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

Abstract

# imgabs0. The invention relates to compounds of formula (I) and related aspects.

Description

Field of the Invention

[0001] The present invention relates to novel cytotoxic compounds which are or are predicted to be inhibitors of human N-myristoyltransferase (human NMT). The invention also relates in particular to said compounds for use as medicaments, in particular for 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 preventive effect. Background of the Invention

[0003] N-myristoyltransferase (NMT) is a monomeric enzyme ubiquitous in eukaryotes. NMT catalyzes the irreversible co-translational transfer of myristic acid (a saturated 14-carbon fatty acid) from myristoyl-CoA (myr-CoA) to a protein substrate containing an N-terminal glycine, forming an amide bond (Farazi, TA, G. Waksman and J. I. Gordon, J. Biol. Chem., 2001. 276 (43): pp. 39501-39504).

[0004] There are two types of human NMT, human NMT1 (HsNMT1) and human NMT2 (HsNMT2). Inhibition of human NMT has been suggested as a target for the treatment or prevention of various diseases or disorders, such as hyperproliferative disorders (e.g., cancer, e.g., human colorectal cancer, gallbladder cancer, brain tumors, and lymphomas, such as B-cell lymphomas) (Resh MD. 1993. Biochern. Biophys. Acta 1115, 307-22; Bertiaume LG, Beuachamp E, WO2017011907); and viral infections, such as 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 J. 1993. Proc. Natl. Acad. Sci. USA 87:523-27) LP, Killington, RA, Rowlands DJ, Tuthill, TJ, 2008 Journal of Virology 824169-4174; Mousnier A, Bell AS, Swieboda DP, Morales-Sanfrutos J, Perez-DoradoI, Brannigan JA, Newman J, Ritzefeld M, Hutton, JA, Guedan A, Asfor AS, Robinson SW, Hopkins-Navratilova I, Wilkinson AJ, Johnston SL, Leatherbarrow RJ, Tuthill TJ, Solari R, Tate EW 2018Nature Chemistry 10(6)599-606), Corbic Ramljak I, StangerJ, 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. Because NMTs play key roles in protein transport, mediation of protein-protein interactions, stabilization of protein structure, and signal transduction in living systems, inhibition of one or more HsNMT1 and / or HsNMT2 enzymes has the potential to disrupt multi-protein pathways.Although human NMT inhibitors are expected to inhibit both HsNMT1 and HsNMT2, their therapeutic and / or prophylactic activity is believed to derive primarily from inhibition of HsNMT1.The above characteristics are believed to be desirable to reduce the risk of developing resistance, for example in the treatment or prevention of microbial infections and hyperproliferative disorders.

[0005] There are two binding pockets in NMT. ​​One is the myr-CoA binding pocket, and the other is the peptide binding pocket. Most of the NMT inhibitors reported so far target the peptide binding pocket.

[0006] Compounds active as NMT inhibitors have been previously disclosed, see, for example, WO00 / 37464 (Roche), WO2010 / 026365 (University of Dundee), WO2013 / 083991 (Imperial Innovations Ltd.), WO2017 / 001812 (Imperial Innovations Ltd.), WO2020 / 128473 (Imperial College Innovations Ltd.), WO2020 / 128475 (Imperial College Innovations Ltd.) and WO2022 / 058745 (Imperial College Innovations Ltd., etc.). Specific uses of NMT inhibitors have been disclosed, see, for example, WO2022 / 090746 (Imperial College Innovations Ltd., etc.) and WO2022 / 082306 (Pacylex Pharmaceuticals).

[0007] However, there remains a need for additional compounds with cytotoxic activity and human NMT inhibitors, in particular those that combine cytotoxic activity and very potent inhibition of human NMT with favorable pharmacokinetic properties such as cell penetration and / or metabolic stability and an improved therapeutic window.

[0008] Surprisingly, the 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 desirably exhibit other properties suitable for specific therapeutic purposes, such as cell permeability and metabolic stability profiles. These properties are expected to make the compounds of the invention particularly suitable for use as drugs for the treatment or prevention of hyperproliferative diseases such as cancer. Summary of the invention

[0009] In a first aspect, the present invention provides a compound of formula (I):

[0010]

[0011] in:

[0012] R 1 is a group of formula OLA;

[0013] L is -(CHR 12 ) m -;

[0014] Each R 12 are independently H or C 1-4 alkyl;

[0015] m is 1, 2 or 3;

[0016] A is:

[0017]

[0018] v is 0, 1, or 2;

[0019] R 9a H, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0020] R 9b H, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0021] R 9c C 1-4 Alkyl or C 1-4 Haloalkyl;

[0022] R 9d H, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0023] R 10 H, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0024] R 11 H, halogenated, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy;

[0025] s is 0, 1, 2, or 3;

[0026] Each R 2is independently F, Cl, Br, OCH3, OCF3 or C optionally substituted with up to 3 halogen groups 1-4 alkyl;

[0027] Y is CH or C 1-4 alkyl;

[0028] R 3 H or C 1-4 alkyl;

[0029] R 4 H or C 1-4 alkyl;

[0030] R 5 H or C 1-4 alkyl;

[0031] R 6 H or C 1-4 alkyl;

[0032] q is 0 or 1;

[0033] R 7 is H or methyl;

[0034] R 8 is H or methyl;

[0035] or R 3 and R 5 and the atoms therebetween form a bond between the atoms therebetween, or between the atoms therebetween and -(CHR a ) r - a 3- to 7-membered non-aromatic heterocyclic ring; or said R 7 The group and the R 5 The groups and the atoms therebetween form a group consisting of the atoms therebetween and -(CHR a ) r -3 to 7-membered non-aromatic heterocyclic ring;

[0036] r is 1, 2, 3, 4 or 5; and

[0037] R a is hydrogen or methyl;

[0038] or a salt and / or solvate thereof.

[0039] The compound of formula (I) may be provided in the form of a salt and / or a solvate. Suitably, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and / or a solvate. Suitably, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt. Suitably, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt. Suitably, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable solvate. Suitably, the compound of formula (I) may be provided.

[0040] 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.

[0041] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use as a medicament.

[0042] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in treating or preventing a hyperproliferative disorder (eg cancer).

[0043] 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 treating or preventing a hyperproliferative disorder (eg cancer).

[0044] The present invention also provides a method for treating or preventing a hyperproliferative disorder (eg, cancer) 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.

[0045] 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 condition in which inhibition of human NMT provides a therapeutic or preventive effect.

[0046] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating or preventing a disease or condition, wherein the disease or condition is a disease or condition in which inhibition of human NMT provides a therapeutic or preventive effect.

[0047] The present invention also provides a method for treating or preventing a disease or condition 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.

[0048] 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, suitably an additional compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1A : Shows the effect of treatment with Examples 5 and 14 on the percent survival of CA46 cancer cells in vitro compared to Comparative Compound 1 and Cisplatin.

[0050] Figure 1B : Shows the effect of treatment with Examples 5 and 14 on the percent survival of Panc-1 cancer cells in vitro compared to Comparative Compound 1 and Cisplatin.

[0051] Figure 1C : Shows the effect of treatment with Examples 5 and 14 on the percent survival of RKO cancer cells in vitro compared to Comparative Compound 1 and Cisplatin.

[0052] Figure 1D : Shows the effect of treatment with Examples 5 and 14 on the percentage survival of MCF-7 cancer cells in vitro compared to Comparative Compound 1 and Cisplatin.

[0053] Figure 1E : Shows the effect of treatment with Examples 5 and 14 on the percent survival of NCI-H1703 cancer cells in vitro compared to Comparative Compound 1 and Cisplatin.

[0054] Figure 1F : Shows the effect of treatment with Examples 5 and 14 on the percent survival of SW480 cancer cells in vitro compared to Comparative Compound 1 and Cisplatin.

[0055] Figure 1G : Shows the effect of treatment with Examples 5 and 14 on the percent survival of MX-1 cancer cells in vitro compared to Comparative Compound 1 and Cisplatin.

[0056] Figure 1H : Shows the effect of treatment with Examples 5 and 14 on the percent survival of DU4475 cancer cells in vitro compared to Comparative Compound 1 and Cisplatin.

[0057] Fig. 1I : Shows the effect of treatment with Examples 5 and 14 on the percentage survival of HCC1806 cancer cells in vitro compared to Comparative Compound 1 and Cisplatin.

[0058] Figure 2A: shows the effect of treatment with Example 12 compared to Comparative Compound 1 and Cisplatin on the percent survival of LU2511 cancer cells in vitro.

[0059] Figure 2B : Shows the effect of treatment with Example 12 on the percent survival of LU0884 cancer cells in vitro compared to Comparative Compound 1 and Cisplatin.

[0060] Figure 3 : Shows the effect of treatment with Example 21 compared to vehicle on tumor volume in the DOHH2 xenograft model.

[0061] Figure 4 : Shows the effect of treatment with Example 5 on tumor volume compared to vehicle in the DOHH2 xenograft model.

[0062] Figure 5 : Shows the effect of treatment with Example 12 on tumor volume compared to vehicle in the DOHH2 xenograft model.

[0063] Figure 6 : Shows the effect of treatment with Example 12 on tumor volume compared to vehicle in the DOHH2 xenograft model.

[0064] Figure 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.

[0065] Figure 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.

[0066] 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.

[0067] 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.

[0068] Fig.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 isotype control antibody (5 mg / kg) on ​​tumor volume in a mouse gastric cancer xenograft model.

[0069] Fig.12 : Shows the effect of treatment with trastuzumab (5 mg / kg), ADC Example 1 (5 mg / kg), de-trastuzumab (5 mg / kg) and isotype control antibody (5 mg / kg) on ​​tumor volume in a mouse gastric cancer xenograft model.

[0070] Fig.13A : Shown in Biological Example 8 (and Fig.11 , 2.5 mg / kg (mpk)) were used to measure the body weight change of mice after the experiment.

[0071] Fig. 13B : Shown in Biological Example 8 (and Fig.12 , 5 mg / kg (mpk)) were used to measure the body weight change of mice after the experiment.

[0072] Fig.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 mouse LNCaP prostate cancer xenograft model.

[0073] Fig.15 : Shows the effect of treatment on body weight with ifinatumomab (5 mg / kg and 10 mg / kg), ifinatumomab-DXd (5 mg / kg and 10 mg / kg), ADC Example 4 (5 mg / kg and 10 mg / kg), and vehicle control in a mouse LNCaP prostate cancer xenograft model.

[0074] Fig.16 : Shows the effect of treatment with ifinatumomab (5 mg / kg), ifinatumomab-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 the mouse VCaP prostate cancer xenograft model.

[0075] Fig.17: Shows the effect of treatment on body weight with ifinatumomab (5 mg / kg), ifinatumomab-DXd (5 mg / kg), ADC Example 4 (2.5 mg / kg, 5 mg / kg and 10 mg / kg) and vehicle control in the mouse VCaP prostate cancer xenograft model.

[0076] Fig.18 : Shows the effect of treatment on tumor volume with sacituzumab (5 mg / kg), sacituzumab govitecan (5 mg / kg) (plus ADC Example 3 5 mg / kg, added on study days 27 and 34) and ADC Example 3 (5 mg / kg) and vehicle control in the mouse JIMT-1 breast cancer xenograft model.

[0077] Fig.19 : Shows the effect of treatment with sacizumab (2.5 mg / kg), gosartuzumab (2.5 mg / kg, plus ADC Example 3 5 mg / kg, added on study day 27), and ADC Example 3 (2.5 mg / kg) and vehicle control on tumor volume in the mouse JIMT-1 breast cancer xenograft model.

[0078] Fig. 20 : Shows the effect of treatment on body weight in the mouse JIMT-1 breast cancer xenograft model with taciturnumab (5 mg / kg), gosaturnumab (5 mg / kg) (plus ADC Example 3 5 mg / kg, added on study days 27 and 34), and ADC Example 3 (5 mg / kg and 10 mg / kg), and vehicle control.

[0079] Fig.21 : Shows the effect of treatment on body weight with sacizumab (2.5 mg / kg), gosartuzumab (2.5 mg / kg, plus ADC Example 3 5 mg / kg, added on study day 27), and ADC Example 3 (2.5 mg / kg) and vehicle control in the mouse JIMT-1 breast cancer xenograft model.

[0080] Sequence Listing

[0081] SEQ ID NO: 1 - Amino acid sequence of the light chain of trastuzumab

[0082] SEQ ID NO:2 - Amino acid sequence of the heavy chain of trastuzumab

[0083] SEQ ID NO:3 - Amino acid sequence of the light chain of rituximab

[0084] SEQ ID NO:4 - Amino acid sequence of the heavy chain of rituximab

[0085] SEQ ID NO:5 - Amino acid sequence of the light chain of ifinatumomab

[0086] SEQ ID NO:6 - Amino acid sequence of the heavy chain of ifinatumomab

[0087] SEQ ID NO:7 - Amino acid sequence of the light chain of taciturnumab

[0088] SEQ ID NO:8 - Amino acid sequence of the heavy chain of taciturnumab DETAILED DESCRIPTION

[0089] As used herein, the term "C 1-4 "Alkyl" refers to straight or branched alkyl chains, whether alone or forming part of a larger group (e.g., C 1-4 Alkoxy) part. 1-4 Examples of alkyl groups are methyl, ethyl, propyl and butyl. References to "propyl" include n-propyl and isopropyl and references to "butyl" include n-butyl, isobutyl, tert-butyl and sec-butyl. Exemplary C 1-4 Particular groups of alkyl are methyl, isopropyl and tert-butyl. 1-4 An example of an alkoxy group is a methoxy group.

[0090] As used herein, the term "C 1-4 The term "haloalkyl" includes straight or branched chain alkyl groups containing 1 to 4 carbon atoms substituted by one or more halogen atoms, such as fluoromethyl, difluoromethyl and trifluoromethyl. 1-4 A specific example of a haloalkyl group is trifluoromethyl.

