min driving; [ka] HPLC RT(A4) 6.45 min.

[0224] (Example 15—(Isomer 1): 1-(4-(2-(6-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol) [ka] Procedure: Reductive amination of Example 13 (Isomer 1) using the same procedure as used for Example 11. Yield: 22 mg, 53.46%. LCMS (HCOOH:ACN): M+H=512.29, R t =1.48 min, 3 min driving; [ka] HPLC RT(A4) 6.49 min.

[0225] (Example 16, (Isomer 2): 1-(4-(2-(6-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol) [ka] Procedure: Reductive amination of Example 14 using the same procedure as used in the synthesis of Example 11. Yield: 16 mg, 51.84%; LCMS (HCOOH:ACN): M+H=512.29, R t =1.48 mins, 3 mins drive. [ka] HPLC RT(A3) 5.32 min.

[0226] Example 6: 1-(4-(2-(6-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol [ka] Procedure: Reductive amination of Example 5 using the same procedure as used for the synthesis of Example 11. Yield: 95.07 mg, 52.87%; LCMS (HCOOH:ACN): M+H=470.26, R t =1.38 min, 3 min driving; [ka] HPLC RT(A1) 5.85 min.

[0227] Example 21: 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol [ka] Step 1 - Intermediate 38: tert-butyl((6-(3,4-difluoro-2-(2-(3-(2-hydroxypropan-2-yl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate Procedure: Conversion of ester intermediate (30) to the corresponding gem dimethyl alcohol (38) using the procedure used in the synthesis of intermediate (23). Yield—340.0 mg, 39.79%; [ka] LC-MS MH+ 570, HCOOH:ACN, Rt=1.59 min, run for 3 min.

[0228] (Step 2 - Example 21: 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol) Procedure: Deprotection of intermediate (38) using the same conditions as used for the synthesis of Example 18. Yield—160.0 mg, 57.03%; [ka] LC-MS MH+ 470, HCOOH:ACN, Rt=1.81 min, 3 min run; HPLC RT(A1) 5.818 min.

[0229] (Intermediate (47): [2-(6-Bromo-imidazo[1,2-a]pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester) [ka] Procedure: Intermediate 47 was prepared according to the method disclosed in WO2020 / 128473.

[0230] Example 23: 2-(4-(2-(2-(3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol [ka] (Step 1 - Intermediate (48): tert-butyl (2-(6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)carbamate) Procedure: Intermediate (48) was prepared by coupling intermediates 47 and 12 using the procedure used for the synthesis of intermediate (29). Yield: 1.0 g, 76.29%; [ka]

[0231] (Step 2 - Intermediate (50): Methyl 4-(2-(2-(3-(2-((tert-butoxycarbonyl)amino)ethyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate) Procedure: Intermediate (50) was synthesized by coupling intermediates 48 and 49 using the same conditions used to synthesize intermediate (30). Yield: 300.0 mg, 67.26%; [ka] LC-MS MH+ 552, NHClOac:ACN, Rt=3.13 min, 5 min run.

[0232] (Step 3 - Intermediate (51): 4-(2-(2-(3-(2-((tert-butoxycarbonyl)amino)ethyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid) Procedure: Intermediate (51) was prepared by hydrolysis of intermediate (50) using the procedure used for intermediate (31). Yield: 290.0 mg, 99.08%; [ka] LC-MS MH+ 538, NHClOac:ACN, Rt=2.63 min, 5 min run.

[0233] (Step 4 - Intermediate (52): tert-butyl (2-(6-(4-fluoro-2-(2-(3-(methoxy(methyl)carbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)carbamate) Procedure: Intermediate (52) was prepared by amidation of intermediate 51 using the same procedure used for the synthesis of intermediate (32). Yield: 100.0 mg, 46.33%; [ka] LC-MS MH+ 581, NHClOac:ACN, Rt=3.04 min, 5 min run.

[0234] (Step 5 - Intermediate (53): tert-butyl (2-(6-(2-(2-(3-acetyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)carbamate) Procedure: Intermediate (53) was prepared from intermediate (52) by addition of MeMgBr using the same procedure used to prepare intermediate (33). Yield—20.0 mg, 21.69%. [ka] LC-MS MH+ 536, NHClOac:ACN, Rt=3.43 min, 5 min run.

[0235] (Step 6 - Intermediate (54): tert-butyl (2-(6-(4-fluoro-2-(2-(3-(2-hydroxypropan-2-yl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)carbamate) Procedure: Intermediate (54) was prepared from intermediate (53) using the same procedure used in the synthesis of Example 19. Yield: 35.0 mg, 56.78%; [ka]

[0236] (Step 7 - Example 23: 2-(4-(2-(2-(3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol) Procedure: Example 23 was prepared from intermediate (54) using the same deprotection procedure used in Example 18. Yield: 15.0 mg, 50.30%; [ka] HPLC RT(B1) 6.674 min.

[0237] Example 7: 1-(4-(2-(2-(3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol [ka] (Step 1 - Intermediate (55): tert-butyl (2-(6-(4-fluoro-2-(2-(3-(1-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)carbamate) Procedure: Intermediate (55) was prepared by reduction of intermediate (53) using the same procedure as for intermediate (21). Yield: 35.0 mg, 58.16%; [ka]

[0238] (Step 2 - Example 7 1-(4-(2-(2-(3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol) Procedure: Example 7 was prepared by deprotection of intermediate (55) using a procedure similar to that for Example 1. Yield: 35.0 mg, 98.00%. [ka] LC-MS MH+ 438, HCOOH:ACN, Rt=1.22 min, 3 min run; HPLC RT(A2) 6.53 min.

[0239] Example 24: 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol [ka] (Step 1 - Intermediate (57): 4-Bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid) Procedure: To a stirred solution of ethyl 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylate (intermediate (56)) (10.0 g, 40.486 mmol) in THF (112 ml) and water (28 ml) was added ethanol (6 ml). Then, at 0° C., LiOH.HO (3.401 g, 80.972 mmol) was added portionwise, and the resulting mixture was stirred at RT for 16 h. TLC was then checked, which indicated the formation of the desired product. The reaction mixture was then distilled under vacuum. The crude reaction mixture was acidified with 6 N HCl solution and extracted with 5% MeOH / DCM. The final organic layer was dried over sodium sulfate and concentrated to give 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (57) (8 g, 90.21%) as a light brown solid. [ka]

[0240] (Step 2 - Intermediate (58)-4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxamide) Procedure: To a stirred solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (intermediate (57)) (8 g, 36.53 mmol) in anhydrous DCM (80 ml) was added oxalyl chloride (3.785 ml, 43.836 mmol) and a catalytic amount of DMF (0.1 ml) at 0° C., and the reaction was stirred at RT for 3 h. The reaction mixture was then evaporated under a N2 atmosphere. The acid chloride was then dissolved in THF and slowly added to a solution of ammonia in THF at 0° C. The reaction mixture was then stirred at RT for 16 h. The reaction mixture was then evaporated, extracted with 10% MeOH / DCM, dried over sodium sulfate, and concentrated in vacuo to give 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxamide (58) (7 g, 87.88%); LCMS (HCOOH:ACN): M+H=218.2, R t =1.45 min, 3 min driving; [ka]

[0241] (Step 3 - Intermediate (59): 4-Bromo-1,5-dimethyl-1H-pyrazole-3-carbonitrile) Procedure: To a stirred solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxamide (intermediate (58)) (7 g, 32.11 mmol) in THF (100 ml) was added TEA (22.522 ml, 160.55 mmol) at 0 °C, followed by slow addition of TFAA (11.157 ml, 80.275 mmol) and stirring at RT for 2 h. The volatiles were then evaporated under a N atmosphere and then quenched with saturated sodium bicarbonate solution. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with brine solution, separated, dried over sodium sulfate, and concentrated in vacuo. The crude material was then purified by column chromatography using 100-200 silica gel and eluted with 10% ethyl acetate / hexane to give 4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonitrile (59) (5.5 g, 85.63%). [ka]

[0242] (Step 4 - Intermediate (60): 1,5-dimethyl-4-vinyl-1H-pyrazole-3-carbonitrile) Procedure: To a solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonitrile (intermediate (59)) (5.5 g, 27.5 mmol) in DMF (26 ml) was added vinylstannane (16.069 ml, 55 mmol). The solution was degassed with argon for 20 min, and Pd(PPh3)4 (1.588 g, 1.375 mmol) was added under argon. The reaction mixture was stirred at 110 °C for 16 h. TLC showed the formation of product with complete consumption of starting material. The reaction mixture was cooled to RT, quenched with water, and extracted with ethyl acetate. The organic layer was washed with saturated KF solution, the precipitate was filtered through a celite pad, and the filtrate was washed with water and finally with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) eluting with 30% ethyl acetate and hexane to give 1,5-dimethyl-4-vinyl-1H-pyrazole-3-carbonitrile (60) (2.9 g, 71.65%). LC-MS MH + 147.93, FA:ACN, R t =1.68 min, 3 min driving; [ka]

[0243] (Step 5 - Intermediate (61): 4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carbonitrile) Procedure: To a stirred solution of 1,5-dimethyl-4-vinyl-1H-pyrazole-3-carbonitrile (intermediate (60)) (2.9 g, 19.728 mmol) and (diacetoxyiodo)benzene (6.67 g, 20.714 mmol) in acetonitrile (56.0 ml) was added dropwise 5% sulfuric acid (5.8 ml) at −30° C. The mixture was stirred at −30° C. for 1 hour. After completion of the reaction, the residue was treated with ethyl acetate and washed with saturated sodium bicarbonate solution, water, and brine solution. The aqueous layer was back-extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and dissolved in ethanol (50.0 ml). Sodium borohydride (1.448 g, 39.141 mmol) was added portionwise under ice-cooling conditions. The reaction mixture was stirred at 0° C. for 30 minutes. After completion of the reaction, the mixture was quenched with sodium bicarbonate solution, diluted with ethyl acetate, washed with water, brine and concentrated in vacuo to give the crude product, which was purified by combiflash column chromatography using 2% MeOH in DCM to give 4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carbonitrile (61) (2 g, 68.05%) as a colorless oil. LCMS (HCOOH:ACN): M+H=165.94, Rt=1.38 min, run for 3 min; [ka]

[0244] (Step 6 - Intermediate (62) tert-butyl((6-(2-(2-(3-cyano-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: Intermediate (62) was prepared by coupling intermediates 61 and 13 using the procedure used for intermediate (14). Yield: 260 mg, 37.3%; [ka] LCMS(HCOOH:ACN): M+H=519.58, Rt=1.55 minutes, run for 3 minutes.

[0245] (Step 7 - Intermediate (63): tert-butyl((6-(4-fluoro-2-(2-(3-isobutyryl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: Intermediate (63) was prepared from intermediate (62) by addition of isopropylMgBr using the same procedure used for the synthesis of intermediate (23). Yield: 450 mg, 75.19%.

[0246] (Step 8 - Intermediate (289): 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2-methylpropan-1-one) Procedure: Intermediate 289 was synthesized by deprotection of intermediate (63) using a procedure similar to that for intermediate (20). Yield: 250 mg, 66.01%. [ka]

[0247] (Step 9 - Intermediate (290): 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2-methylpropan-1-one) Procedure: Intermediate (290) was prepared by reductive amination of intermediate (289) using a procedure similar to that used for the synthesis of (274). Yield: 7 mg, 3.65%; [ka]

[0248] (Step 10—Example 24: 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol) [ka] Procedure: 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol was prepared by reductive amination of intermediate (290) using the procedure used in the synthesis of Example 2. Yield: 13 mg, 32.37%; [ka]

[0249] Example 17: 1-(4-(2-(6-(3-(aminomethyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol [ka] (Step 1 - Intermediate (74): 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)-N-(4-methoxybenzyl)methanamine) Procedure: To a stirred solution of 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (intermediate (73)) (3 g, 13.333 mmol) in methanol (15 ml) was added 4-methoxybenzylamine (2.613 ml, 20.0 mmol) and stirred at RT for 16 h. To the reaction mixture was added NaBH4 (1.035 g, 26.667 mmol) at 0 °C and stirred at the same temperature for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by combiflash column chromatography. 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)-N-(4-methoxybenzyl)methanamine (74) (2.2 g, 47.66%) was obtained. LC-MS MH + 345.6, NHClOac:ACN, R t =3.43 mins, 5 mins drive.

[0250] (Step 2 - Intermediate (75) tert-butyl N-({6-bromoimidazo[1,2-a]pyridin-3-yl}methyl)-N-[(4-methoxyphenyl)methyl]carbamate) Procedure: Intermediate (75) tert-butyl N-({6-bromoimidazo[1,2-a]pyridin-3-yl}methyl)-N-[(4-methoxyphenyl)methyl]carbamate was prepared by Boc protection of intermediate (74) using the procedure used for intermediate (10). Yield: 1.7 g, 59.94%; [ka] LCMS(HCOOH:ACN): M+H=446.33 and 448.28, Rt=1.73 minutes, run for 3 minutes.

[0251] (Step 3 - Intermediate (76): tert-butyl ((6-(3,4-difluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(4-methoxybenzyl)carbamate) Procedure: Intermediate (76) was prepared by coupling intermediates (74) and (5) using the procedure used for intermediate (13). Yield: 1.4 g, 73.96%; LCMS (HCOOH:ACN): M+H=496.3, Rt=2.07 min, 3 min run.

[0252] (Step 4 - Intermediate (77) Ethyl 4-(2-(6-(3-(((tert-butoxycarbonyl)(4-methoxybenzyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate) Procedure: Intermediate (77) was synthesized by coupling intermediates (76) and (7) using the procedure used for intermediate (14). Yield: 200 mg, 35.9%; LCMS (HCOOH:ACN): M+H=690.29, Rt=1.97 min, 3 min run.

[0253] (Step 5 - Intermediate (78) 4-(2-(6-(3-(((tert-butoxycarbonyl)(4-methoxybenzyl)amino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid) Procedure: Intermediate (78) was synthesized by hydrolysis of intermediate (77) using the procedure used for intermediate (15). Yield: 900 mg, 93.71%; LCMS (HCOOH:ACN): M+H=662.6, Rt=2.02 min, 3 min run.

[0254] (Step 6 - Intermediate (79): tert-butyl ((6-(3,4-difluoro-2-(2-(3-(methoxy(methyl)carbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(4-methoxybenzyl)carbamate) Procedure: Intermediate (79) was synthesized by amidation of intermediate (78) using the same procedure as used for intermediate (16). Yield: 430 mg, 44.83%; [ka] LCMS(HCOOH:can): M+H=705.4, Rt=2.16 minutes, run for 3 minutes.

[0255] (Step 7 - Intermediate (80): tert-butyl ((6-(2-(2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2pyridindin-3-yl)methyl)(4-methoxybenzyl)carbamate) Procedure: Intermediate (8) was synthesized from intermediate (79) by addition of tBu using the same procedure as for intermediate (17). Yield: 200 mg, 46.66%. [ka] LCMS(HCOOH:ACN): M+H=702.78, Rt=1.87 minutes, run for 3 minutes.

[0256] (Step 8 - Intermediate (81): tert-butyl ((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(4-methoxybenzyl)carbamate) Procedure: Intermediate (81) was synthesized by reduction of intermediate (80) using the same procedure as for intermediate (21). Yield: 140 mg, 69.75%; [ka] LCMS(HCOOH:ACN): M+H=704.76, Rt=1.76 minutes, run for 3 minutes.

[0257] (Step 9 - Intermediate (82): tert-butyl ((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)carbamate) Procedure: To a stirred solution of intermediate (81) (130 mg, 0.185 mmol) in acetonitrile (2.7 ml) was added cerium ammonium nitrate (202.573 mg, 0.37 mmol) dissolved in water (0.3 ml) at 0° C. The reaction mixture was stirred at the same temperature for 1 hour. TLC and LCMS of the reaction mixture showed that SM was consumed. The reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium sulfite solution, water, and brine. The organic layer was concentrated in vacuo to give the crude product. The crude was purified by preparative TLC plate using 3% methanol in DCM to give tert-butyl ((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)carbamate (82) (40 mg, 37.08%) as a colorless sticky gum. LCMS (HCOOH:ACN): M+H=584.6, Rt=2.05 min, run for 3 min.

[0258] (Step 10 - Example 17: 1-(4-(2-(6-(3-(aminomethyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol) Procedure: Example 17 was synthesized by deprotecting intermediate (82) using the same procedure as used in Example 9 (Isomer 1). Yield: 22 mg, 66.31%; [ka] LCMS(HCOOH:ACN): M+H=484.38, Rt=1.51 min, 3 min run; HPLC RT(A3) 3.84 min.

[0259] Example 12: 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol [ka] (Step 1 - Intermediate (83): 1,5-dimethyl-1H-pyrazole-3-carboxylic acid) Procedure: To a solution of ethyl 1,5-dimethyl-1H-pyrazole-3-carboxylate (intermediate (2)) (20.0 g, 118.984 mmol) in 4:1 THF:water (280 ml, 70 ml) was added ethanol (0.4 ml) and LiOH.HO (9.985 g, 237.968 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. TLC / LCMS showed complete consumption of SM. The reaction mixture was acidified with 3N HCl solution (pH ∼2) at 0 °C and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (83) as a pale yellow solid (16 g, 99%). [ka]

[0260] (Step 2 - Intermediate (84): N-Methoxy-N,1,5-trimethyl-1H-pyrazole-3-carboxamide) Procedure: To a stirred solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (intermediate (83)) (16.6 g, 118.571 mmol) in tetrahydrofuran (350.0 ml) was added N,O-dimethylhydroxylamine hydrochloride (17.34 g, 177.857 mmol). Triethylamine (82.633 ml, 592.857 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34.095 g, 177.857 mmol), and 1-hydroxybenzotriazole (24.032 g, 177.857 mmol) were added and the reaction mixture was stirred at RT for 16 hours. TLC showed the formation of the product. The reaction was washed with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude was purified by combiflash with 5% MeOH in DCM to give N-methoxy-N,1,5-trimethyl-1H-pyrazole-3-carboxamide (84) as a pale yellow solid (15.0 g, 69.05%). [ka] LCMS (NH4Oac:ACN): M+H=184, Rt=2.17 min, run for 5 min.

[0261] (Step 3 - Intermediate (85): 1-(1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one) Procedure: A stirred solution of N-methoxy-N,1,5-trimethyl-1H-pyrazole-3-carboxamide (intermediate (84)) (15.0 g, 81.922 mmol) in tetrahydrofuran (150.0 ml) was cooled to −50° C., and t-butyllithium (1.7 M in pentane) (96.379 ml, 163.844 mmol) was added at −50° C. The reaction mixture was then stirred at −50° C. for 2 hours. TLC showed the formation of the product, and the reaction mixture was quenched with saturated NH4Cl solution. The reaction mixture was diluted with ethyl acetate and washed with water and brine solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude was purified by combiflash chromatography using 5% MeOH in DCM to give 1-(1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (85) as a pale yellow solid (6.0 g, 40.63%). [ka] LCMS(HCOOH:ACN): M+H=181, Rt=1.86 minutes, run for 3 minutes.

[0262] (Step 4 - Intermediate (86): 1-(4-bromo-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one) Procedure: To a solution of 1-(1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (intermediate (85)) (6.0 g, 33.309 mmol) in acetonitrile (100.0 ml) was added N-bromosuccinimide (6.191 g, 34.975 mmol) portionwise under ice-cooled conditions. The resulting reaction mixture was stirred at RT for 16 hours. TLC and LCMS showed the formation of the product. The reaction mixture was then diluted with ethyl acetate and washed with saturated NaHCO3 solution, water, and brine solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 1-(4-bromo-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (86) as a yellow solid compound (8.0 g, 92.68%), which was used in the next step without purification. [ka] LCMS (NH4Oac:ACN): M+H=259, Rt=3.59 min, run for 5 min.

[0263] (Step 5 - Intermediate (87): 1-(1,5-dimethyl-4-vinyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one) Procedure: To a solution of 1-(1,5-dimethyl-4-vinyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (intermediate (86)) (7.0 g, 27.129 mmol) in anhydrous N,N-dimethylformamide (100.0 ml) was added tributylvinyltin (17.2 ml, 54.257 mmol) at room temperature. Argon was then purged through the reaction mixture for 15 minutes, and Pd(PPh3)4 (3.133 g, 2.713 mmol) was added. The reaction mixture was stirred at 110°C for 16 hours. TLC showed that the starting material had been consumed and the desired product had formed. The reaction mixture was then diluted with ethyl acetate, washed with potassium fluoride solution, and the precipitate was filtered through a cinnamon, washed with water and brine, dried over sodium sulfate, and concentrated. The crude material was purified by column chromatography (100-200) in 10% ethyl acetate-hexane to give 1-(1,5-dimethyl-4-vinyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (87) (5.0 g, 89.35%). [ka] LCMS(HCOOH:ACN): M+H=207, Rt=2.19 minutes, run for 3 minutes.

[0264] (Step 6 - Intermediate (88): 2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)acetaldehyde) Procedure: To a solution of 1-(1,5-dimethyl-4-vinyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (intermediate (87)) (4.1 g, 19.903 mmol) and (diacetoxyiodo)benzene (6.729 g, 20.898 mmol) in acetonitrile (60.0 ml) was added 5% sulfuric acid (3.525 ml) dropwise at −30° C. The mixture was stirred at −30° C. for 1 hour. After completion of the reaction, the residue was treated with ethyl acetate and washed with saturated sodium bicarbonate solution, water, and brine solution. The aqueous layer was back-extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)acetaldehyde (88) (2.7 g, 61.03%). This fraction was then used in the next step without purification. [ka] LCMS (NH4Oac:ACN): M+H=223, Rt=1.86 min, 3 min run.