[0091] As used herein, the term "C 1-4 The term "haloalkoxy" includes straight or branched chain alkoxy groups containing 1 to 4 carbon atoms substituted by one or more halogen atoms, for example, fluoromethyl, difluoromethyl and trifluoromethyl. 1-4 Examples of haloalkoxy are trifluoromethoxy and trifluoroethoxy.

[0092] The term heterocycle as used herein, such as in a 3- to 7-membered non-aromatic heterocycle, is a fully or partially saturated hydrocarbon ring containing the specified number of carbon atoms, and may include a carbon atom to which a cycloalkyl group is attached, wherein at least one carbon atom in the ring is replaced by a heteroatom such as N, S or O. The heterocycloalkyl group may be optionally substituted with up to 3 substituents (such as 1 or 2 (e.g. 1) substituents) independently selected from the group consisting of: C 1-4 Alkyl (such as Me), C 1-4 Haloalkyl (e.g. CF3), C 1-4Alkoxy (such as Ome), C 1-4 Haloalkoxy (eg, OCF3), halo (eg, Cl or F), and CN. In an embodiment, the heterocycloalkyl is unsubstituted.

[0093] Examples of 3- to 7-membered non-aromatic heterocyclic groups include pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, hexahydropyridine, tetrahydropyran, thiazinane, diazinon, morpholine, thiomorpholine, dioxane, triazinane, trioxane, trithiazinane, azepane, oxepane and diazepane. An example of a substituted 3- to 7-membered non-aromatic heterocyclic group is N-methylpiperazine.

[0094] The term "prevent" is used herein to mean to provide in advance and thus may involve preventing symptoms of a disease or disorder in a subject or preventing the recurrence of symptoms of a disease or disorder in an afflicted subject, and is not limited to complete prevention of the disorder.

[0095] As used herein, the term "treatment" or "treating" includes the control, alleviation, reduction or modulation of a disease state or symptoms thereof.

[0096] 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 C 1-4 Preferably, each R 12 C 1-4 alkyl.

[0097] 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.

[0098] In one embodiment, R 9a is H. In a second embodiment, R 9a C 1-4 In a third embodiment, R 9a C 1-4 In one embodiment, R 9b is H. In a second embodiment, R 9b C 1-4 In a third embodiment, R 9b C 1-4 In one embodiment, R 9c C 1-4Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, for example methyl, isopropyl or tert-butyl. Suitably, R 9c is methyl. Suitably, R 9c is isopropyl. 9c In a second embodiment, R 9c C 1-4 In one embodiment, R 9d is H. In a second embodiment, R 9d C 1-4 In a third embodiment, R 9d 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 It is methyl.

[0099] In one embodiment, R 10 is H. In a second embodiment, R 10 C 1-4 In a third embodiment, R 10 C 1-4 In one embodiment, R 11 is H. In a second embodiment, R 11 In a third embodiment, R 11 In a fourth embodiment, R 11 C 1-4 In a fifth embodiment, R 11 C 1-4 In a sixth embodiment, R 11 C 1-4 In a seventh embodiment, R 11 C 1-4 Halogenated alkoxy.

[0100] 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.

[0101] In one embodiment, at least one R 2 is F, Cl or Br, such as Cl or F, especially F. Suitably, each R 2 is F, Cl or Br, such as Cl or F, especially F. In a second embodiment, at least one R 2 C 1-4 alkyl, and suitably, each R2 C 1-4 In a third embodiment, at least one R 2 is OCH3, and suitably, each R 2 In a fifth embodiment, at least one R 2 is OCF3, and preferably, each R 2 It is OCF3.

[0102] In one embodiment, s is 1 and R 2 is F. In a second embodiment, s is 2 and each R 2 For F.

[0103] 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 C 1-4 alkyl.

[0104] In one embodiment, R 4 is H. In a second embodiment, R 4 C 1-4 alkyl.

[0105] In one embodiment, R 5 is H. In a second embodiment, R 5 C 1-4 An alkyl group, such as a methyl group.

[0106] In one embodiment, R 6 is H. In a second embodiment, R 6 C 1-4 In one embodiment, R 5 is methyl and R 6 is H. In one embodiment, R 5 and R 6 At least one of them is H.

[0107] In one embodiment, q is 0. In a second embodiment, q is 1.

[0108] In one embodiment, R 7 is H. In a second embodiment, R 7 In one embodiment, R 8 is H. In a second embodiment, R 8 It is methyl.

[0109] In one embodiment, R 3 and R5 and the atoms therebetween form bonds between the atoms therebetween, or between the atoms therebetween and -(CHR a ) r In a second embodiment, R 7 Group and R 5 The groups and the atoms between them form the atoms between them and -(CHR a ) r -a 3- to 7-membered non-aromatic heterocyclic ring.

[0110] 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.

[0111] In one embodiment, R a In a second embodiment, R a It is methyl.

[0112] In one embodiment, a compound of formula (IA) is provided:

[0113]

[0114] in:

[0115] R 2a is H or F;

[0116] R 2b is F;

[0117] R 5a is H or methyl;

[0118] R 6a is H or methyl;

[0119] R 9ca is methyl, isopropyl or tert-butyl;

[0120] R 9cb is H or methyl;

[0121] R 10a is methyl; and

[0122] R 11a is methyl;

[0123] The condition is that when R 2a When H, R 9cb is H;

[0124] or a salt and / or solvate thereof.

[0125] It will be appreciated that references and preferences set forth for compounds of formula (I) or salts and / or solvates thereof with respect to pharmaceutical compositions, compounds for use, uses and methods apply equally to compounds of formula (IA) or salts and / or solvates thereof.

[0126] 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 In one embodiment, R 6a is H. In a second embodiment, R 6a In one embodiment, R 9ca In a second embodiment, R 9ca In a third embodiment, R 9ca In one embodiment, R 9cb is H. In a second embodiment, R 9cb In one embodiment, R 9ca is tert-butyl and R 9cb is H. In a second embodiment, R 9ca is methyl and R 9cb It is methyl.

[0127] In one embodiment, the compound of formula (I) is selected from the group consisting of:

[0128] 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;

[0129] 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;

[0130] (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;

[0131] (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;

[0132] 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;

[0133] 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;

[0134] 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;

[0135] 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;

[0136] (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;

[0137] (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;

[0138] 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;

[0139] 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;

[0140] (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;

[0141] (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;

[0142] (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;

[0143] (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;

[0144] 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;

[0145] 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;

[0146] 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;

[0147] 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;

[0148] 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;

[0149] 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;

[0150] 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;

[0151] 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

[0152] 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.

[0153] Salts and / or solvates thereof (eg, pharmaceutically acceptable salts thereof) are also provided.

[0154] 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.

[0155] 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.

[0156] In one embodiment, the 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.

[0157] 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.

[0158] 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.

[0159] In one embodiment, R 9d H and R 9c and alcohols have the following stereochemistry:

[0160]

[0161] In one embodiment, R 9d H and R 9c and alcohols have the following stereochemical arrangements:

[0162]

[0163] It should be understood that for use in medicine, the salt of the compound of formula (I) should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of the compound of formula (I) may be used in other situations, such as during the preparation of the compound of formula (I). Suitable pharmaceutically acceptable salts are obvious to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge et al. (1977). The pharmaceutically acceptable salts include acid addition salts and base addition salts. Pharmaceutically acceptable acid addition salts may be formed using inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid) and organic acids (e.g., succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid). Other salts (e.g., oxalates or formate) may be used, for example, to separate the compound of formula (I), and are included within the scope of the present invention.

[0164] Certain compounds of formula (I) may 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) may be prepared in crystalline or non-crystalline form, and if crystalline, may be optionally solvated, for example as hydrates. The 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). When additional chiral centers are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. Different isomeric forms may be separated or resolved from each other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

[0165] The present disclosure includes all isotopic forms of the compounds of formula (I) or salts and / or solvates thereof provided herein, whether in the form (i) in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) that predominates in nature (referred to herein as a "natural isotopic form"), or (ii) in which one or more atoms are replaced by atoms having the same atomic number but a mass number different from the mass number of the atoms that predominate in nature (referred to herein as a "non-natural variant isotopic form"). It should be understood that atoms may exist naturally as a mixture of mass numbers. The term "non-natural variant isotopic form" also includes embodiments in which the proportion of atoms of a given atomic number having a mass number that is less common in nature (referred to herein as an "uncommon isotope") has been increased relative to the proportion of naturally occurring atoms, for example, to a level of >20%, >50%, >75%, >90%, >95% or >99% of the number of atoms of that atomic number (the latter embodiment is referred to as an "isotopically enriched variant form"). The term "non-natural variant isotopic form" also includes embodiments in which the ratio of the uncommon isotope has been reduced relative to the ratio of the naturally occurring isotope. Isotopic forms can include radioactive forms (i.e., they have incorporated radioactive isotopes) and non-radioactive forms. Radioactive forms will generally be isotopically enriched variant forms.

[0166] Thus, non-natural variant isotopic forms of the compounds of formula (I) or their salts and / or solvates may contain one or more artificial or unusual isotopes, such as 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 I), or may contain in one or more atoms an increased proportion of said isotope compared to the proportion predominant in nature.

[0167] For example, non-natural variant isotopic forms containing radioactive isotopes are useful in drug and / or substrate tissue distribution studies.3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because of their ease of incorporation and ready means of detection. 2 Non-naturally occurring isotopic variants of isotopes such as H or D may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. In addition, it is possible to prepare isotopes incorporating positron emitting isotopes such as 11 C. 18 F. 15 O and 13 N), and can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. In one embodiment, the compound of formula (I) or its salt and / or solvate is provided in a natural isotopic form.

[0168] In one embodiment, the compound of formula (I) or a salt and / or solvate thereof is provided in a non-natural variant isotopic form. In a specific embodiment, a non-natural variant isotopic form is one in which deuterium (i.e. 2 H or D), wherein hydrogen is specified in the chemical structure in one or more atoms of the compound of formula (I) or its salt and / or solvate. In one embodiment, the atoms of the compound of formula (I) or its salt and / or solvate are in non-radioactive isotopic form. In one embodiment, one or more atoms of the compound of formula (I) or its salt and / or solvate are in radioactive isotopic form. Suitably, the radioactive isotope is a stable isotope. Suitably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

[0169] In one embodiment, a compound of formula (I) or a salt and / or solvate thereof is provided, wherein a single atom of the compound exists in a non-natural variant isotopic form. In another embodiment, a compound of formula (I) or a salt and / or solvate thereof is provided, wherein two or more atoms exist in a non-natural variant isotopic form.

[0170] Non-natural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein (e.g., processes similar to those described in the accompanying Examples for preparing natural isotopic forms). Thus, non-natural isotopic variant forms can be prepared by using appropriate isotopic variant (or labeling) reagents in place of the normal reagents employed in the Examples. Since the compounds of formula (I) are intended for use in pharmaceutical compositions, it should be readily appreciated that each is preferably provided in substantially pure form (e.g., at least 60% pure, more preferably, at least 75% pure and preferably at least 85%, especially at least 98% pure (% is based on weight ratio)). Impure preparations of the compounds can be used to prepare purer forms for use in pharmaceutical compositions.

[0171] In general, the compounds of formula (I) or their salts and / or solvates can be prepared according to organic synthesis techniques known to those skilled in the art, as well as by the following representative methods, methods in the Examples and modifications thereof.

[0172] Patent applications WO2017 / 001812, WO2020 / 128473, and WO2020 / 128475, each of which is incorporated herein by reference in its entirety, provide methods for synthesizing intermediates that can be used to produce compounds of the present invention.

[0173] General synthetic scheme

[0174] Synthesis of the compounds of the present invention

[0175] A person skilled in the art can design a variety of synthetic routes for the compounds of the present invention, and the exemplary synthetic routes described below do not limit the present invention. There are many methods for synthesizing heterocycles in the literature, for example: Joule, JA; Mills, K., Heterocyclic Chemistry, 2010, 5th edition, Pub. Wiley. A large number of possible synthetic routes are illustrated below. Where appropriate, any initially produced compound according to the present invention can be converted into another compound according to the present invention by known methods. In the following description, unless otherwise specified, 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 12As defined above for compounds of formula (I).

[0176] Solution 1

[0177]

[0178] The compound of formula (I) (wherein R 4 and R 5 In this reaction, another compound of formula (I) (wherein R 5 and R 6 One of the two 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.

[0179] Solution 2

[0180]

[0181] The compound of formula (I) (wherein R 5 and R 6 One of them is H and the other is methyl, or R 5 and R 6 Both are H) can be obtained by reacting a compound of formula (II) with an acid such as 2M HCl in diethyl ether (Et2O).

[0182] Solution 3

[0183]

[0184] The compound of formula (II) (wherein R 9d H) can be prepared by reacting a compound of formula (III) with a reducing agent such as NaBH4 in a solvent such as methanol.

[0185] Solution 4

[0186]

[0187] The compound of formula (II) (wherein R 9d C 1-4 Alkyl or C 1-4 The haloalkyl group can be prepared by reacting a compound of formula (IV) (wherein M is a metal ion such as Mg or Li) with a compound of formula (III) (wherein P is C 1-4 Alkyl or C 1-4 alkoxy) in a suitable solvent such as diethyl ether (Et2O) or tetrahydrofuran (THF).

[0188] Option 5a

[0189]

[0190] The compound of formula (III) (wherein P is C 1-4 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, isopropylmagnesium bromide or tert-butyllithium in a suitable solvent such as diethyl ether (Et2O) or tetrahydrofuran (THF).