[0265] (Step 7 - Intermediate (89): 1-(4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one) Procedure: To a solution of 2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)acetaldehyde (intermediate (88)) (2.7 g, 12.162 mmol) in ethanol (60.0 ml) was added sodium borohydride (0.460 g, 12.162 mmol) portionwise under ice-cooled conditions. The reaction mixture was stirred at 0° C. for 30 minutes. After completion of the reaction, the mixture was quenched with sodium bicarbonate solution, diluted with ethyl acetate, washed with water, brine, and concentrated in vacuo to give the crude product. The batch was purified by combiflash using 2% MeOH in DCM to give 1-(4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (89) (2.1 g, 76.98%) as a colorless oil. [ka] LCMS(HCOOH:ACN): M+H=225, Rt=1.81 min, run for 3 min.

[0266] (Step 8 - Intermediate (90): tert-butyl ((6-(2-(2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: To a stirred solution of 1-(4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (intermediate (89)) (2.3 g, 10.268 mmol) and tert-butyl ((6-(3,4-difluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (3.994 g, 10.268 mmol) in toluene (40.0 ml) was added CMBP (5.382 ml, 20.536 mmol) at room temperature, and the reaction mixture was stirred at 110° C. for 16 hours. TLC and LCMS showed the formation of the product, and the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude was purified by combiflash with 5% MeOH-DCM to give tert-butyl ((6-(2-(2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (90) as a brown sticky gum (3.0 g, 49.05%). [ka] LCMS(HCOOH:ACN): M+H=596, Rt=1.75 minutes, run for 5 minutes.

[0267] (Step 9 - Intermediate (91): tert-butyl((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate) Procedure: To a solution of tert-butyl ((6-(2-(2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (intermediate (90)) (2.5 g, 4.202 mmol) in methanol (25.0 ml) was added lithium borohydride (0.458 g, 21.008 mmol). The mixture was stirred at ambient temperature for 5 hours. After completion of the reaction, the solvent was evaporated, diluted with DCM, and washed with sodium bicarbonate solution, water, and brine. The organic layer was dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by preparative TLC using 5% MeOH in DCM to give tert-butyl ((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (91) (1.9 g, 75.66%). [ka] LCMS (NH4Oac:ACN): M+H = 598, Rt = 3.75 min, run for 5 min.

[0268] (Step 10 - Example 12: 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol) Procedure: To a solution of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (91) (1.2 g, 2.009 mmol) in diethyl ether (10.0 ml) was added 2 M HCl in diethyl ether (40.0 ml) at 0° C. The reaction mixture was stirred at rt for 3 h. TLC and LCMS showed that the starting material had been consumed. The reaction mixture was evaporated under reduced pressure to give the crude product. The crude material was triturated with diethyl ether and lyophilized to give 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol as a pale yellow solid (HCl salt) (1.04 g, 96.93 mmol, 49%). [ka] LCMS(HCOOH:ACN): M+H=498, Rt=2.54 min, 5 min run; HPLC RT(B3) 8.739 min.

[0269] Example 20: 2-[4-(2-{6-[3-(aminomethyl)imidazo[1,2-a]pyridin-6-yl]-2,3-difluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]propan-2-ol Example 20 was prepared and purified by the same route as Example 21, starting from tert-butyl N-({6-bromoimidazo[1,2-a]pyridin-3-yl}methyl)-N-[(4-methoxyphenyl)methyl]carbamate. The two amine protecting groups were sequentially cleaved using the procedure used in Example 17 to give 60 mg (49%) of Example 20. [ka] LCMS(HCOOH:ACN): M+H= 456.30., Rt=1.471 min, 3 min run; HPLC RT(A4) 5.672 min.

[0270] Example 22: 2-{4-[2-(2-{3-[(ethylamino)methyl]imidazo[1,2-a]pyridin-6-yl}-5-fluorophenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}propan-2-ol Example 22 was prepared by the same route as Example 18, starting from the corresponding ({6-bromoimidazo[1,2-a]pyridin-3-yl}methyl)(ethyl)amine. Final deprotection step afforded (466 mg, 55%) of Example 22. [ka] LC-MS MH+ 466, NHClOac:ACN, Rt=1.61 min, 3 min run; HPLC RT(A6) 5.257 min.

[0271] Example 25: 1-{4-[2-(2,3-difluoro-6-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}-2-methylpropan-1-ol Example 22 was prepared by the same route as Example 24, starting from intermediate (28). Final deprotection step gave 38 mg, 66% of Example 25. [ka] LC-MS MH+ 484.36, FA:ACN, Rt=1.52 min, 3 min run; HPLC RT(B1) 9.062 min.

[0272] Antibody Drug Conjugate (ADC) Example 1 - Synthesis of Trastuzumab-NMT Inhibitor ADC Drug Conjugate 1: Synthesis of (1S,2R,3S,4R,5R)-5-(4-{[({[6-(3,4-difluoro-2-{2-[3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3yl]methyl}(methyl)carbamoyl)oxy]methyl}-2-[3-(3-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}propanamido)propanamido]phenoxy)-3,4-dihydroxy-2-methylcyclohexane-1-carboxylic acid (as the hydrate) [ka] Step 1: To a solution of (1S,2R,3S,4R,5R)-5-[2-(3-{[(9H-fluoren-9-yloxy)carbonyl]amino}propanamide)-4-({[(4-nitrophenoxy)carbonyl]oxy}methyl)phenoxy]-2,3,4-trihydroxycyclohexane-1-carboxylic acid (ADC intermediate 1, 100 mg, 0.11 mmol) (Bioconjugate Chem., 2006, 17, 831-840) in anhydrous DMF (2 mL) was added Example 12 (50 mg), followed by DIEA (40 mL) and HOAt (3 mg), and the reaction was stirred at room temperature (22° C.). After 16 h, the mixture was directly purified by RP-HPLC to give (1S,2R,3S,4R,5R)-5-(4-{[({[6-(3,4-difluoro-2-{2-[3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}(methyl)carbamoyl)oxy]methyl}-2-(3-{[(9H-fluoren-9-yloxy)carbonyl]amino}propanamido)phenoxy)-2,3,4-trihydroxycyclohexane-1-carboxylic acid (ADC intermediate 2) as a white solid (107 mg) after lyophilization.

[0273] Step 2: (1S,2R,3S,4R,5R)-5-(4-{[({[6-(3,4-difluoro-2-{2-[3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}(methyl)carbamoyl)oxy]methyl}-2-(3-{[(9H-fluoren-9-yloxy)carbonyl]amino}propanamido)phenoxy)-2,3,4-trihydroxycyclohexane-1-carboxylic acid (ADC intermediate 2, 105 mg) was dissolved in acetonitrile / water (6 / 4, v / v, 4 mL), and NaOH (1N, aqueous, 0.5 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 8 hours. HCl (4N in dioxane, 0.1 mL) was added and the mixture was purified by RP-HPLC to give (1S,2R,3S,4R,5R)-5-[2-(3-aminopropanamido)-4-{[({[6-(3,4-difluoro-2-{2-[3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}(methyl)carbamoyl)oxy]methyl}phenoxy]-2,3,4-trihydroxycyclohexane-1-carboxylic acid (ADC intermediate 3) as a white solid (TFA salt, 42 mg) after lyophilization.

[0274] Step 3: To a solution of (1S,2R,3S,4R,5R)-5-[2-(3-aminopropanamido)-4-{[({[6-(3,4-difluoro-2-{2-[3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}(methyl)carbamoyl)oxy]methyl}phenoxy]-2,3,4-trihydroxycyclohexane-1-carboxylic acid (ADC intermediate 3, 40 mg) in acetonitrile / water (6 / 4, v / v, 2 mL) was added Mal-PEG2-OSu (15 mg) followed by DIEA (14 mL). The reaction mixture was stirred at room temperature for 1 h and directly purified by RP-HPLC to give (1S,2R,3S,4R,5R)-5-(4-{[({[6-(3,4-difluoro-2-{2-[3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}(methyl)carbamoyl)oxy]methyl}-2-(3-{[(9H-fluoren-9-yloxy)carbonyl]amino}propanamido)phenoxy)-2,3,4-trihydroxycyclohexane-1-carboxylic acid hydrate (drug conjugate 1) as a white solid (36 mg) after lyophilization.

[0275] ADC Example 1 - Preparation of Trastuzumab-NMT Inhibitor ADC (DAR 5) Trastuzumab was purchased and reconstituted to give a 25 mg / mL solution. 5% v / v of 500 mM Tris, 25 mM EDTA, pH 8.5 was added to adjust the pH before reduction and conjugation. 2.5 molar equivalents of TCEP (tris(2-carboxyethyl)phosphine) relative to antibody were added from a 10 mM stock in water, and the antibody was allowed to reduce for 90 minutes. Eight molar equivalents of drug conjugate 1 were added from a 10 mM stock in DMA (dimethylacetamide), and the reduced antibody was allowed to conjugate for 60 minutes. Eight molar equivalents of NAC (N-acetylcysteine) were added from a 10 mM stock in water to quench unreacted drug conjugate 1 and allowed to react for 20 minutes. The conjugate was purified by preparative SEC (size exclusion chromatography) using a Superdex 200PG column equilibrated in PBS. Protein-containing fractions were pooled and finally filtered through a suitably sized 0.2 μm PES filter (chromatography direct / FIL-S-PES-022-13-100-S) under grade A laminar flow. The final product was sampled for QC tests—monomer and [ADC] mg / ml by SEC-HPLC, mean DAR (drug-antibody ratio) by PLRP-HPLC (polymer reversed-phase HPLC), residual NMT inhibitor 1 by RP-HPLC, and endotoxin by Endosafe kinetic chromogenic assay.

[0276] ADC Example 3 was prepared using the same method as described for ADC Example 1, except that sacituzumab was used as the antibody instead of trastuzumab.

[0277] ADC Example 4 was prepared using the same method as described for ADC Example 1, except that ifinatamab was used as the antibody instead of trastuzumab.

[0278] Preparation of ADC Example 5 ADC Example 5 was prepared using Drug Conjugate 2. Drug Conjugate 2 was prepared using the same method as Drug Conjugate 1, except that NMT inhibitor 21 was used instead of NMT inhibitor 1: [ka] (where steps 1-3 are as described for Drug Conjugate 1).

[0279] Herceptin (trastuzumab) was purchased and reconstituted to yield a 25.6 mg / mL solution. 5% v / v of 500 mM Tris, 25 mM EDTA, pH 8.5 was added to adjust the pH before reduction and conjugation. 2.55 molar equivalents of TCEP (tris(2-carboxyethyl)phosphine) relative to antibody were added from a 5 mM stock in water, and the antibody was allowed to reduce for 120 minutes. The reduced mAb was diluted 1 / 3 with PBS before conjugation. Eight molar equivalents of drug conjugate 2 were added from a 10 mM stock in DMA (dimethylacetamide), and the reduced antibody was allowed to conjugate for 90 minutes. Eight molar equivalents of NAC (N-acetylcysteine) were added from a 100 mM stock in water to quench unreacted drug conjugate 2 and allowed to react for 20 minutes. The conjugate was further buffer exchanged into PBS using G25 resin (NAP25 column), after which activated charcoal was added at a ratio of 1 mg carbon:1 mg ADC and incubated overnight at room temperature on a roller mixer at 10 rpm. The conjugate was then spun down at 4000 x G for 15 minutes to pellet the carbon, and the supernatant (ADC) was removed and filtered through a 0.2 μM PES filter. The conjugate was then further purified and concentrated by diafiltration using an Amicon 15 device, using 6x diafiltration volume (DV) of PBS, pH 7.4 for buffer exchange. The conjugate was then finally filtered through a 13 mm 0.2 μm PES filter (chromatography direct / FIL-S-PES-022-13-100-S) under grade A laminar flow and subsequently formulated to 0.02% PS80. The final product was sampled for QC tests - monomer and [ADC] mg / ml by SEC-HPLC, average DAR by PLRP, residual NMT inhibitor by RP-HPLC, and endotoxin by Endosafe.

[0280] Preparation of ADC Example 6 ADC Example 6 was prepared using the same method as described for ADC Example 1, except that drug conjugate 3 was used (in this case, the linker used was GGFG).

[0281] Structure of drug conjugate 3: [ka] (This can be prepared using the same method as drug conjugate 1).

[0282] Biological Examples Biological Example 1: HsNMT1 IC 50 ) IC of specific example compounds and comparative compound 1 against human NMT1 (HsNMT1) 50 Values ​​were measured using a sensitive fluorescence-based assay based on the detection of CoA with 7-diethylamino-3-(4-maleimido-phenyl)-4-methylcoumarin as described in Goncalves, V. et al., Analytical Biochemistry, 2012, 421, 342-344 and Goncalves, V. et al., J. Med. Chem, 2012, 55, 3578.

[0283] Results: HsNMT1 IC of certain example compounds of the present invention and comparative compound 1 50 The values ​​are shown below in Table 1. These results demonstrate that the tested example compounds of the present invention are highly potent inhibitors of human NMT.

[0284] Biological Example 2: Cytotoxicity in SU-DHL-10 cell line Certain example compounds of the present invention and comparative compound 1 were tested in the SU-DHL-10 cell line (human B-cell lymphoma). Compounds that demonstrate efficacy in this assay are believed to be useful as drugs for treating or preventing hyperproliferative disorders such as cancer.

[0285] Cells were seeded in 96-well microplates and treated in technical triplicates with nine increasing concentrations of compounds or cisplatin (as a positive control). IC values ​​of tested compounds and cisplatin were 50 was determined for each cell line after 72 hours of treatment.

[0286] 1. On day 1, 90 μL of various cell suspensions with cell numbers ranging from 5,000 to 8,000 cells / well were seeded into wells of a 96-well plate (Corning). The cell numbers to be seeded were determined previously. 2. All 96-well plates with cells were placed in an incubator at 37°C with 5% CO2 overnight. 3. On the second day, the cells were observed under a microscope to confirm that the cells treated with the vehicle control were in good condition. 4. A dilution series of test compounds and cisplatin was prepared at 10x the required final concentration. 10 μL / well of the 10x compound solution was added to the corresponding plate. The final volume was 100 μL / well for all plates. The final DMSO concentration was 0.1%. 5. On the fifth day (72 hours after incubation), 50 μL of CTG reagent was added to each well. 6. The contents were mixed on an orbital shaker for 5 minutes to facilitate cell lysis. 7. The plate was allowed to incubate at room temperature for 10 minutes to allow the luminescent signal to stabilize.

[0287] Luminescence was recorded using an EnVision Multi Label Reader, and data analysis was performed using GraphPad Prism 8.0.

[0288] I C 50 Concentration response curves were generated using a nonlinear regression model for a sigmoidal concentration response to calculate the IC. The formula for calculating the % of surviving cells is shown below. 50 is automatically generated by GraphPad Prism 8.0.

number

[0289] Results: IC of certain example compounds of the invention 50 The values ​​are provided in Table 1 below. Table 1 shows the IC of Comparative Compound 1. 50 The values ​​are also shown. These results indicate that the tested compounds of the present invention exhibit potent cytotoxic activity. Many of the example compounds were significantly more potent than the comparative compound 1. Table 1: Results of Biological Examples 1 and 2 [Table 5]

[0290] Biological Example 3: Cytotoxicity in additional cell lines The effects of Comparative Compound 1 and specific Example compounds on the survival of various cell lines (LYXFDLBC2835, LYXFDLBC4009, and LYXFDLBC411 (patient-derived xenograft lymphomas), HT1080 (human fibrosarcoma), CA46 (human B-cell lymphoma), RKO (human colon carcinoma), NCI-H1703 (human lung squamous cell carcinoma), MX-1 (human breast carcinoma), DU4475 (human breast carcinoma), LU2511 (human lung large cell undifferentiated carcinoma), LU0884 (human lung squamous cell carcinoma)), Panc-1 (human pancreatic carcinoma), MCF-7 (human breast carcinoma), SW480 (human colon adenocarcinoma), and HCC1806 (human breast ductal carcinoma) were measured using a standard CellTiter-Glo assay (CTG, Promega) as described in Biological Example 2. Compounds that demonstrate efficacy in these assays are believed to be useful as drugs for treating or preventing hyperproliferative disorders such as cancer.

[0291] Results: IC of certain example compounds of the invention 50The values ​​are provided in Table 2 below. Table 2 shows the IC of Comparative Compound 1. 50 1A-2B show percent inhibition values ​​for certain example compounds, comparative compound 1, and cisplatin (as a control) tested in the above specific assays. These results demonstrate that the tested compounds of the present invention exhibit potent cytotoxic activity across a variety of cell lines. The tested example compounds were more potent than comparative compound 1 across a variety of cell lines. Table 2: IC of Comparative Compound 1 and Selected Example Compounds 50 value [Table 6]

[0292] Biological Example 4: Mouse Xenograft Model The in vivo efficacy of certain example compounds was evaluated in a subcutaneous xenograft DOHH-2 lymphoma model using 10 6-8 week old female CB17 / SCID mice. Each mouse was implanted in the right front with DOHH-2 tumor cells (5 x 10) in 0.1 ml of PBS mixed with Matrigel (1:1 PBS:Matrigel) for tumor development. 6 The average tumor diameter was approximately 100-150 mm. 3 Once the tumor volume reached 100 μg / cm, test compound administration was initiated. Compounds were administered either IP (vehicle 10 mM sodium phosphate + 0.2% Tween-80, pH 7.4) or orally (vehicle 15 NaHPO buffer (10 mM) pH 4.5 + 0.2% Tween 80). Tumor volume was measured in two dimensions using calipers, and volume was calculated in mm using the formula: V = (L × W × W) / 2, where V is tumor volume, L is tumor length (largest tumor dimension), and W is tumor width (largest tumor dimension perpendicular to L). 3 It is expressed as:

[0293] Mice were orally administered Example 21 (12.5 or 25 mg / kg) once daily for nine consecutive days (Figure 3). Example 5 was administered intraperitoneally (7 or 20 mg / kg) in cycles consisting of three days of QD administration, followed by a three-day treatment-free period, followed by three more days of QD administration (Figure 4). Example 12 was administered intraperitoneally (0.7 or 2 mg / kg) in cycles consisting of three days of QD administration, followed by a three-day treatment-free period, followed by three more days of QD administration (Figure 5). In another study, Example 12 was administered at 2 mg / pk in cycles consisting of two days of QD administration, followed by either a four-day or six-day treatment-free period, and this cycle was repeated three times (Figure 6).

[0294] The protocol and any amendments or procedures for the care and use of animals in this study were reviewed and approved by CrownBio's Institutional Animal Care and Use Committee (IACUC) prior to implementation. During the study, animal care and use was conducted in accordance with Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) regulations.

[0295] Results: Figures 3-6 show that intraperitoneal administration of Examples 5 and 12 and oral administration of Example 21 resulted in a significant reduction in tumor volume or a reduction in tumor volume growth when compared to vehicle. These results demonstrate that the high in vitro potency of the tested Example compounds in Biological Examples 2 and 3 (especially Examples 12 and 21) translates into high in vivo potency.

[0296] The tested example compounds are therefore believed to be useful as pharmaceuticals, particularly in the treatment of hyperproliferative disorders such as cancer.

[0297] Biological Example 5: Caco-2 Cell Permeability Assay Certain example compounds and Comparative Example 1 were tested for their apical to basolateral (AB) and basolateral to apical (BA) permeability in Caco-2 cells.

[0298] Cell culture: Caco-2 cells were grown for 10 days in 96-well plates in HBSS buffer containing 10 mM HEPES. Both apical and basal pH were buffered at pH 7.4. The apical / basal volumes were 75 μl and 250 μl, respectively. The incubation time was 2.5 h at 37°C (without shaking) under 5% CO2 and 95% relative humidity.

[0299] Cell seeding: Cells were seeded in 96-well plates at 18750 cells / well (membrane area = 0.0804 cm). 2 ) and sown at a density of 1000 kJ / cm.

[0300] AB assay: Add 75 μl of cell suspension to the apical well and 2.5 × 10 cells. 5 The cells were added at a density of 1000 cells / ml. 40 ml of medium was added to the feeder tray. The plate was placed in an incubator (37°C, 5% CO2, and controlled humidity). Caco-2 cells were grown for 10 days with medium changes every other day.

[0301] BA assay: Add 25 μl of cell suspension to the bottom side of the apical well (plate inverted) and inoculate 7.5 × 10 5 Cells were added at a density of 1000 cells / ml. The plate (inverted) was placed in an incubator (37°C, 5% CO2, and 95% relative humidity) for 2 hours. The plate was then turned right-side up. 75 μl of medium was added to the apical well and 40 ml of medium was added to the feeder tray.

[0302] Permeability assay: The apical and basal wells were washed with buffer (pH 7.4), and 250 μl of buffer was added to the wells of the basal plate. 75 μl of compound solution (2 μM, dissolved in 1% DMSO in water) was transferred to the apical wells (n=2). The apical plate was placed on top of the basal plate. A lid was placed on top to prevent evaporation. The assembly was incubated at 37°C under 5% CO2 and 95% relative humidity for 2.5 hours (without shaking). After incubation, the apical plate was separated from the basal plate. Aliquots were removed from the acceptor and donor wells, diluted, and quantified, along with the initial donor sample, using LC-MS / MS.