[0191] Option 5b

[0192]

[0193] The compound of formula (III) (wherein P is C 1-4 Alkoxy) can be obtained by reacting a compound of formula (VIII) with a compound of formula (IX) (wherein P is C 1-4 The alkyloxy) is obtained by reaction in the presence of a phosphine reagent such as (tributylphosphoranylidene)acetonitrile in a suitable solvent such as toluene.

[0194] Solution 6

[0195]

[0196] The compound of formula (V) can be obtained by reacting a compound of formula (VI) with an amine such as N,O-dimethylhydroxylamine hydrochloride in the presence of a base such as triethylamine (Et3N), a carbodiimide such as N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) and hydroxybenzotriazole (HOBt) in a suitable solvent such as tetrahydrofuran (THF).

[0197] Solution 7

[0198]

[0199] The compound of formula (VI) can be prepared by making a compound of formula (VII) (wherein P is C 1-4 alkoxy) with a metal hydroxide such as lithium hydroxide monohydrate (LiOH H2O) in a suitable solvent such as methanol.

[0200] Solution 8

[0201]

[0202] The compound of formula (VII) (wherein P is C 1-4Alkoxy) can be obtained by reacting a compound of formula (VIII) with a compound of formula (IX) (wherein P is C 1-4 The alkyloxy) is obtained by reacting a phosphine reagent such as (tributylphosphoranylidene)acetonitrile in a suitable solvent such as toluene.

[0203] The compound of formula (IX) may be a compound of formula (IXA):

[0204]

[0205] Where P is C 1-4 Alkoxy.

[0206] The compound of formula (IXA) can be prepared by the method described in WO2017 / 001812.

[0207] Intermediates of the present invention

[0208] The present invention also relates to novel intermediates in the synthesis of compounds of formula (I) (such as compounds of formula (II) to (VII)). Specific intermediates of interest are those of the following general formula, wherein the variable groups and associated preferences are as previously defined for compounds of formula (I):

[0209] -Compound of formula (II):

[0210]

[0211] -Compound of formula (III):

[0212]

[0213] Where P is C 1-4 Alkyl or C 1-4 Alkoxy;

[0214] -Compound of formula (V):

[0215]

[0216] - Compound of formula (VI)

[0217]

[0218] - Compound of formula (VII)

[0219]

[0220] Where P is C 1-4 Alkoxy.

[0221] Included as an aspect of the present invention are salts, such as pharmaceutically acceptable salts, of any of the intermediates disclosed herein, such as any of the compounds of formula (II) to (VII).

[0222] Uses of the compounds and ADCs of the present invention

[0223] In any of the medical use embodiments below, the same use can be applied to the ADC of the present invention or a pharmaceutically acceptable salt thereof, since the ADC of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0224] Hyperproliferative disorders

[0225] Since the compound of formula (I) has cytotoxic activity, it is expected that the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate can be used to treat or prevent hyperproliferative disorders. Therefore, in one embodiment of the present invention, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is used to treat or prevent hyperproliferative disorders. In a particularly suitable embodiment, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is used to treat hyperproliferative disorders.

[0226] Since the ADC of the present invention has cytotoxic activity, it is expected that the ADC of the present invention or a pharmaceutically acceptable salt thereof can be used to treat or prevent hyperproliferative disorders.

[0227] Therefore, the present invention provides an ADC of the present invention or a pharmaceutically acceptable salt thereof for use in treating or preventing a hyperproliferative disorder. In a particularly suitable embodiment, the ADC of the present invention or a pharmaceutically acceptable salt thereof is used to treat a hyperproliferative disorder.

[0228] 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 treating or preventing a hyperproliferative disorder. In a particularly suitable 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 treating a hyperproliferative disorder.

[0229] In one embodiment, the present invention provides a method for treating or preventing a hyperproliferative disorder 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. In a particularly suitable embodiment, the present invention provides a method for treating a hyperproliferative disorder 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.

[0230] In one embodiment, the hyperproliferative disorder is cancer.

[0231] In one embodiment, the cancer is selected from the group consisting of hematological malignancies: lymphoma (e.g., B-cell lymphoma, in particular 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 malignant melanoma, amelanotic melanoma, and acral lentiginous melanoma).

[0232] Cancer may additionally 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 cancer (e.g., colon cancer), gallbladder cancer, kidney cancer, and liver cancer. For example, cancer may be ovarian serous cystadenocarcinoma, esophageal cancer, lung squamous cell carcinoma, lung adenocarcinoma, bladder urothelial carcinoma, uterine carcinosarcoma, stomach cancer (stomach cancer) (referred to herein as "gastric cancer") (such as gastric adenocarcinoma), invasive breast cancer, or liver hepatocellular carcinoma. In a suitable embodiment, cancer is breast cancer, such as triple-negative breast cancer or invasive breast cancer. In a suitable embodiment, cancer is brain cancer, breast cancer, prostate cancer, colon cancer, gallbladder cancer, or kidney cancer. In certain embodiments, cancer is breast cancer, colon cancer, or gallbladder cancer. In another embodiment, cancer is stomach cancer.

[0233] The cancer may additionally or alternatively be a blastoma, in particular a neuroblastoma, such as a retinoblastoma, a glioblastoma, a small cell lung cancer or an astrocytoma.

[0234] In particularly suitable embodiments, the cancer may be selected from the group consisting of: a hematological malignancy (such as a lymphoma, in particular a B-cell lymphoma (e.g. high-grade mantle zone lymphoma, follicular lymphoma, plasmablastic lymphoma, diffuse large B-cell lymphoma and Burkitt's lymphoma), a myeloma (e.g. multiple myeloma) or a leukemia (e.g. chronic lymphocytic leukemia, AML and B-acute lymphocytic leukemia)), a solid tumor (such as brain cancer, lung cancer, breast cancer (e.g. triple-negative breast cancer or invasive breast cancer), prostate cancer, ovarian cancer, colorectal cancer (e.g. colon cancer), gallbladder cancer, kidney cancer or liver cancer, or a neuroblastoma (e.g. retinoblastoma, glioblastoma, small cell lung cancer or astrocytoma)) and a melanoma (such as superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, amelanotic melanoma or acral lentigo melanoma).

[0235] In suitable embodiments, cancer may 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 suitable embodiments, cancer may 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 suitable embodiments, cancer may be selected from the group consisting of diffuse large B-cell lymphoma, neuroblastoma, B-acute lymphocytic leukemia, and triple-negative breast cancer. In suitable embodiments, cancer may 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 suitable embodiments, cancer may be selected from the group consisting of multiple myeloma, neuroblastoma, AML, B-acute lymphocytic leukemia, and triple-negative breast cancer. In suitable embodiments, the cancer may be selected from the group consisting of multiple myeloma, neuroblastoma, and triple negative breast cancer.

[0236] In one embodiment, the cancer is a MYC-addicted cancer as described in WO2020 / 128475, which is incorporated by reference in its entirety for the purpose of defining MYC-addicted cancer.

[0237] Inhibition of human NMT

[0238] As described above, it has been suggested that the inhibition of human NMT is used as a target for the treatment or prevention of various diseases or conditions. The present invention provides compounds that are or are expected to be human NMT inhibitors. The present invention also provides ADCs comprising human NMT inhibitors. The term "human NMT inhibitor" as used herein is intended to encompass any part that is bound to human NMT. ​​Human NMT is suitably HsNMT1. The inhibitor can be used as a competitive inhibitor or a partially competitive inhibitor. The inhibitor can be bound to human NMT at the myr-CoA binding pocket or the peptide binding pocket (or inhibit human NMT by another mechanism). Since the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is or is expected to be a human NMT inhibitor, it is expected that the compound of the present invention is suitably bound to and inhibits human NMT through the peptide binding pocket. In addition, since the ADC of the present invention or its pharmaceutically acceptable salt comprises an NMT inhibitor (which is a human NMT inhibitor), it is expected that after the NMT inhibitor is released from the ADC cell of the present invention, the NMT inhibitor is suitably bound to and inhibits human NMT through the peptide binding pocket.

[0239] Since the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is or is expected to be a human NMT inhibitor, it is expected that the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate can be used to treat or prevent diseases or conditions associated with human NMT activity, or it is expected to be used to treat or prevent diseases or conditions by targeting human NMT activity (e.g., viral infections other than hyperproliferative diseases such as cancer (such as picornavirus infection)). Therefore, the present invention provides a compound of formula (I) or its pharmaceutically acceptable salt and / or solvate for use as a drug. The present invention also provides an ADC of the present invention or its pharmaceutically acceptable salt for use as a drug.

[0240] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in treating or preventing a disease or condition for which inhibition of human NMT provides a therapeutic or prophylactic effect. In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is provided for use in treating a disease or condition for which inhibition of human NMT provides a therapeutic effect. In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is provided for use in preventing a disease or condition for which inhibition of human NMT provides a prophylactic effect.

[0241] The present invention also provides a method for treating or preventing a disease or condition in a subject, wherein the inhibition of human NMT provides a therapeutic or preventive effect in a subject (e.g., a mammal, such as a human), the method 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 a method for treating a disease or condition in a subject, wherein the inhibition of human NMT provides a therapeutic effect in a subject (e.g., a mammal, such as a human), the method 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 a method for preventing a disease or condition in a subject, wherein the inhibition of human NMT provides a preventive effect in a subject (e.g., a mammal, such as a human), the method 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.

[0242] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating or preventing a disease or condition, wherein the disease or condition is a disease or condition in which the 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 treating a disease or condition in which the 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 preventing a disease or condition in which the inhibition of human NMT provides a preventive effect.

[0243] Diseases and conditions in which inhibition of human NMT provides a therapeutic or preventive effect 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. Therefore, in suitable embodiments, the compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof can be used to treat or prevent those disorders / diseases.

[0244] In another particularly suitable embodiment, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is used to treat or prevent viral infection, specifically enteroviral infection, retroviral infection, poxvirus infection, arenavirus infection, flavivirus infection, alpha herpesvirus infection, varicella infection or beta herpesvirus infection. In another particularly suitable embodiment, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is used to treat viral infection, specifically enteroviral infection, retroviral infection, poxvirus infection, arenavirus infection, flavivirus infection, alpha herpesvirus infection, varicella infection or beta herpesvirus infection. In another particularly suitable embodiment, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is used to prevent viral infection, specifically enteroviral infection, retroviral infection, poxvirus infection, arenavirus infection, flavivirus infection, alpha herpesvirus infection, varicella infection or beta herpesvirus infection. In an even more preferred embodiment, the enteroviral infection may be a picornavirus infection (e.g., a rhinovirus, poliovirus, foot-and-mouth disease virus, coxsackievirus, hepatitis A virus, or enterovirus 71 infection); the retroviral infection may be a lentiviral 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 lentiviral 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 a particularly preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is used to treat or prevent 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).

[0245] The above-mentioned viral infections cause many types of diseases. For example: rhinovirus infection causes the common cold; various picornavirus infections, specifically coxsackievirus and enterovirus 71, cause hand, foot and mouth disease and polio-like syndrome; coxsackievirus can also cause flaccid paralysis, herpangina, acute hemorrhagic conjunctivitis, nonspecific febrile illness, rash, upper respiratory tract disease, and enterovirus 71 can also cause severe neurological diseases 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); poxvirus can cause smallpox; arenavirus can cause Lassa fever; flavivirus can cause dengue fever; alpha herpesvirus can cause simple infection, varicella infection, Marek's disease or laryngotracheitis; and betaherpesvirinae can cause congenital CMV infection, HHV-6 and HHV-7.

[0246] Therefore, in particularly suitable embodiments, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is used to treat or prevent the above-mentioned diseases caused by the above-mentioned viral infection. In particularly suitable embodiments, the compound of formula (I) is used to treat the above-mentioned diseases caused by the above-mentioned viral infection. In particularly suitable embodiments, the compound of formula (I) is used to prevent the above-mentioned diseases caused by the above-mentioned viral infection. Suitably, the compound of formula (I) can be used to treat or prevent (e.g., treat) other diseases and disorders caused by enterovirus infection, retrovirus infection, poxvirus infection, arenavirus infection, flavivirus infection, alpha herpesvirus infection, varicella infection or beta herpesvirus infection.

[0247] Combination therapy

[0248] Although the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate can be used as the sole active ingredient in a drug, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate can also be used in combination with one or more additional therapeutic agents. Therefore, the present invention also provides a compound of formula (I) or its pharmaceutically acceptable salt and / or solvate and an additional therapeutic agent. The additional therapeutic ingredients can be used for simultaneous, sequential or separate administration. The present invention also provides a multi-part kit comprising: (a) a first pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt and / or solvate and a pharmaceutically acceptable carrier; and (b) a second pharmaceutical composition comprising an additional therapeutic agent, and a pharmaceutically acceptable carrier. The additional therapeutic agent may be an additional compound of formula (I) or its pharmaceutically acceptable salt and / or solvate.

[0249] The compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof may be used in combination with one or more additional therapeutic agents useful for treating or preventing a hyperproliferative disorder (such as cancer), or another disease or disorder in which inhibition of human NMT provides a therapeutic or prophylactic effect (e.g., agents useful for treating or preventing hyperproliferative disorders, viral infections, neurological diseases, ischemia, osteoporosis, diabetes, autoimmune diseases and inflammatory diseases, in particular hyperproliferative disorders (e.g., cancer) and viral infections (e.g., HRV or HIV infection). The individual components of the combination may be administered separately at different times during the course of treatment, or simultaneously in separate or single combination forms. The present invention is therefore to be understood as covering all such regimens of simultaneous or alternating treatment, and the term "administering" should be interpreted accordingly. It should be understood that the scope of combinations of the compounds of the present invention with other therapeutic agents useful for treating or preventing a disease or disorder in which inhibition of human NMT provides a therapeutic or prophylactic effect includes in principle any combination with any pharmaceutical composition useful for treating or preventing a disease or disorder in which inhibition of human NMT provides a therapeutic or prophylactic effect.

[0250] When used in combination with a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, the additional therapeutic agent may be used, for example, in amounts as indicated for that agent in the Physicians' Desk Reference (PDR), or as otherwise determined by a person skilled in the art. In the case where a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is used in combination with one or more additional therapeutic agents simultaneously or sequentially, the following combination ratios and dosage ranges are suitable: When combined with an additional therapeutic agent, a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof may be used, for example, in a weight ratio with the additional therapeutic agent in the range of about 10:1 to about 1:10.

[0251] In one embodiment, in the case where the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is used to treat or prevent cancer, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate can be used in combination with one or more additional therapeutic agents simultaneously or sequentially for treating or preventing cancer. More preferably, in the case where the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is used to treat cancer, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate can be used in combination with one or more additional therapeutic agents simultaneously or sequentially for treating cancer.

[0252] The combination therapy can be achieved by administering a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof simultaneously, sequentially or separately and one or more other therapeutic agents of the treatment. The combination product can employ the NMT inhibitor of the present invention within any suitable dosage range (such as, for example, the dosage range described above), and the other pharmaceutically active agent can be within its approved dosage range.

[0253] 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.

[0254] In one embodiment, where a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is used to treat or prevent rhinovirus (HRV, also known as the common cold), the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof may be used in combination with one or more additional 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 one or more additional therapeutic agents can be selected from the group consisting of: pleconaril, pirodavir, vapendavir BTA-798, V-073, rupintrivir, enviroxime, IFN-β (SNG001); corticosteroids (inhaled and oral, such as beclomethasone, fluticasone, budesonide, ciclesonide), beta agonists (such as salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate), mesylate, ritodrine, isoproterenol, salmeterol, formoterol, bambuterol, clenbuterol, olodaterol, and indacaterol), muscarinic antagonists (e.g., ipratropium and diphenhydramine), leukotriene receptor antagonists (e.g., montelukast, zafirlukast, In some embodiments, the present invention relates to anti-IL-4 inhibitors, such as drupole inhibitors, drupole inhibitors, drupole inhibitors, drupole inhibitors, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example, drupole inhibitors for example,

[0255] ADC of the present invention

[0256] Payload

[0257] It is expected that the compound of formula (I) can be used as a payload for antibody drug conjugates (ADCs). The payload is a drug that is tethered to the antibody in the ADC and released at the site of action (targeted by the antibody, typically a cancer cell, such as a tumor cell expressing an antigen to which the antibody can bind) after administration, for example as described in Coats et al., Clin Cancer Res 2019; 25: 5441-8. For example, the cancer cell may express HER2 and the antibody may be trastuzumab, or the cancer cell may express CD20 and the antibody may be rituximab. Alternatively, the cancer cell may express CD276 / B7-H3 and the antibody may be ifinatumomab. Alternatively, the cancer cell may express Trop-2 and the antibody may be saccharotuzumab.

[0258] In one embodiment, the antibody binds to HER2. In one embodiment, the antibody is trastuzumab, pertuzumab, margetuxim ab, ertumaxomab, MM-111, HER2Bi-aATC, MCLA-128, ZW25, MDX-210ado-trastuzumab and fam-trastuzumab. Suitably, the antibody is trastuzumab. In one embodiment, the antibody is an antibody with 6 CDRs of trastuzumab. Trastuzumab comprises a heavy chain of SEQ ID NO: 2 and a light chain of SEQ ID NO: 1.

[0259] In one embodiment, the antibody binds to CD20. Suitably, the antibody is rituximab. In one embodiment, the antibody is an antibody having 6 CDRs of rituximab. Rituximab comprises a heavy chain of SEQ ID NO: 4 and a light chain of SEQ ID NO: 3.

[0260] In one embodiment, the antibody binds to Trop-2. ADCs comprising the antibody can be used to treat metastatic triple-negative breast cancer and metastatic urothelial carcinoma. In this embodiment, suitably, the antibody is taciturnin. In one embodiment, the cancer expresses Trop-2. Taciturnin comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 7.

[0261] In one embodiment, the antibody binds to CD276 (B7-H3). An ADC comprising the antibody can be used to treat prostate cancer. In this embodiment, suitably, the antibody is ifinatumomab. In one embodiment, the cancer expresses CD276 (B7-H3). Ifinatumomab comprises a heavy chain of SEQ ID NO: 6 and a light chain of SEQ ID NO: 5.

[0262] Means of tethering 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 WO 2019 / 923654, each of which is incorporated herein by reference.

[0263] The antibody may be tethered 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 WO2007 / 011968).

[0264] In order to tether the antibody to the compound of formula (I) via a linker, the antibody has a functional group that can form a bond with the functional group of the linker, such as a functional group of the amino side chain of the antibody. Useful functional groups that may be present on the antibody naturally or by chemical manipulation include, but are not limited to, sulfhydryl (-SH), amino, hydroxyl, carboxyl, anomeric hydroxyl of a carbohydrate, and carboxyl. In some embodiments, the antibody functional group is a sulfhydryl and / or amino group, especially a sulfhydryl. The sulfhydryl group can be generated by reducing the intramolecular disulfide bonds of the antibody. The sulfhydryl group can also be generated by reacting the amino group of the antibody lysine moiety using 2-iminothiolane (Traut reagent) or another sulfhydryl generating reagent.

[0265] In one embodiment, the linker forms a bond with a sulfur atom of the antibody. The sulfur atom may be derived from a thiol group of the antibody.

[0266] The linker can be tethered 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 include a carbonyl group that can bind to an amino functional group (e.g., a group NR 5 R 6) to form a covalent bond. When the linker forms a covalent bond with the compound of formula (I), such as 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 reacting with a suitable functional group on the linker to form a covalent bond. For example, the amino group in the compound of formula (I) must have an available hydrogen atom (for example, R 5 or R 6 H) to allow reaction with the corresponding functional group of the linker (e.g. carbonyl), that is, the amino group in the compound of formula (I) cannot be a tertiary amino group.

[0267] The linker can be connected by a cleavable linkage (e.g., derived from a 5 and R 6 The cleavable linkage, when cleaved, provides a carbamate of the nitrogen atom of the group and the carboxylic acid group on the linker to a compound of formula (I). 5 A compound of formula (I) wherein:

[0268] The drug loading (referred to as the variable "p") is the average number of NMT inhibitors per antibody. In the case of compounds of the invention bound to cysteine ​​residues, the drug loading may be in the range of 1 to 10 NMT inhibitors per antibody, i.e., where 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 NMT inhibitors are covalently attached to the antibody. The composition of the conjugate includes a collection of antibodies conjugated to a range of 1 to 10 NMT inhibitors. Suitably, p is between 1 and 10, for example, between 2 and 6, between 4 and 6, between 8 and 10 or between 6 and 8. Most suitably, p is, for example, about 5.

[0269] 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 its salt further comprises a linker.

[0270] In one embodiment, the linker has formula (LI):

[0271]

[0272] in represents the point of attachment to a chain terminus (such as the N-terminus) or a functional group on an amino acid side chain of the antibody; and

[0273] represents the point of attachment to the functional group of the compound of formula (I).

[0274] In one embodiment, the linker has formula (LII):

[0275]

[0276] in represents the point of attachment to a chain terminus (such as the N-terminus) or a functional group on an amino acid side chain of the antibody; and

[0277] represents the point of attachment to the functional group of the compound of formula (I).

[0278] In one embodiment, the linker has formula (LIII):

[0279]

[0280] in represents the point of attachment to a chain terminus (such as the N-terminus) or a functional group on an amino acid side chain of the antibody; and

[0281] Indicates the point of attachment to the functional group of the NMT inhibitor.

[0282] In one embodiment, the linker has formula (LIV):

[0283]

[0284] in represents the point of attachment to a chain terminus (such as the N-terminus) or a functional group on an amino acid side chain of the antibody; and

[0285] Indicates the point of attachment to the functional group of the NMT inhibitor.

[0286] The ADC of the present invention can be prepared using a drug conjugate or a salt and / or solvate thereof that is later covalently bonded to an antibody. Therefore, in one embodiment, a drug conjugate or a salt and / or solvate thereof is provided that comprises a group capable of forming a covalent bond with a functional group (e.g., a sulfhydryl group) on a chain end (such as an N-terminus) or an amino acid side chain of an antibody.

[0287] In one embodiment, the drug conjugate has the formula (DC-1):

[0288]

[0289] or its salts and / or solvates, wherein It is a compound of formula (I) or a salt and / or solvate thereof.

[0290] In one embodiment, the drug conjugate is a compound of formula (DC-2):

[0291]

[0292] or its salts and / or solvates, wherein It is a compound of formula (I) or a salt and / or solvate thereof.

[0293] In one embodiment, the drug conjugate is a compound of formula (DC-3):

[0294]

[0295] or its salts and / or solvates, wherein It is a compound of formula (I) or a salt and / or solvate thereof.

[0296] In one embodiment, the drug conjugate is a compound of formula (DC-4):

[0297]

[0298] or its salts and / or solvates, wherein It is a compound of formula (I) or a salt and / or solvate thereof.

[0299] As used herein, the phrase " The term "compound of formula (I)" will be understood by those skilled in the art as the portion that remains after the NMT inhibitor (such as an NMT inhibitor comprising a suitable functional group for attachment to a linker (such as an amino group (which comprises a hydrogen atom) or an alcohol (-OH))) reacts with a suitable functional group on the linker (e.g. a carbonyl group) to form a linker-compound of formula (I) covalent bond.

[0300] 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-3-yl]methyl}(methyl)carbamoyl)oxy]methyl}-2-[3-(3-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl-1-yl)ethoxy]ethoxy}propionamido)propionamido]phenoxy)-3,4-dihydroxy-2-methylcyclohexane-1-carboxylic acid:

[0301]

[0302] or a salt and / or solvate thereof.

[0303] In one embodiment, the ADC of the present invention comprises the formula:

[0304]

[0305] wherein Ab is an antibody as defined herein and Represents an NMT inhibitor, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof. Suitably, the ADC of the present invention or a salt thereof is bound to the antibody via a sulfhydryl group on the side chain of a cysteine ​​amino acid on the antibody. Suitably, the antibody is trastuzumab or rituximab, in particular trastuzumab. Alternatively, the antibody is saccharotuzumab. Alternatively, the antibody is ifinatumomab. Suitably, p is between 1 and 10, for example, between 2 and 6, between 4 and 6, between 8 and 10 or between 6 and 8. Most suitably, p is, for example, about 5.

[0306] In one embodiment, the ADC of the present invention comprises the formula:

[0307]

[0308] Wherein Ab is an antibody as defined herein. Suitably, the ADC of the present invention or a salt thereof is bound to the antibody via a sulfhydryl group on the side chain of a cysteine ​​amino acid on the antibody. Suitably, the antibody is trastuzumab or rituximab, in particular trastuzumab. Alternatively, the antibody is saccharotuzumab. Alternatively, the antibody is ifinatumomab. Suitably, p is between 1 and 10, for example, between 2 and 6, between 4 and 6, between 8 and 10 or between 6 and 8. Most suitably, p is, for example, about 5.

[0309] Dosage and preparation

[0310] The amount of active ingredient required to achieve a therapeutic effect will of course vary with the specific compound, route of administration, subject to be treated or prevented (including the type, species, age, weight, sex and medical condition of the subject and the renal and liver function of the subject), and the specific condition or disease to be 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 disorder.

[0311] When used for the effects shown, for adult humans, the oral dosage of the present invention will be in the range of about 0.01 mg / kg body weight / day (mg / kg / day) to about 100 mg / kg / day, suitably 0.01 mg / kg body weight / day (mg / kg / day) to 10 mg / kg / day and most suitably 0.1 mg / kg / day to 5.0 mg / kg / day. For oral administration, the composition is suitably provided in tablet form or in other presentation forms provided in discrete units, the form 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 the dosage for the patient to be treated. The drug typically contains about 0.01 mg to about 500 mg of active ingredient, suitably about 1 mg to about 100 mg of active ingredient. During the constant rate infusion, the most suitable dose intravenously will be in the range of about 0.1 to about 10 mg / kg / minute. Advantageously, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate can be applied in a single daily dose, or the total daily dose can be applied in separate doses twice, three times or four times a day. In addition, suitably, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate can be applied in intranasal form by topical use of a suitable intranasal vehicle, or by transdermal routes using those transdermal skin patches well known to those skilled in the art. When applied in the form of a transdermal delivery system, the dosage application should certainly be continuous rather than intermittent in the entire dosage regimen.

[0312] The dose provided to the subject will generally be a safe and effective dose, that is, an amount that provides an acceptable balance of desired benefits and undesirable side effects. A "safe and effective amount" is intended to include an amount of a compound that is effective in achieving a desired effect in the treatment and / or prevention of a disease state. The desired effect is generally clinically significant and / or measurable, such as in the following cases: (a) preventing the disease state from occurring in a mammal, specifically when the mammal is susceptible to the disease state but has not yet been diagnosed with the disease state; (b) inhibiting the disease state, that is, slowing or preventing its development; and / or (c) slowing the disease state, that is, causing the disease state to subside or related symptoms to decrease. A safe and effective amount may be an amount sufficient to achieve the desired effect when the compound is administered alone, or when it is administered in combination with one or more additional APIs, the additional API being an additional compound for use of the present invention, or a compound different from the present invention for use.

[0313] For the avoidance of doubt, a "safe and effective amount" as described herein may be achieved by any suitable dosage regimen (including, but not limited to, the exemplary dosage regimens described elsewhere herein). Thus, for example, reference herein to a compound such as being administered in a safe and effective amount by a particular route of administration includes obtaining a safe and effective amount by a single dose or by multiple doses (such as by a specified route of administration). For example, an amount that is safe and effective for oral administration includes a single dose administered orally and any multiple doses administered orally, provided that a safe and effective amount is achieved by oral administration.