[0303] Membrane integrity test: The solution in the apical wells was discarded by inverting the plate and dipping it into tissue paper. 250 μl of buffer (pH 7.4) was added to each well of the basal plate, and 75 μl of Lucifer Yellow (LY; 0.1 mg / ml) in buffer (pH 7.4) was added to the wells of the apical plate. The apical plate was placed on top of the basal plate, and a lid was used to prevent evaporation. The assembly was incubated at 37°C under 5% CO2 and 95% relative humidity for 1 hour (without shaking). The apical plate was separated from the basal plate. The fluorescence (Ex: 432 nm, Em: 530 nm) of an aliquot (100 μl) was measured from the basal well. The fluorescence of 100 μl of buffer (pH 7.4) and 100 μl of LY (0.1 mg / ml) was also measured. Wells with a fluorescence intensity of just over 1% for 0.1 mg / ml LY were considered to have incomplete membranes, and such wells were not considered for calculation of permeability, if any.

[0304] Calculation: Drugs were detected and quantified by LC-MS / MS. The data generated took the form of apparent permeability (Papp) values. Papp = [Va / (area x time)] x (LC-MS area of ​​acceptor sample x sample dilution factor / LC-MS area of ​​initial donor). Va = volume of acceptor well (in ml) = 0.25, Vd = volume of donor well (in ml) = 0.075, Area = surface area of ​​membrane (cm2) = 0.0804, Time = incubation time (sec) = 9000

[0305] Results: The results of the assay are shown in Table 3 below. The results indicate that many of the tested Example Compounds are more permeable to cells in this assay than Comparative Compound 1. Therefore, it is believed that the tested Example Compounds, or at least some of them, have better bioavailability than Comparative Compound 1.

[0306] Biological Example 6: Rat Hepatocyte Half-Life Certain example compounds and comparative compound 1 were tested for metabolic stability in a metabolic assay using hepatocytes derived from mice and rats. Compounds with good metabolic stability in this assay are considered to be particularly useful as drugs for preventing and / or treating cancer by having a long half-life in human patients.

[0307] Frozen pooled rat and mouse hepatocytes obtained from Life Technologies were thawed and purified according to the manufacturer's instructions. Test compounds (4 mM) in DMSO were diluted with acetonitrile to provide 100 μM substocks, which were then further diluted with Krebs-Henseleit buffer, pH 7.4 (supplemented with CaCl, NaHCO, HEPES, fructose, and glycine) to provide 2 μM working solutions. 25 μL of the working solution was incubated at 37 °C and 25 μL of (1 × 10) PBS was added. 6Plates were treated with rat or mouse hepatocyte suspensions (containing 1000 cells / mL) and incubated at 37°C with 95% relative humidity and 5% CO2. Wells were incubated for the appropriate time (0, 15, 30, 45, 60, and 75 minutes) and then quenched with 250 μL of acetonitrile containing reference standards (diltiazem, 7-ethoxycoumarin, and propranolol). Plates were shaken and sonicated for 5 minutes, then cooled to 4°C until all sampling was complete. All plates were centrifuged at 4000 rpm for 20 minutes to pellet debris. 110 μL of supernatant was diluted with 110 μL of water and quantified using LC-MS / MS.

[0308] The results were used to calculate % test compound remaining at time t = 100 x ~[(AUC at time t) / (AUC at T = 0)]. A linear regression curve was fitted to the plot of the natural logarithm (ln) of AUC versus time: T - half-life (min) = 0.693 / slope.

[0309] Results: The results of Biological Example 6 are shown in Table 3 below. The results demonstrate that certain example compounds exhibit lower metabolic stability than Comparative Compound 1. The combination of high in vitro and in vivo potency (as outlined in Biological Examples 2-4) and lower metabolic stability is believed to make the compounds of the invention, or at least some of them, more suitable than Comparative Compound 1 for certain applications, such as as payloads for antibody drug conjugates. Table 3: Results of Biological Examples 5 and 6 [Table 7]

[0310] Biological Example 7: Orthotopic Breast Cancer Xenograft Model The day before tumor inoculation, NOD / SCID mice were subcutaneously implanted with an estrogen pellet (17β-estradiol, 60-day release, 0.36 mg) in the right flank. Then, on day -8, each mouse received 1 × 10 Estrogen pellets resuspended in 0.2 mL of phosphate-buffered saline (PBS) mixed with Matrigel (1:1) in the right mammary fat pad.7 Each mouse was injected with live BT474 breast cancer cells. The tumor volume averaged 149.78 mm on day 0 of the study. 3 When the tumor volume reached 1000 mg / kg, the mice were assigned to a treatment group. Dosing began the following day, with all animals receiving intravenous administration of trastuzumab, Example 12, or ADC Example 1. The study was terminated on study day 35. Mice were administered once weekly for 4 weeks with either vehicle alone (Group 1), 2.5 mg / kg trastuzumab (Group 2), 5 mg / kg trastuzumab (Group 3), 2.5 mg / kg ADC Example 1 (Group 4), or 5 mg / kg ADC Example 1 (Group 5), or 2 mg / kg Example 12 for 2 days followed by a 5-day rest period (Group 6). Each group consisted of 10 mice. Tumor volumes in the mice were measured 3 times weekly and calculated using the formula 0.5(L×W 2 Tumor volumes were calculated using the Statistical Model (SEM). The mean tumor volumes (+SEM) for each test group at each measurement time are plotted with the last observation carried forward in Figures 7 and 8. Statistical analysis was performed on tumor readings for Groups 1, 2, 3, 4, and 5 through study day 23 (after which time point, >50% of animals in one of the test groups died; Group 2) using a two-way ANOVA, or, if values ​​were missing from a group, a mixed-effects model was fitted (PRISM GraphPad Software). Statistical analysis for Group 6 was performed through day 12 (at which point the study was terminated due to the significant loss of body weight observed). Using ROUT outlier analysis in GraphPad Prism, one mouse in Group 5 was identified as an outlier (at a 5% confidence level) across all time points and was therefore excluded from the analysis.

[0311] Tumor growth inhibition, ΔTGI% = ((mean(C) - mean(C0)) - (mean(T) - mean(T0))) / (mean(C) - mean(C0)) x 100%, where T is the mean tumor volume on the day of measurement, and T0 is the mean tumor volume of the treatment group on day 0 of the study. C is the mean tumor volume of the control Group 1 mice on the day of measurement, and C0 is the mean tumor volume on day 0 of the study.

[0312] All animals were weighed three times a week during the study. Animals were fed Diet Gel throughout the study. The average body weights of each group during the treatment period are presented in Figures 9 and 10.

[0313] (result) The results of treatment with trastuzumab alone or ADC Example 1 on tumor size are shown in Table 4 as percent tumor growth inhibition and in Figures 7 and 8 as tumor volume (mm 3 7 and 8 also show tumor volumes in mice treated with Example 12 alone, however, the study was terminated early due to significant weight loss observed in the treatment group. Table 4: Tumor growth inhibition [Table 8]

[0314] Mice treated with 2.5 mg / kg ADC Example 1 (Group 4) had significantly reduced tumor volume compared to animals treated with 2.5 mg / kg trastuzumab (Group 2; p<0.0001) (Figure 7). Furthermore, animals treated with 5.0 mg / kg ADC Example 1 (Group 5) had significantly reduced tumor volume compared to animals treated with 5 mg / kg trastuzumab (Group 3; p<0.0001) (Figure 8). Mice treated with 5.0 mg / kg ADC Example 1 (Group 5) had significantly reduced tumor volume compared to animals treated with 2.5 mg / kg ADC Example 1 (Group 4; p<0.0001) (see Table 4). Mice treated with ADC Example 1 at 5.0 mg / kg (Group 5) had significantly reduced tumor volume compared to animals treated with Example 12 at 2.0 mg / kg. Mice treated with Example 12 at 2.0 mg / kg (Group 6) had reduced tumor size (see Figures 7 and 8), but the study was stopped on Day 13 due to a significant decrease in observed body weight in this study group. ADC Example 1 administered at 2.5 mg / kg was approximately equally effective at that time compared to Example 12 (Group 4, see Figure 7), while ADC Example 1 administered at 5.0 mg / kg was more effective (Figure 8). The dose of Example 12 delivered when administered as ADC Example 1 administered at 2.5 mg / kg was approximately 100-fold less than Example 12 administered alone, meaning that ADC Example 1 is approximately 100-fold more potent in vivo than Example 12.

[0315] The effect of treatment with trastuzumab alone, Example 12 alone, or ADC Example 1 on mouse body weight is shown in Figures 9 and 10. Mice treated with trastuzumab or ADC Example 1 were not significantly different from vehicle controls, but mice in Group 6 (Example 12) lost weight significantly (Figures 9 and 10), after which the study was terminated early due to the marked decrease in observed body weight.

[0316] Biological Example 8: Gastric Cancer Xenograft Model The objective of this study was to preclinically evaluate the in vivo therapeutic efficacy of an antibody-drug conjugate (ADC Example 1) in treating a subcutaneous NCI-N87 human gastric xenograft model in female BALB / c nude mice.

[0317] In this study, 143 mice were injected with 1 × 10 cells resuspended in 0.1 mL of PBS (1:1) mixed with Matrigel into the right flank for tumor development. 7 102 mice were inoculated subcutaneously with live NCI-N87 tumor cells. Tumor volumes averaged 168.08 mm on day 0 of the study. 3 When the mice reached the maximum dose, they were assigned to one of nine treatment groups. The next day, dosing began, and animals were intravenously administered vehicle control, trastuzumab, ADC Example 1, trastuzumab deruxtecan, and an isotype control antibody conjugated to NMT inhibitor 1 (isotype control). The study was terminated on study day 28. Mice were administered once weekly for two weeks with either vehicle control (Group 1), 2.5 mg / kg trastuzumab (Group 2), 5 mg / kg trastuzumab (Group 3), 2.5 mg / kg ADC Example 1 (Group 4), 5 mg / kg ADC Example 1 (Group 5), 2.5 mg / kg trastuzumab deruxtecan (Group 6), 5 mg / kg trastuzumab deruxtecan (Group 7), or 5 mg / kg isotype control antibody (Group 8). Table 5: Summary of dosing regimens [Table 9]

[0318] Tumor volumes were measured in mice three times a week, and tumor volume was calculated using the formula 0.5(L×W2). The mean tumor volume (+SEM) for each test group at each measurement is shown in Figures 11 and 12.

[0319] Tumor growth inhibition, ΔTGI%=((Mean(C)-Mean(C0))-(Mean(T)-Mean(T0))) / (Mean(C)-Mean(C0)) *100% where T is the mean tumor volume of the treatment group on the day of measurement, T0 is the mean tumor volume on day 0 of the study, C is the mean tumor volume of the control group 1 mice on the day of measurement, and C0 is the mean tumor volume on day 0 of the study.

[0320] All animals were weighed three times weekly during the study. Animals were given Diet Gel throughout the study. The mean body weights for each group during the treatment period are presented in Figures 13A (2.5 mg / kg) and 13B (5 mg / kg).

[0321] (result) Significant weight loss (>10%) was observed in 3 of 10 animals in Group 1 (vehicle control), 1 animal in Group 2 (2.5 mg / Kg trastuzumab), and 1 animal in Group 3 (5 mg / Kg trastuzumab); all mice regained weight by the next measurement. No significant weight loss was observed in any of the other groups.

[0322] A significant reduction (p<0.0001) in tumor volume was observed in mice treated with trastuzumab, ADC Example 1, and trastuzumab deruxtecan at all concentrations (2.5 mg / kg or 5 mg / kg) when compared to vehicle alone (Group 1). The isotype control ADC (Group 8; p=0.7935) showed no significant difference compared to vehicle alone (Group 1).

[0323] Mice treated with 5 mg / kg trastuzumab (Group 3; p<0.0001) and 5 mg / kg ADC Example 1 (Group 5; p<0.0001) showed significantly reduced tumor volume compared to mice treated with 2.5 mg / kg trastuzumab (Group 2). Mice treated with 2.5 mg / kg trastuzumab deruxtecan (Group 6; p<0.0001) and isotype control-ADC (Group 8; p<0.0001) showed significantly larger tumor volumes compared to Group 2 (2.5 mg / kg trastuzumab). There was no significant difference between ADC Example 1 at 2.5 mg / kg (Group 4; p=0.8757) and trastuzumab deruxtecan at 5 mg / kg (Group 7; p=0.9965) compared to trastuzumab at 2.5 mg / kg (Group 2).

[0324] Mice treated with 5 mg / kg ADC Example 1 (Group 5; p<0.0001) showed a significant reduction in tumor volume compared to 5 mg / kg trastuzumab (Group 3). There was no significant difference between Group 3 (5 mg / kg trastuzumab) and Group 4 (2.5 mg / kg ADC Example 1). Otherwise, all other groups (Groups 6-8) had significantly larger tumor volumes compared to Group 3 (5 mg / kg trastuzumab).

[0325] Mice treated with 5 mg / kg ADC Example 1 (Group 5; p<0.0001) showed a significant reduction in tumor volume compared to 2.5 mg / kg ADC Example 1 (Group 4). There was no significant difference between Groups 4 and 7 (5 mg / kg trastuzumab deruxtecan, p=0.9932). Otherwise, all other groups (Groups 6 and 8) had significantly larger tumor volumes compared to Group 4 (2.5 mg / kg ADC Example 1).

[0326] Mice in Group 5, treated with 5 mg / kg ADC Example 1, had significantly smaller tumor volumes compared to all other groups (p<0.0001).

[0327] Mice treated with 5 mg / kg trastuzumab deruxtecan (Group 7, p<0.0001) showed a significant reduction in tumor volume compared to 2.5 mg / kg trastuzumab deruxtecan (Group 6). Group 8 showed significantly larger tumor volumes compared to Group 6 (p<0.0001).

[0328] Mice treated with isotype control-ADC (Group 8; p<0.0001) had significantly larger tumor volumes compared to Group 7 (5 mg / kg trastuzumab deruxtecan).

[0329] Increased tumor growth inhibition (TGI) compared to the vehicle group (Group 1) was evident in all treatment groups except Group 8. Treatment with 5.0 mg / kg ADC Example 1 was the most effective when comparing tumor growth inhibition of all treatment groups (Group 5; TGI=224.01%).

[0330] TGI = (mean tumor volume of vehicle group - mean tumor volume of treatment group) / (mean tumor volume of vehicle group - mean initial tumor volume) x 100

[0331] Biological Example 9: LNCaP Prostate Xenograft Model The purpose of this study was to evaluate the efficacy of ADC Example 4 in male NOD SCID mice bearing LNCaP tumors.

[0332] A total of 84 male NOD SCID mice, 5-8 weeks old and weighing 25-30 g, were used in the study. 1 × 10 mice were cultured at 78% survival rate and approximately 70-80% confluency. 7 LNCaP tumor cells were implanted subcutaneously into the flanks of male NOD SCID mice. Tumors grew to approximately 80–100 mm. 3 When tumors reached 100% tumor volume, the animals were assigned to treatment groups shown in Table 6 below, with 10 mice per group assigned to groups with similar tumor volume means and distributions. Mice were treated with vehicle alone, unconjugated ifinatamab, ifinatamab-deruxtecan (ifinatamab-DXd), or ADC Example 4. Table 6: Dosing regimen for Biological Example 11 [Table 10] Observation period: 35 days Dosage volume: 5 mL / kg for all IV doses

[0333] No adverse responses were observed to any dose during the course of the study, and the mean body weight of each group remained within 10% of pre-treatment levels (Figure 15).

[0334] Individual cases of weight loss >10% were observed at various time points throughout the study. Three weeks after the first animals entered treatment, all mice were offered DietGel to ameliorate weight loss. No animals were euthanized early due to weight loss, and these instances of weight loss were likely related to tumor burden.

[0335] Animals receiving three Q7D doses of 10 mg / kg ADC Example 4 exhibited significantly higher mean body weights than animals receiving vehicle control treatment on Study Day 28 (Dunnett's One-Way Anova, p=0.0046). No other treatment groups were significantly different from vehicle in terms of body weight at this time point.

[0336] Two animals were euthanized early due to welfare concerns. One was euthanized on day 26 of treatment with 10 mg / kg ifinatamab, while the second was euthanized on day 33 of treatment with 5 mg / kg ifinatamab-DXd. Both animals were euthanized primarily due to gasping for breath. At necropsy for each, large spontaneous thymic tumors were noted.

[0337] Tumors in the vehicle-treated group grew steadily over the course of the study, reaching a size of 752 ± 89.4 mm by study day 28. 3 reached an average volume of

[0338] Treatment with either 10 mg / kg or 5 mg / kg ifinatamab had no significant effect on LNCaP tumor volume at day 28, and animals receiving this treatment exhibited tumor growth curves similar to those of animals treated with vehicle alone (Figure 14, Table 7).

[0339] Treatment with 10 mg / kg ifinatamab-DXd significantly reduced the mean volume of LNCaP tumors by day 28 compared to vehicle controls. Animals receiving this treatment mostly exhibited a slower tumor growth rate than control animals. A dosage of 5 mg / kg ifinatamab-DXd did not significantly slow LNCaP tumor growth (Figure 14, Table 7).

[0340] All animals receiving 10 mg / kg ADC Example 4 showed tumor regression within 3 weeks of initiating treatment (Figure 14, Table 7), and this therapy resulted in a significant reduction in mean tumor volume (Mann-Whitney) compared to vehicle from Day 7 onwards. By Day 28, each tumor had regressed to ≤25% of its volume at the start of treatment.

[0341] Similarly, animals receiving 5 mg / kg of ADC Example 4 showed a significant reduction in tumor volume (Mann-Whitney) from day 7 to day 28 compared to the control group (Figure 14, Table 7). By day 28, all but one animal exhibited lower tumor volumes than those recorded at the start of treatment. Table 7. Tumor volume comparison of treatment groups. Adjusted p-values ​​calculated by Kruskal-Wallis test and Dunn's multiple comparisons against vehicle control. [Table 11]

[0342] Biological Example 10: VCaP Prostate Cancer Xenograft Model The objective of this study was to preclinically evaluate the in vivo therapeutic efficacy of ADC Example 4 in treating a subcutaneous VCaP human prostate cancer xenograft model in intact male CB17 / SCID mice.

[0343] In this study, 144 mice were injected into the right anterior flank with 1 × 10 mice resuspended in 0.1 mL of PBS (1:1) mixed with Matrigel for tumor development. 7 Live VCaP tumor cells were inoculated subcutaneously on day -20 of the study. The tumor volume averaged approximately 162.16 mm on day 0 of the study. 3 When the study population reached 100, 80 mice were assigned to eight treatment groups. The following day, dosing began, and all animals received intravenous administration of ADC Example 4, ifinatamab-deruxtecan (ifinatamab-Dxd), or unconjugated ifinatamab. All mice received two doses of study drug, on Study Day 1 and Study Day 8. The study ended on Study Day 30.

[0344] The eight groups were assigned as follows: Group 1: Vehicle control Arm 2: 5mpk unconjugated ifinatamab Group 3: 2.5mpk unconjugated ifinatamab Group 4: 5mpk ifinatamab-deruxtecan Group 5: 2.5mpk ifinatamab-deruxtecan Group 6 10mpk ADC Example 4 Group 7 5mpk ADC Example 4 Group 8 2.5mpk ADC Example 4

[0345] No significant weight loss was observed in any of the animals tested (Figure 17).

[0346] A significant reduction (p<0.0001) in tumor volume was observed in mice treated with all concentrations of ADC Example 4 (Group 8, 2.5 mg / kg; Group 7, 5 mg / kg; and Group 6, 10 mg / kg) compared to vehicle alone (Group 1). Ifinatamab-Dxd at 5 mg / kg (Group 4; p=0.0078) exhibited significantly higher tumor volumes compared to vehicle alone (Group 1), whereas ifinatamab-Dxd at 2.5 mg / kg (Group 5; p=0.8127) and both concentrations of unconjugated ifinatamab (Group 2; p=0.1104 and Group 3; p=0.6703) did not exhibit significant differences compared to vehicle alone (Group 1). See Figure 16.

[0347] Mice treated with all three concentrations of ADC Example 4 (Group 6, 10 mg / kg; Group 7, 5 mg / kg, and Group 8, 2.5 mg / kg) showed significant reductions in tumor volume compared to all other treatment groups (Groups 2-5; p<0.0001). There was also evidence of a dose response, with the greatest tumor volume reductions in Group 6 (10 mg / kg), followed by Group 7 (5 mg / kg), and then Group 8 (2.5 mg / kg); significant differences were observed between each group (p<0.0001). See Figure 16.

[0348] No significant differences in tumor volume were observed between mice treated with 2.5 mg / kg ifinatamab-Dxd (Group 5) and mice treated with Groups 2, 3, and 4 (5 mg / kg unconjugated ifinatamab, 2.5 mg / kg unconjugated ifinatamab, and 5 mg / kg ifinatamab-Dxd, respectively). Mice treated with 5 mg / kg ifinatamab-Dxd (Group 4) had significantly larger tumor volumes compared to mice treated with 5 mg / kg unconjugated ifinatamab (Group 2, p=0.0002) and 2.5 mg / kg unconjugated ifinatamab (Group 3, p=0.0216). See Figure 16.

[0349] An increase in tumor growth inhibition (ΔTGI) compared to the vehicle group (Group 1) was evident in all treatment groups. When comparing tumor growth inhibition across all treatment groups, treatment with 10 mg / kg and 5 mg / kg ADC Example 4 was most effective (Group 6; ΔTGI = 114.03% and Group 7; ΔTGI = 114.69%). See Table 8. Table 8. Dosing regimen and results for Biological Example 10 [Table 12]

[0350] Biological Example 11: JIMT-1 Breast Cancer Xenograft Model The objective of this study was to preclinically evaluate the in vivo therapeutic efficacy of ADC Example 3 in treating a subcutaneous JIMT-1 human breast xenograft model in female NOD / SCID mice.