[0314] Although the active ingredient can be administered alone, it is preferably present in a pharmaceutical preparation or composition. Therefore, the present invention provides a pharmaceutical preparation or composition comprising a compound of 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" material). The pharmaceutical composition of the present invention can take the form of a pharmaceutical preparation as described below.

[0315] Therefore, in one embodiment, the present 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 present invention also provides a pharmaceutical composition comprising an ADC of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The following uses of the pharmaceutical composition are also applicable to a pharmaceutical composition comprising an ADC of the present invention or a pharmaceutically acceptable salt thereof.

[0316] In one embodiment, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a pharmaceutically acceptable salt) thereof is provided for use in treating or preventing a disease or condition as described herein. In one embodiment, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a pharmaceutically acceptable salt) thereof is provided for use in treating a disease or condition as described herein. In one embodiment, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a pharmaceutically acceptable salt) thereof is provided for use in preventing a disease or condition as described herein.

[0317] In another embodiment, a method for treating or preventing a disease or condition as described herein is provided, the method comprising administering an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate (e.g., a pharmaceutically acceptable salt) to a subject in need. In another embodiment, a method for treating a disease or condition as described herein is provided, the method comprising administering an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate (e.g., a pharmaceutically acceptable salt) to a subject in need. In another embodiment, a method for preventing a disease or condition as described herein is provided, the method comprising administering an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate (e.g., a pharmaceutically acceptable salt) to a subject in need. The pharmaceutical composition of the present invention may take the form of a pharmaceutical preparation as described below.

[0318] 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 (e.g., a pharmaceutically acceptable salt) thereof in the manufacture of a medicament for treating or preventing a disease or condition as 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 (e.g., a pharmaceutically acceptable salt) thereof in the manufacture of a medicament for treating a disease or condition as 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 (e.g., a pharmaceutically acceptable salt) thereof in the manufacture of a medicament for preventing a disease or condition as described herein.

[0319] Pharmaceutical formulations according to the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion] and intraarticular), intranasal (also known as nasal administration), inhalation (including fine particle dusts or mists which may be generated by various types of metered dose pressurized aerosols, nebulizers or insufflators), insufflation, rectal, intraperitoneal and topical (including dermal, buccal, sublingual and intraocular) administration, although the most suitable route may depend, for example, on the disease and condition of the recipient.

[0320] Suitable pharmaceutical formulations according to the invention are those suitable for oral and parenteral administration; and more suitably those suitable for oral administration. Said embodiments are particularly suitable, for example, for the treatment or prevention of hyperproliferative disorders, in particular cancer.

[0321] In another suitable embodiment, the compound according to formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is administered by intranasal, inhalation (including fine dust or mist that can be generated by various types of metered dose pressurized nebulizers, sprayers or insufflators) or insufflation administration. The embodiment is particularly suitable, for example, for the treatment or prevention of picornavirus infections, such as human rhinovirus infections. This method of administration allows the administration of low doses of the compounds of the invention, which can reduce side effects. For example, a daily dose of the compounds of the invention in the range of 10 to 0.01 μg, suitably 1 to 0.01 μg and more suitably as low as 0.1 μg (100 ng) can be used.

[0322] The preparation can be conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. All methods include the step of associating the active ingredient with a carrier which constitutes one or more auxiliary ingredients. In general, the preparation is prepared by uniformly and adequately associating the active ingredient with a liquid carrier or a fine solid carrier or both, and then (if necessary) shaping the product into the desired preparation.

[0323] Formulations of the invention suitable for oral administration may be presented as discrete units each containing a predetermined amount of the active ingredient, such as capsules, cachets, pills or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids, such as elixirs, tinctures, suspensions or syrups; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. The active ingredient may also be presented as a bolus, electuary or paste.

[0324] Tablets can be prepared by compressing or molding optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing an active ingredient in a free-flowing form (such as a powder or granules) in a suitable machine, and the active ingredient is optionally mixed with a binder, a lubricant, an inert diluent, a lubricant, a surfactant or a dispersant. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and can be formulated to provide a slow or controlled release of the active ingredient therein. Formula (I) compound or its pharmaceutically acceptable salt and / or solvate can be administered, for example, in a form suitable for immediate release or extended release.

[0325] Immediate release or extended release can be achieved by using a suitable pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, or, particularly in the case of extended release, by using devices such as subcutaneous implants or osmotic pumps. A compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof can also be administered via liposomes.

[0326] Exemplary compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose for imparting bulkiness, alginic acid or sodium alginate as suspending agents, methylcellulose as viscosity enhancers, and sweeteners or flavorings, 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, extenders, disintegrants, diluents and lubricants, such as those known in the art. Suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth or sodium alginate), carboxymethyl cellulose, polyethylene glycol, wax, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. Formula (I) compounds or pharmaceutically acceptable salts and / or solvates thereof may also be delivered by oral cavity by sublingual and / or buccal administration. Molded tablets, compressed tablets or lyophilized tablets are exemplary forms that can be used. Exemplary compositions include those that are formulated with fast dissolving diluents (such as mannitol, lactose, sucrose and / or cyclodextrin) of the compounds of the present invention. High molecular weight excipients, such as cellulose (avicel) or polyethylene glycol (PEG) may also be included in the formulation. The formulation may also include excipients that contribute to mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez) and controlled release agents (such as polyacrylic acid copolymers (e.g., Carbopol 934)). Lubricants, glidants, flavoring agents, colorants and stabilizers may 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, oral drug components may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, etc.).

[0327] The compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof can also be administered in the form of a liposome delivery system (such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles). Liposomes can be formed from a variety of phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (cephalin) or phosphatidylcholine (lecithin).

[0328] Preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, antibacterial agents, and solutes that can make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The preparation may be presented in unit dose or multi-dose containers (e.g., sealed ampoules and vials), and may be stored under freeze-dried (lyophilized) conditions, requiring only the addition of sterile liquid carriers, such as saline or water for injection, just before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the aforementioned types. Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, suitable nontoxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersants or wetting agents and suspending agents, including synthetic monoglycerides or diglycerides and fatty acids, including oleic acid or Cremaphor.

[0329] Exemplary compositions for intranasal, aerosol or inhalation administration include saline solutions, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0330] Formulations for rectal administration may be presented as a suppository with a conventional carrier such as cocoa butter, synthetic glycerides or polyethylene glycols which are typically solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug.

[0331] 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 troches 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 a resin base (Plastibase) (mineral oil gelled with polyethylene).

[0332] Suitable unit dosage formulations are those containing an effective dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0333] It should be understood that the formulations of this invention may include, in addition to the ingredients particularly mentioned above, other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0334] The compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof are expected to exhibit one or more of the following advantageous properties:

[0335] - inhibition of human NMT, for example as demonstrated in the fluorescence-based assay of HsNMT1 sensitivity of Biological Example 1;

[0336] - cytotoxic activity, for example as demonstrated in the cell line assays of Biological Examples 2 and 3;

[0337] - In vivo cytotoxic activity, e.g. as demonstrated in the mouse xenograft model of Biological Example 4.

[0338] The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates may also exhibit one or more of the following advantageous properties:

[0339] - Cell permeability, for example as demonstrated in the Caco-2 cell permeability assay of Biological Example 5;

[0340] - 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 in vivo mouse xenograft studies of Biological Example 7.

[0341] ADC or a pharmaceutically acceptable salt and / or solvate thereof may also exhibit one or more of the following advantageous properties:

[0342] - in vivo cytotoxic activity, e.g. as demonstrated in the mouse xenograft model of Biological Examples 7, 8, 9, 10 and 11; and

[0343] - In vivo tolerance, e.g. as demonstrated in the mouse xenograft model of Biological Examples 7, 8, 9, 10 and 11.

[0344] Such properties are expected to make the compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof, or the ADCs of the present invention or pharmaceutically acceptable salts thereof, suitable for 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 preventive effect.

[0345] abbreviation

[0346] ALT Alanine aminotransferase

[0347] AST Aspartate aminotransferase

[0348] ALP alkaline phosphatase

[0349] GGT γ-glutamyl transferase

[0350] CK Creatine kinase

[0351] LDH Lactate dehydrogenase

[0352] TP Total Protein

[0353] ALB albumin

[0354] GLO Globulin

[0355] A / G Albumin / Globulin Ratio

[0356] TBIL Total bilirubin

[0357] BU blood urea nitrogen

[0358] CRE Creatinine

[0359] BUN / C blood urea nitrogen / creatinine ratio

[0360] GLU Glucose

[0361] CHO Cholesterol

[0362] TG triglyceride

[0363] Na Sodium

[0364] K Potassium

[0365] Cl Chloride ion

[0366] Ca Calcium

[0367] P Phosphate

[0368] WBC

[0369] ABNEUT Neutrophils

[0370] ABLYMP Lymphocytes

[0371] ABMONO monocytes

[0372] ABBASO Basophils

[0373] ABEOS Eosinophils

[0374] PLT Platelets

[0375] MPV Mean platelet volume

[0376] RBC Red blood cells

[0377] HCT Hematocrit

[0378] HGB Hemoglobin

[0379] MCV mean corpuscular volume

[0380] MCH mean corpuscular hemoglobin

[0381] MCHC mean corpuscular hemoglobin concentration

[0382] ABRETIC Reticulocytes

[0383] QW Once a week

[0384] Example

[0385] Synthesis of Example Compounds

[0386] General experimental details

[0387] LCMS Method_Formic Acid Buffer_3min Run

[0388] Column - YMC Triart C18 (33 x 2.1 mm, 3u), (mobile phase: 98% [0.05% HCOOH in water] and 2% [0.05% HCOOH in can: water (90: 10)] for 0.75 min, then to 90% [0.05% HCOOH in water] and 10% [0.05% HCOOH in ACN: water (90: 10)] in 1.0 min, further to 2% [0.05% HCOOH in water] and 98% [0.05% HCOcan in ACN: water (90: 10)] in 2.0 min, keep this mobile phase composition until 2.25 min, and finally return to the initial condition in 3.0 min). Flow rate = 1.0 ml / min.

[0389] LCMS method_Ammonium acetate buffer_3min run

[0390] Column - Xbridge C18 (50 x 3.0 mm, 3.5 u), (mobile phase: 95% [5 mM NH4Oac in water] and 5% [5 mM NcanAc in ACN: water 90:10] for 0.75 min, then to 70% [5 mM NH4Oac in water] and 30% [5 mM canH4Oac in ACN: water 90:10] in 1.00 min, further to 2% [5 mM NH4Oac in water] and 98% canM NH4Oac in ACN: water 90:10] in 2.0 min, keep this mobile phase until 2.25 min, return to initial conditions in 2.75 min, keep this mobile phase until 3.0 min). Flow rate = 1.2 ml / min.

[0391] LCMS method_Ammonium acetate buffer_5 min run

[0392] Column: Xbridge C18 (50×3.0 mm, 3.5 u), (mobile phase: 95% [5 mM NH4Oac in water] and 5% [5 mM NH4Oac in ACN: water 90:10] for 0.75 min, then to 85% [5 mM NH4Oac in water] and 15% [5 mM NH4Oac in ACN: water 90:10] in 1.25 min, further to 30% [5 : 10], again to 2% [0.05% HCOOH in water] and 98% [5 mM NH4Oac in ACN: water 90: 10] in 3.75 min, keeping this mobile phase composition until 4.25 min and finally returning to the initial conditions in 4.50 min and keeping the initial conditions until 5.10 min). Flow rate = 1.2 ml / min.

[0393] HPLC

[0394] The purity of certain examples was determined by TyeEclipse Extend or XDB 5μm C18 (150×4.6 mm), Xbridge 5μm C18 (100×4.6 mm), Zorbax Extend 5μm C18 (150×4.6 mm) or Shimadzu L Column 2ODS 5μm C18 (150×4.6 mm) columns using a gradient elution of acetonitrile in water containing 10 mM ammonium acetate over 15 min (HPLC B), 17 min (B1) and 18 min (B3).

[0395] The purity of certain examples was determined by analytical HPLC using Poroshell 120 2.7 μm EC18 (100×4.6 mm), Luna OmegaPolar 3 μm C18 (100×4.6 mm), Xbridge 5 μm C18 (150×4.6 mm), or Sunfire 5 μm C18 (100×4.6 mm) 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).

[0396] The purity of certain examples was determined by analytical HPLC using a Gemini NX 3 μm C18 (100×4.6 mm) column with a gradient elution of acetonitrile in water containing 0.05% formic acid over 16 min (A6).

[0397] NMR

[0398] Recorded at 400 MHz and 101 MHz at room temperature 1 H NMR and 13 C spectra, unless otherwise stated, are referenced to the residual solvent signal. Data are presented as follows: chemical shift in ppm, integration, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet) and coupling constants in Hz.

[0399] ADC Test Methods

[0400] SEC-HPLC

[0401] Column: TOSOH TSKgel G3000SWXL 7.8 mm × 30 cm 5 μm particles (MERCK808541) combined with a safety guard column (MERCK 822858) with a GFC3000 4 × 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. Monomers are reported based on peak integration, and [ADC] mg / mL is reported based on the calibration curve of the antibody.

[0402] RP-HPLC for residual NMT inhibitors

[0403] column: 2.6μm C8 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 ACN; gradient: at 60° C. at 2 ml / min:

[0404] time B％ 0.00 5 8.00 95 8.10 100 9.00 100 9.10 5 10.00 5

[0405] 50 μl sample (ADC or PBS / PS20 matrix) + 2 μl 5M NaCl + 150 μl cold MeOH (from -20 ° C freezer). Incubate at -20 ° C for 30 minutes. Centrifuge at 21,000g for 30 minutes at 4 ° C. Extract 125 μl supernatant and mix with 125 μl WFI. 100 μl of this mixture is injected onto a Kinetex column. Data is analyzed at 214 nm, and the residual NMT inhibitor in the sample is estimated from the external calibration curve of the relevant NMT inhibitor-connector. The results are expressed as a percentage of free relative to free and bound, wherein the amount of bound NMT inhibitor is determined using ADC concentration and calculated DAR.

[0406] HIC-HPLC for average DAR (drug to antibody ratio) calculation

[0407] This method can be used as an alternative to the PLRP-HPLC method for determining the mean DAR.

[0408] Column: TOSOH Butyl-NPR 4.6 mm×3.5 cm, 2.5 μm particle size (Merck 822855); Mobile phase A: 1.5 M (NH 4 ) 2 SO 4 , 25 mM NaPi, pH 6.95±0.05; Mobile phase B: 25 mM NaH 2 PO 4 pH 6.95±0.05+25% IPA; Gradient, at 25° C., at 0.8 ml / min:

[0409] time B％ 0 0 12 100 12.1 0 18 0

[0410] Load cartridge. 10 μg and report results / analyze at 214 nm.

[0411] RP-HPLC for average DAR calculation

[0412] 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 at 80° C., 1 mL / min:

[0413] time B％ 0 22.5 2 22.5 21.5 49.5 22.5 90.0 26.5 90.0 27.5 |22.5 32.0 22.5

[0414] About 10ug sample (ADC) + 5μl 0.1M DTT, make up to 50μL with 0.5M Tris (pH 8.0), incubate at 37°C for 15 minutes. Then dilute the sample with 49% water, 49% acetonitrile, 2% formic acid at 1:1 (+50μL). Then inject 20uL of this solution onto the RP-HPLC column. Analyze the data at 214nm and calculate the average DAR.

[0415] Endotoxin Kinetic Chromogenic Assay

[0416] Endotoxin was determined by 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.

[0417] Preparation of comparative compound 1

[0418] Comparative compound 1 is 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:

[0419]

[0420] And prepared according to the method described in WO2020 / 128473.

[0421] Preparation of Example Compounds 1 to 25

[0422]

[0423] Step 1-Intermediate (2): 1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester

[0424] 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 iodomethane (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 that the starting material was completely consumed. The product was formed. 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 =1.35min, 3min operation; 1 H NMR (400MHz, CDCl3) δ6.52 (s, 1H), 4.34 (q, 2H), 3.81 (s, 3H), 2.26 (s, 3H), 1.34 (t, 3H).

[0425] Step 2-Intermediate (3): 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester

[0426] 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) in portions at 0°C. The resulting mixture was stirred at RT for 16 h. TLC showed product formation with complete consumption of the starting material. 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) (eluted 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 and 249, NH4Oac:ACN, R t =3.32min, 6min running; 1 H NMR (400MHz, CDCl3) δ4.37 (q, 2H), 3.85 (s, 3H), 2.26 (s, 3H), 1.36 (t, 3H).

[0427] Step 3-Intermediate (4): 1,5-Dimethyl-4-vinyl-1H-pyrazole-3-carboxylic acid ethyl ester

[0428] Procedure: To a solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester (intermediate (3)) (50g, 202.429mmol) in DMF (250ml) was added tributyl vinyl tin (118.286ml, 404.858mmol). The solution was degassed with argon for 20min and Pd(PPh3)4 (11.69g, 10.121mmol) was added under argon. The reaction mixture was stirred at 110°C for 16h. TLC showed that the product was completely consumed by the 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) (eluted with 20%-30% ethyl acetate and hexanes) to give ethyl 1,5-dimethyl-4-vinyl-1H-pyrazole-3-carboxylate (4) (30 g, 76.3%) as a brown gum. LC-MS MH + 195,FA:ACN,R t =1.59 min, 3 min operation; 1H NMR (400MHz, CDCl3) δ6.96 (dd, 1H), 5.39 (d, 1H), 5.27 (d, 1H), 4.24 (q, 2H), 3.81 (s, 3H), 2.33 (s, 3H), 1.26 (t, 3H).

[0429] Step 4-Intermediate (5): 1,5-dimethyl-4-(2-oxo-ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester

[0430] 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 and extracted with ethyl acetate and finally 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 used in the next step without purification. LC-MS MH + 211,FA:ACN,R t =1.32min, 3min operation; 1 H NMR (400MHz, CDCl3) δ9.56 (s, 1H), 4.19 (q, 2H), 3.80 (s, 3H), 3.74 (s, 2H), 2.17 (s, 3H), 1.23 (t, 3H).

[0431] Step 5-Intermediate (6): 4-(2-Hydroxy-ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester

[0432] 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) was added NaBH4 (9.7 g, 261.905 mmol) in portions at 0°C. 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) (eluted 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 =1.27min, 3min running. 1 H NMR (400MHz, CDCl3) δ 4.50 (t, 1H), 4.21 (q, 2H), 3.75 (s, 3H), 3.42 (q, 2H), 2.73 (t, 2H), 2.18 (s, 3H), 1.25 (t, 3H).

[0433]

[0434] Step 1-Intermediate (8): 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde

[0435] Procedure: Phosphorus oxychloride (6.102ml, 65.469mmol) was added dropwise to anhydrous DMF (50ml) at 0°C and stirred for 1h at this temperature. A solution of 6-bromoimidazo [1,2-a] pyridine (5g, 25.376mmol) in DMF (10ml) was added at 0°C. The reaction mixture was heated to 100°C for 5h and stirred at RT for 16h. The reaction mixture was quenched with a cold saturated sodium bicarbonate solution and extracted with ethyl acetate, 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) (3.2g, 56.04%) as a brown solid. 1 HNMR (d6-DMSO, 400MHz) δ9.95 (s, 1H), 9.49 (s, 1H), 8.54 (s, 1H), 7.89-7.81 (m, 2H).

[0436] Step 2-Intermediate (9): 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)-N-methylmethanamine

[0437] 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. NaBH4 (1.56 g, 40.179 mmol) was added to the reaction mixture at 0 °C and stirred for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate solution and 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 =1.46min, 5min operation; 1 H NMR (d6-DMSO, 400MHz) δ 8.69 (s, 1H), 7.54 (d, 1H), 7.50 (s, 1H), 7.36-7.29 (m, 1H), 3.98 (s, 2H), 2.24 (s, 3H).

[0438] Step 3-Intermediate (10): tert-butyl ((6-bromoimidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate

[0439] 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 and 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 =3.36min, 5min running. 1 H NMR (d6-DMSO, 400MHz) δ 8.70 (bs, 1H), 7.62 (s, 1H), 7.59 (d, 1H), 7.38 (d, 1H), 4.75 (s, 2H), 2.67 (s, 3H), 1.46 (s, 9H).

[0440]

[0441] Step 1 - Intermediate (12): (4-fluoro-2-hydroxyphenyl)boronic acid

[0442] 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 (1M 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, the organic layer was separated and 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, NH4Oac:ACN, Rt=2.73 min, 5 min run.

[0443] Step 2-Intermediate (13): tert-butyl ((6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate

[0444] 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 min followed by addition of tetrakis(triphenylphosphine)palladium(0) (2.31 g, 2.0 mmol) and the reaction mixture was heated at reflux for 2 h. 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 afford tert-butyl ((6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate (13) (5.0 g, 67.31%). 1H NMR (d6-DMSO, 400 MHz) δ 10.2 (s, 1H), 8.53-8.51 (bs, 1H), 7.73-7.71 (m, 2H), 7.59-7.57 (m, 1H), 7.32-7.30 (m, 1H), 6.76-6.74 (m, 2H), 4.78 (s, 2H), 2.67 (s, 3H), 9.36 (s, 9H); LC-MS MH+ 372, NH4Oac:ACN, Rt = 1.48 min, 5 min run.

[0445] Step 3-Intermediate (14): 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 ethyl ester

[0446] 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 cyanomethyltributylphosphane (CMBP) (2.118 ml, 8.081 mmol) at room temperature and the reaction mixture was stirred at 110 °C for 16 h. TLC and LCMS showed product formation. The reaction mixture was diluted with ethyl acetate and washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography (silica gel, 100-200 mesh) using 5% MeOH-DCM to give 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. 1H NMR (d6-DMSO, 400MHz) δ8.46-8.25 (m, 1H), 7.63 (s, 1H), 7.56 (d, 1H), 7.32 (bs, 1H), 7.24 (d, 1H), 7.08 (d, 1H), 6.85-6.83 (m, 1H), 4.7 6(s, 2H), 4.20(q, 2H), 4.11(t, 2H), 3.66(s, 3H), 2.99-2.97(m, 2H), 2.66(s, 3H), 1.88-1.86(m, 3H), 1.31(s, 9H), 1.20(t, 3H); LC-MS MH+566, NH4Oac:ACN, Rt=3.41min, 5min operation.

[0447] 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

[0448] 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 h. LCMS was checked, which showed product formation. The reaction mixture was cooled at 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%). 1H NMR (d6-DMSO, 400MHz) δ8.56 (s, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.28 (bs, 1H), 7.26 (d, 1H), 7.13 (d, 1H), 6.88-6.86 ( LC-MS MH+538, FA:ACN, Rt=1.53min, 3min operation.

[0449] 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

[0450] 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 h. TLC was checked which showed the formation of the product. The reactant 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%). 1H NMR (d6-DMSO, 400MHz) δ8.46 (bs, 1H), 7.61 (s, 1H), 7.56 (d, 1H), 7.33 (bs, 1H), 7.26 (d, 1H), 7.06 (d, 1H), 6.84-6.82 (m, 1H) , 4.77(t, 2H), 4.09(t, 2H), 3.65(s, 6H), 3.25(s, 3H), 2.88-2.86(m, 2H), 2.67(s, 3H), 1.90-1.88(m, 3H), 1.32(s, 9H); LC-MS MH+581, NH4Oac:ACN, Rt=3.33min, 5min operation.

[0451] 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

[0452]

[0453] 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

[0454] 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 tert-butyl lithium (1.26 ml, 2.155 mmol) was added at -50 °C. The reaction mixture was then stirred at -50 °C for 2 hrs. TLC was checked, which showed product formation, 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 combi flash column chromatography using MeOH in DCM to afford 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 =4.14min, 5min operation;1 H NMR (d6-DMSO, 400MHz) δ8.44 (bs, 1H), 7.61 (s, 1H), 7.56 (d, 1H), 7.33 (bs, 1H), 7.25 (d, 1H), 7.09-7.07 (m, 1H), 6.84-6.8 0 (m, 1H), 4.76 (t, 2H), 4.07 (t, 2H), 3.72 (s, 3H), 2.96-2.94 (d, 3H), 2.67 (s, 3H), 1.84-1.77 (m, 3H), 1.31-1.28 (m, 18H).

[0455] 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

[0456] 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 h. 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, followed by water, followed by brine. The organic layer was separated, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by combiflash using 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, NH4Oac:ACN, R t =3.73min, 5min operation; 1H NMR (d6-DMSO, 400MHz) δ8.50 (bs, 1H), 7.66-7.53 (m, 2H), 7.36 (d, 2H), 7.07 (d, 1H), 6.84 (bs, 1H), 4.87-4.72 (m, 3H), 4.21 (d, 1H), 4.13-3.83 (m, 2H), 3.56 (s, 3H), 3.02-2.72 (m, 2H), 2.68 (s, 3H), 1.89 (s, 3H), 1.33 (s, 9H), 0.86 (s, 9H).

[0457] 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

[0458] 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 2M HCl in diethyl ether (25 ml) at 0° C. The reaction mixture was stirred at RT for 2 h. After complete consumption of SM, the reaction mixture was evaporated under vacuum, triturated with 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 =1.52min, 3min operation; 1 H NMR (400MHz, DMSO-d6)d 10.06-9.65(m,2H),9.20(s,1H),8.42(s,1H),8.17(d,1H),8.01(d,1H),7.75(t,1H),7.17(d,1H),6.99(t,1H),4.88(s,2H),4 HPLC RT(A)5.22min.

[0459] 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

[0460]

[0461] 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 for 1 h at RT. NaCNBH3 (43 mg, 0.699 mmol) was then added at 0°C and continued for 16 h at RT. The reaction mixture was evaporated under reduced pressure and diluted with DCM and washed with saturated NaHCO3 solution, water and brine. The organic layer was separated and dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product. The crude was purified by preparative TLC plate using 7% MeOH in DCM to afford 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-MSMH + 494.4, NH4Oac:ACN, R t =3.36min, 5min running. 1 H NMR (400MHz, DMSO-d6)d 8.50(s, 1H), 7.57(d, 1H), 7.50(s, 1H), 7.43(t, 1H), 7.34(d, 1H), 7.05(d, 1H), 6.88(t, 1H), 4.85(d, 1H), 4.22(d, 1H), 4. 13-3.98 (m, 2H), 3.73 (s, 2H), 3.56 (s, 3H), 3.01-2.89 (m, 1H), 2.77-2.67 (m, 1H), 2.15 (s, 6H), 1.90 (s, 3H), 0.87 (s, 9H). HPLC RT(A6)5.07min.

[0462] 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

[0463]

[0464] 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

[0465] 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 at 0°C and methylmagnesium bromide (3M in diethyl ether) (2.9 ml, 8.615 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 h. TLC and LCMS were checked, which showed product formation, and 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 column chromatography using MeOH in DCM to afford 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, 75.84mmol). 1 H NMR (d6-DMSO, 400MHz) δ8.44-8.26 (brs, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.35-7.25 (brs, 1H), 7.24 (d, 1H), 7.10 (d, 1H), 6.85-6.7 8(brs, 1H), 4.76(s, 2H), 4.08(t, 2H), 3.68(s, 3H), 2.98(s, 2H), 2.66(s, 3H), 2.37(s, 3H), 1.93-1.78(brs, 3H) 1.31(s, 9H); LC-MS MH+536, NH4Oac:ACN, Rt=3.54min, 5min operation.