[0351] In this study, 128 mice were injected with 5 × 10 , resuspended in 0.1 mL of PBS, into the right anterior flank for tumor development. 6 Live JIMT-1 tumor cells were subcutaneously inoculated on day 15 of the study. The tumor volume was approximately 160.66 mm on average on day 0 of the study. 3 When the mice reached 60 days old, 80 mice were assigned to eight treatment groups. The next day, dosing began and all animals received ADC Example 3, sacituzumab govitecan, or unconjugated sacituzumab intravenously. The study ended on Study Day 60. The eight groups were assigned as follows: Group 1: Vehicle control Arm 2: 5mpk unconjugated sacituzumab Arm 3: 2.5mpk unconjugated sacituzumab Group 4 5 mg / kg sacituzumab govitecan (ADC Example 3, 5 mg / kg added on days 27 and 34) Group 5: 2.5 mg / kg sacituzumab govitecan (ADC Example 3, 5 mg / kg added on day 27) Group 6 10mpk ADC Example 3 Group 7 5mpk ADC Example 3 Group 8 2.5mpk ADC Example 3

[0352] Significant weight loss (>10%) was observed in one animal in Group 7. No significant weight loss was observed in any of the other groups tested (see Figures 20 and 21). On day 10 of the study, one animal in Group 2 was found dead.

[0353] When compared with vehicle alone (Group 1), mice treated with all concentrations of ADC Example 3 (Group 8, 2.5 mg / kg; Group 7, 5 mg / kg, and Group 6, 10 mg / kg) showed significant reductions in tumor volume (p<0.0001). Both concentrations of sacituzumab govitecan (Group 4, 5 mg / kg, p<0.0001; Group 5, 2.5 mg / kg, p=0.0348) showed significant reductions in tumor volume compared with vehicle alone (Group 1). When compared with vehicle alone (Group 1), unconjugated sacituzumab in Group 2 (5 mg / kg, p=0.0028) showed significant reductions in tumor volume, but no significant difference was seen in Group 3 (2.5 mg / kg, p=0.0586). Data for the 5 mg / kg and 10 mg / kg groups are shown in Figure 18. Data for the 2.5 mg / kg group are shown in Figure 19.

[0354] Mice treated with all three concentrations of ADC Example 3 (Group 6, 10 mg / kg; Group 7, 5 mg / kg, and Group 8, 2.5 mg / kg) showed significant reductions in tumor volume compared to all other treatment groups (Groups 2-5; p<0.0001). There was also evidence of a dose response, with Groups 6 (10 mg / kg) and 7 (5 mg / kg) showing the greatest tumor volume reductions (p<0.0001) compared to Group 8 (2.5 mg / kg).

[0355] Sacituzumab govitecan at 5 mg / kg in Group 4 demonstrated significant reductions in tumor volume compared with unconjugated sacituzumab in Groups 2 (5 mg / kg, p = 0.0097) and 3 (2.5 mg / kg, p = 0.0499), but no significant differences were observed between Group 5 (2.5 mg / kg sacituzumab govitecan) and Groups 2 (p = 0.8424) or 3 (p = 0.9995). There was also no significant difference between the two concentrations of unconjugated sacituzumab in Groups 2 (5 mg / kg) and 3 (2.5 mg / kg) (p = 0.9837). However, there was a significant difference between the two concentrations of sacituzumab govitecan in Groups 4 (5 mg / kg) and 5 (2.5 mg / kg) (p = 0.3802).

[0356] An increase in tumor growth inhibition (ΔTGI) compared to the vehicle group (Group 1) was evident in all treatment groups. When comparing tumor growth inhibition across all treatment groups, treatment with 10 mg / kg and 5 mg / kg ADC Example 3 was most effective (Group 6: ΔTGI=121.55% and Group 7: ΔTGI=122.04%).

[0357] Because treatment with sacituzumab govitecan was only partially effective in Group 4, additional doses of ADC Example 3 were administered IV at 5 mpk on Study Days 27 and 34. This resulted in a significant reduction in tumor volume compared to vehicle controls (see Figure 18). Group 5 also received ADC Example 3 (5 mpk IV) on Study Day 27 (see Figure 19), but no significant response was observed. Table 9. Dosing regimen and results for Biological Example 11 [Table 13] QW = Once a week

[0358] Conclusion: The results of Biological Examples 1 and 2 demonstrate that the tested compounds of the present invention are highly potent inhibitors of human NMT1 and exhibit potent cytotoxic activity in cancer cell lines. Biological Example 3 demonstrates that the tested compounds of the present invention exhibit potent activity in a variety of cancer cell lines. The results of Biological Example 4 demonstrate that the tested compounds of the present invention reduce tumor volume increase or significantly reduce tumor volume compared to vehicle. Biological Example 5 demonstrates that the tested compounds of the present invention exhibit improved cell permeability compared to Comparative Compound 1. Biological Example 6 demonstrates that the tested compounds of the present invention have a better metabolic stability profile for specific purposes than Comparative Compound 1. Biological Example 7 demonstrates that the tested example compounds are effective payloads for ADCs and, as ADCs, reduce tumor growth in vivo in breast cancer xenograft models without adverse effects on body weight. The results of Biological Example 8 further demonstrate that the tested example compounds are effective payloads for ADCs and, as ADCs, reduce tumor growth in vivo in gastric cancer xenograft models without adverse effects on body weight.

[0359] The results of Biological Example 9 show that ADC Example 4 was well tolerated in mice at both 5 mg / kg and 10 mg / kg doses in the LNCaP prostate cancer xenograft model. Animals receiving these doses of ADC Example 4 showed significant reductions in tumor volume, unlike treatment with ifinatamab alone, which had no significant effect on tumor volume. ADC Example 4 also performed better than ifinatamab-DXd at both doses.

[0360] The results of Biological Example 10 show that ADC Example 4 was well tolerated in mice at doses of 2.5 mg / kg, 5 mg / kg, and 10 mg / kg in a VCaP human prostate cancer xenograft model. ADC Example 4 reduced tumor volume to a greater extent than infinatamab-Dxd and unconjugated infinatamab. In fact, the use of unconjugated infinatamab showed no significant difference compared to vehicle alone. ADC Example 4 produced the greatest increase in tumor growth inhibition compared to the control (see Table 8).

[0361] The results of Biological Example 11 show that ADC Example 3 was well tolerated in mice at doses of 2.5 mg / kg, 5 mg / kg, and 10 mg / kg in the JIMT-1 human breast xenograft model. Mice treated with all three concentrations of ADC Example 3 showed significant reductions in tumor volume compared to all other treatment groups, as also shown by the ΔTGI results in Table 9, where ADC Example 3 produced the greatest tumor growth inhibition.

[0362] The compounds of the present invention are therefore believed to be useful pharmaceutical agents, particularly for the treatment or prevention of hyperproliferative disorders such as cancer.

[0363] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a specified integer, step, group of integers, or group of steps, but not the exclusion of any other integer, step, group of integers, or group of steps.

[0364] All patents and patent applications referred to herein are incorporated by reference in their entirety.

Claims

1. A compound of formula (I): or a salt and / or solvate thereof 【Chemical 1】 (In the formula: R 1 is a group of formula OLA; L is -(CHR 12 ) m - and; Each R 12 are independently H or C 1-4 is alkyl; m is 1, 2, or 3; A is, 【Chemistry 2】 : and v is 0, 1, or 2; R 9a is H, C 1-4 Alkyl, or C 1-4 is haloalkyl; R 9b is H, C 1-4 Alkyl, or C 1-4 is haloalkyl; R 9c is C 1-4 Alkyl or C 1-4 is haloalkyl; R 9d is H, C 1-4 Alkyl, or C 1-4 is haloalkyl; R 10 is H, C 1-4 Alkyl, or C 1-4 is haloalkyl; R 11 H, halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; s is 0, 1, 2, or 3; Each R 2 are independently F, Cl, Br, OCH 3 , OCF 3 or C optionally substituted with up to three halogen groups 1-4 is alkyl; Y is CH or C 1-4 is alkyl; R 3 is H or C 1-4 is alkyl; R 4 is H or C 1-4 is alkyl; R 5 is H or C 1-4 is alkyl; R 6 is H or C 1-4 is alkyl; q is 0 or 1; R 7 is H or methyl; R 8 is H or methyl; or R 3 and R 5 and an intervening atom, the intervening atom and a bond, or the intervening atom and -(CHR a ) r -, or R 7 group and the R 5 The group and the intervening atom are separated by a -(CHR a ) r -, forming a 3- to 7-membered non-aromatic heterocycle consisting of; r is 1, 2, 3, 4, or 5; and R a is hydrogen or methyl).

2. 2. The salt and / or solvate according to claim 1.

3. 3. The salt and / or solvate according to claim 2, which is a pharmaceutically acceptable salt and / or solvate.

4. 3. The salts and solvates of claim 2, which are pharmaceutically acceptable solvates of said pharmaceutically acceptable salts.

5. 3. The salt of claim 2, which is a pharmaceutically acceptable salt.

6. 3. The solvate of claim 2, which is a pharmaceutically acceptable solvate.

7. The compound of claim 1.

8. Each R 12 The compound according to any one of claims 1 to 7, or a salt and / or solvate thereof, wherein is H.

9. The compound, salt and / or solvate thereof according to any one of claims 1 to 8, wherein m is 2.

10. The compound, salt and / or solvate thereof according to any one of claims 1 to 9, wherein v is 0.

11. R 9c But C 1-4 11. The compound according to any one of claims 1 to 10, wherein the alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, or tert-butyl, such as methyl, iso-propyl, or tert-butyl, a salt and / or solvate thereof.

12. R 9c 12. The compound, salt and / or solvate thereof according to claim 11, wherein is methyl.

13. R 9c 12. The compound, salt and / or solvate thereof according to claim 11, wherein is iso-propyl.

14. R 9c The compound, salt and / or solvate thereof according to claim 11, wherein is tert-butyl.

15. R 9d The compound according to any one of claims 1 to 14, or a salt and / or solvate thereof, wherein is H.

16. R 9d C 1-4 15. The compound according to any one of claims 1 to 14, a salt and / or solvate thereof, wherein alkyl is, for example, methyl.

17. R 9c is tert-butyl and R 9d The compound according to any one of claims 1 to 10, or a salt and / or solvate thereof, wherein is H.

18. R 9c is methyl and R 9d The compound, salt and / or solvate thereof according to any one of claims 1 to 10, wherein is methyl.

19. R 10 C 1-4 19. The compound according to any one of claims 1 to 18, a salt and / or solvate thereof, wherein alkyl is, for example, methyl.

20. R 11 C 1-4 20. The compound according to any one of claims 1 to 19, a salt and / or solvate thereof, wherein alkyl is, for example, methyl.

21. 21. The compound, salt and / or solvate thereof according to any one of claims 1 to 20, wherein s is 1.