[0466] 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

[0467] 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) at 0°C. The reaction mixture was stirred at room temperature for 3 h. TLC and LCMS showed consumption of starting material. The reaction mixture was evaporated under reduced pressure to give the crude. The crude was triturated with diethyl ether to afford 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 HCl salt compound. 1 H NMR (d6-DMSO, 400MHz) δ9.70 (brs, 2H), 9.19 (s, 1H), 8.41 (s, 1H), 8.07 (d, 1H), 8.00 (d, 1H), 7.71 (t, 1H), 7.20 (d, 1 LC-MS MH+436, NH4Oac:ACN, Rt=2.76min, 5min operation.

[0468] 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

[0469] 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 h. NaCNBH3 (300.81 mg, 4.825 mmol) was then added at 0°C and the reaction was stirred at room temperature for 16 h. 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 was purified by combiflash column chromatography (12 g silica column, 2% MeOH-DCM) to give 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. 1 H NMR (d6-DMSO, 400MHz) δ8.44 (s, 1H), 7.54 (d, 1H), 7.50 (s, 1H), 7.40 (t, 1H), 7.25 (d, 1H), 7.09 (d, 1H), 6.87(t, 1H), 4.08(t, 2H), 3.72-3.69(m, 5H), 3.00(t, 2H), 2.39(s, 3H), 2.13(s, 6H), 1.86(s, 3H); LC-MS MH+450, HCOOH:ACN, Rt=1.31min, 3min run; HPLC RT(A1) 6.054min.

[0470] 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

[0471] 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 (3M in diethyl ether) (0.133 ml, 0.4 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 h. TLC and LCMS were checked, which showed product formation, and 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 column chromatography using MeOH in DCM to afford 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%). 1 H NMR (d6-DMSO, 400MHz) δ8.49 (s, 1H), 7.56 (d, 1H), 7.50 (s, 1H), 7.42 (t, 1H), 7.33 (d, 1H), 7.04 (d, 1H), 6.88 (t, 1H LC-MS MH+466, NH4Oac:ACN, Rt=2.95min, 5min run; HPLC RT(B3)8.587min.

[0472] 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

[0473]

[0474] 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) at 0 °C was added NaBH4 (34.554 mg, 0.89 mmol) and stirred at room temperature for 3 h. TLC showed about 50% unreacted starting material. 18 mg NaBH4 was added again 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 by 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%); 1 H NMR (d6-DMSO, 400MHz) δ 8.48 (s, 1H), 7.56 (d, 1H), 7.50 (s, 1H), 7.42 (t, 1H), 7.32 (d, 1H), 7.03 (d, 1H), 6.88 (t, 1H), 4.84 (d, 1H), 4.66 (t, 1H), 4. 08 (t, 2H), 3.72 (s, 2H), 3.54 (s, 3H), 2.89-2.79 (m, 2H), 2.14 (s, 6H), 1.87 (s, 3H), 1.29 (d, 3H); LC-MSMH+452, NH4Oac:ACN, Rt=3.13min, 5min operation.

[0475] 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

[0476]

[0477] 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

[0478] 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 NaBH4 (5.447 mg, 0.14 mmol) was added at 0 °C. The reaction mixture was then stirred at RT for 1 h. TLC was checked, which showed product formation. 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 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%). 1 H NMR (d6-DMSO, 400MHz) δ8.48 (brs, 1H), 7.61.7.57 (m, 2H), 7.36-7.33 (m, 2H), 7.04 (d, 1H), 6.83 (brs, 1H), 4.81-4.77 (m, 3H), 4.66(brs, 1H), 4.08(t, 2H), 3.54(s, 3H), 2.85-2.80(m, 2H), 2.67(s, 3H), 1.87(brs, 3H), 1.33-1.23(m, 12H); LC-MS MH+538, NH4Oac:ACN, Rt=3.13min, 5min operation.

[0479] 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

[0480] 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 2M HCl in diethyl ether (5.0 ml) at 0° C. The reaction mixture was stirred at rt for 2 h. After complete consumption of the starting material, the reaction mixture was evaporated under vacuum, triturated with diethyl ether and lyophilized to yield 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%). 1 H NMR (d6-DMSO, 400MHz) δ9.54 (s, 2H), 9.16 (s, 1H), 8.37 (s, 1H), 8.11 (d, 1H), 7.98 (d, 1H), 7.69 (t, 1H), 7.15 (d, 1H), 6.99 (t, 1 LC-MS MH+438, NH4Oac:ACN, Rt=2.98min, 5min run; HPLC RT(B3)6.945min.

[0481] 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 produce 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

[0482]

[0483] 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

[0484]

[0485] Procedure: 100 mg 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 from Example 2 was separated in chiral preparative HPLC [column name: CHIRALPAK IC (21×250 mm, 5μ), flow rate: 21.0 ml / min, mobile phase: HEX / ETOH / EA / DEA: 70 / 15 / 15 / 0.1 solubility: MEOH] to obtain (peak-1) Example 3 (isomer 1, Rt 11.84min) 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 (16.0mg, 16.0%) and (peak-2, Rt13.60min) 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 (15.0mg, 15.0%). Example 3 (isomer 1): LC-MS MH+452, NH4Oac:ACN, Rt=2.78 min, 5 min run; Example 4 (isomer 2): LC-MS MH+452, NH4Oac:ACN, Rt=2.78 min, 5 min run.

[0486] 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

[0487]

[0488] 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

[0489] Procedure: Racemic ((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)carbamic acid tert-butyl ester (intermediate (18)) (190 mg, 0.328 mmol) was separated by chiral preparative SFC [Chiralpak IG, 0.3% Ipamine in MEOH instrumental method (M-2-25F), injection volume (10), column (IG), well position (21B), temperature (35.3), flow (2), modifier % (25), pressure (100)]. After evaporation of the preparative fractions, 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 were obtained.

[0490] 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 =2.41min, 5min operation; 1 H NMR (d6-DMSO, 400MHz) δ8.50 (bs, 1H), 7.66-7.53 (m, 2H), 7.36 (d, 2H), 7.07 (d, 1H), 6.84 (bs, 1H), 4.87-4.72 (m, 3H), 4.21 (d, 1H), 4.13-3.83 (m, 2H), 3.56 (s, 3H), 3.02-2.72 (m, 2H), 2.68 (s, 3H), 1.89 (s, 3H), 1.33 (s, 9H), 0.86 (s, 9H).

[0491] 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 =2.39min, 5min operation; 1 H NMR (d6-DMSO, 400MHz) δ8.50 (bs, 1H), 7.66-7.53 (m, 2H), 7.36 (d, 2H), 7.07 (d, 1H), 6.84 (bs, 1H), 4.87-4.72 (m, 3H), 4.21 (d, 1H), 4.13-3.83 (m, 2H), 3.56 (s, 3H), 3.02-2.72 (m, 2H), 2.68 (s, 3H), 1.89 (s, 3H), 1.33 (s, 9H), 0.86 (s, 9H).

[0492] 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:

[0493]

[0494] Procedure: To a stirred solution of intermediate 18a (45 mg, 0.078 mmol) in diethyl ether (2 ml) was added 2M 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 under vacuum, 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 HCl salt. LC-MS MH + 480.5, NH4Oac:ACN, R t =1.57min, 3min operation; 1H NMR (400MHz, DMSO-d6)d 9.79(bs, 2H), 9.20(s, 1H), 8.41(s, 1H), 8.17(d, 1H), 8.01(d, 1H), 7.74(t, 1H), 7.19-7.14(m, 1H), 7.02-6.94(m, 1H), 4.74(bs, 2H ), 4.25 (s, 1H), 4.18-4.07 (m, 2H), 3.68 (s, 3H), 2.99-2.89 (m, 1H), 2.81-2.71 (m, 1H), 2.62 (t, 3H), 2.06 (s, 3H), 0.85 (s, 9H); HPLC RT(A6)4.96min.

[0495] 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

[0496]

[0497] 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 2M 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 under vacuum, 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, NH4Oac:ACN, R t =1.37min, 3min operation; 1H NMR (400MHz, DMSO-d6)d 9.67(bs, 2H), 9.18(s, 1H), 8.39(s, 1H), 8.16(d, 1H), 8.00(d, 1H), 7.72(t, 1H), 7.22-7.15(m, 1H), 7.02-6.96(m, 1H), 4.73(t, 2H ), 4.22(s, 1H), 4.17-4.03(m, 3H), 3.65(s, 3H), 2.96-2.89(m, 1H), 2.76-2.69(m, 1H), 2.62(t, 3H), 2.05(s, 3H), 0.85(s, 9H); HPLC RT(A6)4.96min.

[0498] 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

[0499]

[0500] 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

[0501] 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 (3M in diethyl ether) (4.717 ml, 14.152 mmol) was added at 0°C. The reaction mixture was then stirred at RT for 2 h. TLC was checked, which showed product formation. 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 using 5% MeOH in DCM to afford 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. 1H NMR (d6-DMSO, 400MHz) δ8.50-8.45(brs, 1H), 7.65-7.57(m, 2H), 7.33(d, 2H), 7.06(d, 1H), 6.83(t, 1H), 4.78(s , 3H), 4.10(t, 2H), 3.52(s, 2H), 2.95-2.88(brs, 2H), 2.68(s, 3H), 1.86(s, 3H), 1.38(s, 6H), 1.33(s, 9H); LC-MS MH+552, NH4Oac:ACN, Rt=1.32min, 5min operation.

[0502] 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

[0503] 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 h. After complete consumption of starting material, the reaction mixture was quenched with sodium bicarbonate solution at 0 °C and diluted with dichloromethane and the organic layer was separated and evaporated to give the compound, which was purified by combi flash column chromatography using 5% MeOH in DCM to afford 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%). 1 H NMR (d6-DMSO, 400MHz) δ8.51 (s, 1H), 7.54 (d, 1H), 7.47 (s, 1H), 7.43 (t, 1H), 7.32 (d, 1H) 7.04 (d, 1H), 6.87 (t, 1H) LC-MS MH+452, NH4Oac:ACN, Rt=1.52min, 3min run; HPLC RT(A6)5.247min.

[0504] Intermediate (28): (3,4-difluoro-2-hydroxyphenyl)boronic acid

[0505]

[0506] Intermediate (28) was prepared according to the method disclosed in WO2017 / 001812.

[0507] Intermediate (29): tert-butyl ((6-(3,4-difluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamate

[0508]

[0509] Procedure: Suzuki coupling of intermediate (28) and (10) was performed using the procedure used for the synthesis of intermediate (13). LCMS (HCOOH:ACN): M+H=390.3, R t =1.54min, 3min operation; 1 H NMR (400MHz, DMSO-d6)d 10.44 (s, 1H), 8.50 (bs, 1H), 7.67-7.54 (m, 2H), 7.41 (d, 1H), 7.12 (bs, 1H), 6.95 (d, 1H), 4.77 (s, 2H), 2.68 (s, 3H), 1.35 (s, 9H).

[0510] 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

[0511]

[0512] Step 1-Intermediate (30): 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 ethyl ester

[0513] Procedure: Coupling of intermediate (29) and (6) was carried out using the procedure used for the synthesis of intermediate (14). Yield - 900 mg, 60.01%. 1H NMR (d6-DMSO, 400MHz) δ8.48-8.44 (brs, 1H), 7.63 (s, 1H), 7.56 (d, 1H), 7.27 (d, 3H), 4.76 (s, 2H), 4.12-4. 07(q, 2H), 3.95(t, 2H), 3.63(s, 3H), 2.84(t, 2H), 2.66(s, 3H), 1.85(s, 3H), 1.32(s, 9H) 1.14(t, 3H); LC-MS MH+584.1, NH4Oac:ACN, Rt=3.63min, 5min operation.

[0514] 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

[0515] Procedure: Hydrolysis of intermediate (30) was performed as used for the synthesis of intermediate (15). Yield - 2.3 g, 92.87%. 1 H NMR (d6-DMSO, 400MHz) δ12.40-12.20 (brs, 1H), 8.50-8.42 (brs, 1H) 7.67 (s, 1H), 7.58 (d, 1H), 7.32 (d, 1H), 7.30 -7.22(brs,2H)4.77(s,2H),4.05-3.98(m,2H),3.61(s,3H),2.84(t,2H),2.78(s,3H),1.83(s,3H),1.32(s,9H). LC-MS MH+556, NH4Oac:ACN, Rt=1.83min, 3min run.

[0516] 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

[0517] Procedure: Amidation of intermediate (31) was performed as used for the synthesis of intermediate (16).

[0518] Yield - 2.0 g, 80.65%; 1H NMR (d6-DMSO, 400MHz) δ8.48-8.44(brs, 1H), 7.63(s, 1H), 7.55(d, 1H), 7.27(d, 3H), 4.77(s, 2H), 3.95( t, 2H), 3.61 (s, 3H), 3.59 (s, 3H), 3.16 (s, 3H), 2.71 (t, 2H), 2.68 (s, 3H), 1.84 (s, 3H), 1.33 (s, 9H); LC-MS MH+599, NH4Oac:ACN, Rt=3.38min, 5min operation.

[0519] 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

[0520] Procedure: Addition of MeMgBr to intermediate (32) as used for the synthesis of intermediate (19). Yield - 600.0 mg, 64.84%; 1 H NMR (d6-DMSO, 400 MHz) δ 8.46-8.42 (brs, 1H), 7.65 (s, 1H), 7.55 (d, 1H), 7.27 (d, 3H), 4.76 (s, 2H), 3.95 (t, 2H), 3.66 (s, 3H), 2.82 (t, 2H), 2.67 (s, 3H), 2.26 (s, 3H), 1.89 (s, 3H), 1.32 (s, 9H). LC-MS MH+ 554, NH4Oac:ACN, Rt = 3.69 min, 5 min run.