22. 21. The compound, salt and / or solvate thereof according to any one of claims 1 to 20, wherein s is 2.

23. At least one R 2 23. The compound according to any one of claims 1 to 22, wherein is halo, such as Cl, F, or Br, such as Cl or F, in particular F, a salt and / or solvate thereof.

24. 24. The compound, salt and / or solvate thereof according to any one of claims 1 to 23, wherein Y is CH.

25. R 3 The compound according to any one of claims 1 to 24, or a salt and / or solvate thereof, wherein is H.

26. R 4 The compound according to any one of claims 1 to 25, or a salt and / or solvate thereof, wherein is H.

27. R 5 The compound according to any one of claims 1 to 26, or a salt and / or solvate thereof, wherein is H.

28. R 5 C 1-4 27. The compound according to any one of claims 1 to 26, a salt and / or solvate thereof, wherein alkyl is, for example, methyl.

29. R 6 The compound according to any one of claims 1 to 28, or a salt and / or solvate thereof, wherein is H.

30. R 6 C 1-4 29. The compound according to any one of claims 1 to 28, a salt and / or solvate thereof, wherein alkyl is, for example, methyl.

31. R 5 is methyl and R 6 The compound according to any one of claims 1 to 28, or a salt and / or solvate thereof, wherein is H.

32. 32. The compound, salt and / or solvate thereof according to any one of claims 1 to 31, wherein q is 0.

33. 33. The compound according to any one of claims 1 to 32, which is a compound of formula (IA): or a salt and / or solvate thereof 【Chemistry 3】 (In the formula: R 2a is H or F; R 2b is F; R 5a is H or methyl; R 6a is H or methyl; R 9ca is methyl, iso-propyl, or tert-butyl; R 9cb is H or methyl; R 10a is methyl; and R 11a is methyl; However, R 2a When is H, R 9cb is H).

34. R 2a The compound according to claim 33, or a salt and / or solvate thereof, wherein is F.

35. R 5a 35. The compound according to claim 33 or 34, wherein is H, or a salt and / or solvate thereof.

36. R 6a The compound, salts and solvates thereof according to any one of claims 33 to 35, wherein is methyl.

37. R 9cb The compound according to any one of claims 33 to 36, its salts and solvates, wherein is H.

38. R 9ca is tert-butyl and R 9cb The compound according to any one of claims 33 to 36, its salts and solvates, wherein is H.

39. R 9ca is methyl and R 9cb The compound, salt, and solvate thereof according to any one of claims 33 to 36, wherein is methyl.

40. 1-{4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}ethan-1-ol; 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol; (Isomer 1) 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol; (Isomer 2) 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol; 1-{4-[2-(2,3-difluoro-6-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}ethan-1-ol; 1-(4-(2-(6-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol; 1-(4-(2-(2-(3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol; 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 1) 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 2) 1-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 1) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 2) 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 1) 1-(4-(2-(6-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; (Isomer 2) 1-(4-(2-(6-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; 1-(4-(2-(6-(3-(aminomethyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol; 2-(4-(2-(5-fluoro-2-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol; 2-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol; 2-[4-(2-{6-[3-(aminomethyl)imidazo[1,2-a]pyridin-6-yl]-2,3-difluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]propan-2-ol; 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol; 2-{4-[2-(2-{3-[(ethylamino)methyl]imidazo[1,2-a]pyridin-6-yl}-5-fluorophenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}propan-2-ol; 2-(4-(2-(2-(3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol; 1-(4-(2-(2-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-fluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol; and 1-{4-[2-(2,3-difluoro-6-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}-2-methylpropan-1-ol; 2. The compound according to claim 1, or a salt and / or solvate thereof, which is a compound selected from the group consisting of:

41. 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol: 【Chemistry 4】 or a salt and / or solvate thereof according to claim 1.

42. 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol: 【Chemistry 5】 42. The compound according to claim 41, a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of:

43. 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol: 【Chemistry 6】 42. The compound according to claim 41, a pharmaceutically acceptable salt of the compound, a salt and / or a solvate thereof.

44. 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol: 【Chemistry 7】 42. The compound according to claim 41, or a salt and / or solvate thereof, which is a pharmaceutically acceptable solvate of:

45. 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol: 【Chemistry 8】 42. The compound according to claim 41, or a salt and / or solvate thereof, wherein:

46. 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol: 【Chemistry 9】 or a salt and / or solvate thereof according to claim 1.

47. 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol: 【Chemistry 10】 47. The compound according to claim 46, a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of:

48. 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol: 【Chemistry 11】 47. The compound according to claim 46, a pharmaceutically acceptable salt of the compound, a salt and / or a solvate thereof.

49. 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol: 【Chemistry 12】 47. The compound according to claim 46, a pharmaceutically acceptable solvate of the compound, a salt and / or a solvate thereof.

50. 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)propan-2-ol: 【Chemistry 13】 47. The compound according to claim 46, a salt and / or solvate thereof, wherein:

51. s is 2 and each R 2 The compound according to any one of claims 1 to 39, wherein is F, or a salt or solvate thereof.

52. 52. A pharmaceutical composition comprising a compound of any one of claims 2 to 51, a pharmaceutically acceptable salt and / or solvate, and a pharmaceutically acceptable carrier.

53. 52. A compound according to any one of claims 2 to 51, a pharmaceutically acceptable salt and / or solvate thereof, for use as a pharmaceutical.

54. 54. A compound, pharmaceutically acceptable salt and / or solvate according to claim 53 for use in the prevention or treatment of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect.

55. 52. Use of a compound, pharmaceutically acceptable salt and / or solvate according to any one of claims 2 to 51 in the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of human NMT provides a therapeutic or prophylactic effect.

56. 52. A method for treating or preventing a disease or disorder in a subject in which inhibition of human NMT results in a therapeutic or prophylactic effect in the subject, said method comprising administering to said subject a therapeutically effective amount of a compound of any one of claims 2 to 51, a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier.

57. 57. The compound, pharmaceutically acceptable salt and / or solvate for use according to claim 54, the use according to claim 55, or the method according to claim 56, wherein the disease or disorder is selected from the group consisting of a hyperproliferative disorder, a viral infection, a neurological disease, ischemia, osteoporosis, diabetes, an autoimmune disease, an inflammatory disease, and a microbial infection.

58. 58. The compound, pharmaceutically acceptable salt and / or solvate, use, or method for use according to claim 57, wherein said disease or disorder is a hyperproliferative disorder, and said hyperproliferative disorder is cancer.

59. 59. The compound, pharmaceutically acceptable salt and / or solvate, use, or method for use according to claim 58, wherein the cancer is colorectal cancer, gallbladder cancer, brain cancer, lymphoma (e.g., B-cell lymphoma or diffuse large B-cell lymphoma), leukemia (e.g., AML), or neuroblastoma.

60. 59. The compound, pharmaceutically acceptable salt and / or solvate, use, or method of claim 58, wherein the cancer is a hematological malignancy (e.g., lymphoma, in particular B-cell lymphoma (e.g., high-grade mantle zone lymphoma, follicular lymphoma, plasmablastic lymphoma, diffuse large B-cell lymphoma, and Burkitt's lymphoma), myeloma (e.g., multiple myeloma), or leukemia (e.g., chronic lymphocytic leukemia, AML, and B-acute lymphocytic leukemia)), or a solid tumor (e.g., brain cancer, lung cancer, breast cancer, prostate cancer, ovarian cancer, colorectal cancer, gallbladder cancer, kidney cancer, or liver cancer, or a blastoma (e.g., neuroblastoma, retinoblastoma, or glioblastoma)).

61. Compound of formula (II) 【Chemistry 14】 ; - a compound of formula (III): 【Chemistry 15】 (Wherein, P is C 1-4 Alkyl or C 1-4 alkoxy); - a compound of formula (V): 【Chemistry 16】 ; Compound of formula (VI) 【Chemistry 17】 and Compound of formula (VII) 【Chemistry 18】 (Wherein, P is C 1-4 alkoxy); or a salt thereof, for example, a pharmaceutically acceptable salt (where s, q, v, L, A, R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9a , and R 9b is as defined in claim 1) A compound selected from the group consisting of:

62. 52. Use of the compound, salt or solvate thereof according to any one of claims 1 to 51 as a payload for an antibody drug conjugate.

63. 52. An antibody-drug conjugate or a salt thereof comprising the compound according to any one of claims 1 to 51 or a salt and / or solvate thereof as a payload.

64. 64. A salt of the ADC of claim 63.

65. 65. The salt of claim 63 or 64, which is a pharmaceutically acceptable salt.

66. 64. The ADC of claim 63.

67. 67. The ADC or salt thereof of any one of claims 63 to 66, which comprises a linker.

68. The linker has formula (LII): 【Chemistry 19】 (In the formula, 【Chemistry 20】 represents the point of attachment to a chain terminus (e.g., N-terminus) or functional group on an amino acid side chain of the antibody; and 【Chemical 21】 represents the point of attachment to the functional group of the compound, salt and / or solvate thereof according to any one of claims 1 to 51) 68. The ADC or salt thereof of claim 67, having the following structure:

69. The following formula: 【Chemical 22】 (In the formula: Ab is antibody; 【Chemical 23】 represents an NMT inhibitor, for example a compound of formula (I) according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof; and p is an integer from 1 to 10.

69. The ADC or salt thereof of any one of claims 63 to 68, having the following structure:

70. 70. The ADC or salt thereof of claim 69, wherein the antibody binds to HER2.

71. 70. The ADC or salt thereof of claim 69, wherein the antibody binds to CD20.

72. 70. The ADC or salt thereof of claim 69, wherein the antibody binds to Trop-2.

73. 70. The ADC or salt thereof of claim 69, wherein the antibody binds to CD276 (B7-H3).

74. 74. A pharmaceutical composition comprising the ADC of any one of claims 65 to 73, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

75. 75. The ADC of any one of claims 65 to 73, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 74, for use as a pharmaceutical.

76. 75. The ADC of any one of claims 65 to 73, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 74, for use in the treatment or prevention of a hyperproliferative disorder, such as cancer.

77. 52. A drug conjugate, or a salt and / or solvate thereof, comprising a compound of formula (I) according to any one of claims 1 to 51 and a linker, wherein the linker comprises a group capable of forming a covalent bond with a chain terminus (e.g., N-terminus) or a functional group, e.g., a sulfhydryl group, on an amino acid side chain of an antibody.

78. 78. The drug conjugate of claim 77, or a salt and / or solvate thereof, wherein the linker is that of claim 66, or a salt and / or solvate thereof.

79. The drug conjugate has the formula (DC-1): 【Chemistry 24】 or a salt and / or solvate thereof (In the formula, 【Chemistry 25】 is a compound of formula (I), a salt and / or a solvate thereof according to any one of claims 1 to 51 79. The drug conjugate of claim 77 or 78, its salt and / or solvate having the formula:

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