[0521] 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

[0522] Procedure: Reduction of intermediate (33) was carried out using the procedure used for the synthesis of intermediate (274). Yield - 430.0 mg, 71.41%; 1H NMR (d6-DMSO, 400MHz) δ8.50-8.46 (brs, 1H), 7.63 (s, 1H), 7.58 (d, 1H), 7.33 (d, 1H), 7.30-7.18 (brs, 2H), 4.77 (s, 2H), 4.69(d, 1H), 4.53(t, 1H), 3.91(t, 2H), 3.49(s, 3H), 2.67(s, 5H), 1.75(s, 3H), 1.33(s, 9H), 1.18(d, 3H); LC-MS MH+556, HCOOH:ACN, Rt=1.87min, 3min operation.

[0523] 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

[0524] Procedure: Deprotection of intermediate (34) was performed as used for the synthesis of intermediate (20). Yield - 205.0 mg, 85.79%. 1 H NMR (d6-DMSO, 400MHz) δ9.95-9.80 (brs, 2H), 9.22 (s, 1H), 8.42 (s, 1H), 8.00 (d, 1H), 7.92 (d, 1H), 7.62 (t, 1H), 7.44-7.37 (m, 1 LC-MS MH+456, HCOOH:ACN, Rt=1.35min, 3min run; HPLC RT(A5) 4.68min.

[0525] 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

[0526]

[0527] 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

[0528] Procedure: Addition of tBu group to intermediate (32) as used in the synthesis of intermediate (17). Yield: 270 mg, 27.12%; LC-MS MH+ 595.6, NH4Oac:ACN, Rt = 4.48 min, 5 min run; 1 H NMR (400MHz, DMSO-d6) d8.49 (bs, 1H), 7.63 (s, 1H), 7.55 (d, 1H), 7.31-7.13 (m, 3H), 4.76 (s, 2H) ), 3.93(t, 2H), 3.67(s, 3H), 2.81(t, 2H), 2.67(s, 3H), 1.87(s, 3H), 1.32(s, 9H), 1.19(s, 9H).

[0529] 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

[0530] Procedure: Reduction of intermediate (35) was performed as for the synthesis of intermediate (18). Yield: 150 mg, (49.8%). LC-MS MH+ 598.3, NH4Oac:ACN, Rt = 3.77 min, 5 min run; 1 H NMR (400MHz, DMSO-d6)d 8.52(bs, 1H), 7.63(s, 1H), 7.60(d, 1H), 7.38(d, 1H), 7.32-7.21(m, 2H), 4.78(s, 2H), 4.61(d, 1H), 4.07(d, 1H), 3.96-3.87(m, 1H), 3.85-3.77(m, 1H), 3.52(s, 3H), 2.81-2.72(m, 1H), 2.68(s, 3H), 2.62-2.54(m, 1H), 1.78(s, 3H), 1.34(s, 9H), 0.73(s, 9H).

[0531] 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

[0532] Procedure: Intermediate (36) (150 mg, 0.251 mmol) was chirally separated by chiral preparative HPLC [column name: CHIRALPAK IC (250×20 mm, 5i), flow rate: 18.0 ml / min, mobile phase: HEX / ETOH / IPAMINE: 80 / 20 / 0.1 solubility: MEOH]. Preparative fractions were evaporated to give 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 was assigned arbitrarily). Intermediate (37a) (Isomer 1): LCMS (HCOOH:ACN): M+H=598.3, R t =2.48 min, 5 min running; Intermediate (37b) (Isomer 2): LCMS (HCOOH:ACN): M+H=598.3, R t =2.46min, 5min running.

[0533] 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

[0534]

[0535] Procedure: Deprotection of intermediate (37a) (Isomer 1) was carried out using the procedure used for Example 9 (Isomer 1). Yield: 40 mg, 91.09%. LC-MS MH+ 498.4, NH4Oac:ACN, Rt = 3.15 min, 5 min run; 1 H NMR (400MHz, DMSO-d6)d 9.83(bs, 2H), 9.23(s, 1H), 8.42(s, 1H), 8.07(d, 1H), 7.97(d, 1H), 7.62(t, 1H), 7.47-7.38(m, 1H), 4.74(s, 2H ), 4.11 (s, 1H), 3.97 (t, 2H), 3.63 (s, 3H), 2.88-2.78 (m, 1H), 2.73-2.52 (m, 4H), 2.04 (s, 3H), 0.76 (s, 9H); HPLC RT(A4)6.47min.

[0536] 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

[0537]

[0538] Procedure: Deprotection of intermediate (37b) (Isomer 2) was carried out using the procedure as in Example 10 (Isomer 2). Yield: 394 mg, 95.93%; LCMS (HCOOH:ACN): M+H=498.33, R t =1.53min, 3min operation; 1 H NMR (400MHz, DMSO-d6)d 10.10-9.86(m, 2H), 9.26(s, 1H), 8.44(s, 1H), 8.08(d, 1H), 7.98(d, 1H), 7.64(t, 1H), 7.46-7.38(m, 1H), 4.75(s, HPLC RT(A4)6.45min.

[0539] 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

[0540]

[0541] Procedure: The reductive amination of Example 13 (Isomer 1) was carried out using the same procedure as used for Example 11.

[0542] Yield: 22 mg, 53.46%. LCMS (HCOOH:ACN): M+H=512.29, R t =1.48min, 3min operation; 1 HNMR(400MHz, DMSO-d6)d 8.53 (s, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.38 (d, 1H), 7.32-7.24 (m, 2H), 4.635 (d, 1H), 4.08 (d, 1H), 3.99-3.91 (m, 1H), 3.88 HPLC RT(A4)6.49min.

[0543] 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

[0544]

[0545] Procedure: The reductive amination of Example 14 was carried out 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 =1.48min, 3min running. 1H NMR (400MHz, DMSO-d6)d 8.53 (s, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.38 (d, 1H), 7.35-7.26 (m, 2H), 4.635 (d, 1H), 4.08 (d, 1H), 3.97-3.91 (m, 1H), 3.8 HP LC RT(A3)5.32min.

[0546] 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

[0547]

[0548] Procedure: The reductive amination of Example 5 was carried out using the same procedure used for the synthesis of Example 11. Yield: 95.07 mg, 52.87%; LCMS (HCOOH:ACN): M+H=470.26, R t =1.38min, 3min operation; 1 H NMR (400MHz, DMSO-d6)d 8.49(s, 1H), 7.56(d, 1H), 7.52(s, 1H), 7.37-7.25(m, 3H), 4.77-4.67(m, 1H), 4.61-4.51(m, 1H), 3.95(t, 2H), 3.73(s, 2H), 3.51(s, 3H), 2.73(t, 2H), 2.14(s, 6H), 1.79(s, 3H), 1.21(d, 3H); HPLC RT(A1)5.85min.

[0549] 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

[0550]

[0551] 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

[0552] Procedure: The ester intermediate (30) was converted to the corresponding geminal dimethanol (38) using the procedure used for the synthesis of intermediate (23). Yield - 340.0 mg, 39.79%; 1 H NMR (d6-DMSO, 400MHz) δ8.52-8.48 (brs, 1H), 7.63 (s, 1H), 7.58 (d, 1H), 7.36 (d, 1H), 7.32-7.20 (brs, 2H), 4.77 (s, 2H), 4.61(s, 1H), 3.92(t, 2H), 3.43(s, 3H), 2.79(t, 2H), 2.68(s, 3H), 1.73(s, 3H), 1.33(s, 9H), 1.26(s, 6H); LC-MS MH+570, HCOOH:ACN, Rt=1.59min, 3min operation.

[0553] 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

[0554] Procedure: Intermediate (38) was deprotected using the same conditions as used for the synthesis of Example 18. Yield: 160.0 mg, 57.03%; 1 H NMR (d6-DMSO, 400MHz) δ8.52 (s, 1H), 7.55 (d, 1H), 7.49 (s, 1H), 7.35-7.25 (m, 3H), 4.64 (s, 1H), 3 .99(s, 2H), 3.95(d, 2H), 3.49(s, 3H), 2.83(t, 2H), 2.24(s, 3H), 1.79(s, 3H), 1.28(s, 6H); LC-MS MH+470, HCOOH:ACN, Rt=1.81min, 3min run; HPLC RT(A1)5.818min.

[0555] Intermediate (47): [2-(6-Bromo-imidazo[1,2-a]pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester

[0556]

[0557] Procedure: Intermediate 47 was prepared according to the method disclosed in WO2020 / 128473.

[0558] 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

[0559]

[0560] Step 1-Intermediate (48): tert-butyl (2-(6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)carbamate

[0561] Procedure: Intermediate (48) was prepared by coupling intermediate 47 and 12 using the procedure used for the synthesis of intermediate (29). Yield: 1.0 g, 76.29%; 1 H NMR (d6-DMSO, 400MHz) δ10.27 (s, 1H), 8.36 (s, 1H), 7.70-7.62 (brs, 1H), 7.54 (d, 1H) , 7.45-7.38(m, 2H), 6.98(t, 1H), 6.74(d, 2H) 3.27(t, 2H), 3.04(t, 2H), 1.30(s, 9H).

[0562] Step 2-Intermediate (50): 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 methyl ester

[0563] Procedure: Intermediate (50) was synthesized by coupling intermediates 48 and 49 using the same procedure used for the synthesis of intermediate (30). Yield: 300.0 mg, 67.26%; 1 H NMR (d6-DMSO, 400MHz) δ8.33 (s, 1H), 7.49 (d, 1H), 7.44 (d, 1H), 7.41 (s, 1H), 7.20 (d, 1H), 7.07 (d, 1H), 6.97 (t, 1H), 6.87 (t, 1H), 4.12 (t, 2H) , 3.70 (s, 3H), 3.68 (s, 3H), 3.32-3.24 (m, 2H), 3.03-3.00 (m, 4H), 1.90 (s, 3H), 1.29 (s, 9H); LC-MSMH+552, NH4Oac:ACN, Rt=3.13min, 5min operation.

[0564] 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

[0565] Procedure: Intermediate (51) was prepared by hydrolysis of intermediate (50) using the procedure used for intermediate (31). Yield: 290.0 mg, 99.08%; 1 H NMR (CDCl3, 400MHz) δ8.15 (s, 1H), 7.90-7.86 (m, 1H) 7.63-7.59 (m, 2H), 7.51-7.45 (m, 2H), 6.75-6.72 (m, 2 LC-MS MH+538, NH4Oac:ACN, Rt=2.63min, 5min operation.

[0566] 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

[0567] 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%; 1 H NMR (d6-DMSO, 400MHz) δ8.62 (s, 1H), 7.74-7.66 (m, 3H), 7.50 (t, 1H), 7.12-7.09 (m, 1H), 6.99 (t, 1H), 6.92 (t, 1H), 4 .12(t, 2H), 3.68(s, 3H), 3.65(s, 3H), 3.25(s, 3H), 3.11-3.09(m, 2H), 2.89(t, 3H), 1.99(s, 3H), 1.27(s, 9H); LC-MS MH+581, NH4Oac:ACN, Rt=3.04min, 5min operation.

[0568] 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

[0569] Procedure: Intermediate (53) was prepared from intermediate (52) by addition of MeMgBr using the same procedure used for the preparation of intermediate (33). Yield - 20.0 mg, 21.69%. 1 H NMR (d6-DMSO, 400MHz) δ8.36 (s, 1H), 7.50 (d, 1H), 7.45-7.41 (m, 2H), 7.21 (d, 1H), 7.09 (d, 1H), 6.97 (t, 1H), 6.87 (t, 1H), 4.10 (t, 1H), 3. 70 (s, 3H), 3.29-3.26 (m, 2H), 3.03-2.97 (m, 4H), 2.32 (s, 3H), 1.90 (s, 3H), 1.30 (s, 9H); LC-MSMH+536, NH4Oac:ACN, Rt=3.43min, 5min operation.

[0570] 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

[0571] Procedure: Intermediate (54) was prepared from intermediate (53) using the same procedure used for the synthesis of Example 19. Yield: 35.0 mg, 56.78%; 1 H NMR (d6-DMSO, 400MHz) δ8.34 (s, 1H), 7.50 (d, 1H), 7.42 (t, 1H), 7.38 (s, 1H), 7.28 (d, 1H), 7.03 (d, 1H), 6.95 (s, 1H), 6.84 (t , 1H), 4.78(s, 1H), 4.09(t, 2H), 3.51(s, 3H), 3.24(d, 2H), 3.00(t, 2H), 2.90(t, 2H), 1.88(s, 3H), 1.37(s, 9H), 1.27(s, 6H).

[0572] 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

[0573] Procedure: Example 23 was prepared from intermediate (54) using the same deprotection procedure as used for Example 18. Yield: 15.0 mg, 50.30%; 1H NMR (d6-DMSO, 400MHz) δ8.41 (s, 1H), 7.52 (d, 1H), 7.44-7.41 (m, 2H), 7.28 (d, 1H), 7.06 (d, 1H), 6.86 (t , 1H), 4.89-4.85 (brs, 1H), 4.11 (t, 2H), 3.54 (s, 3H), 2.97-2.87 (m, 6H), 1.90 (s, 3H), 1.40 (s, 6H); HPLC RT(B1)6.674min.

[0574] 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

[0575]

[0576] 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

[0577] Procedure: Intermediate (55) was prepared by reducing intermediate (53) using the same procedure as intermediate (21). Yield: 35.0 mg, 58.16%; 1 H NMR (d6-DMSO, 400MHz) δ8.36 (s, 1H), 7.52 (d, 1H), 7.47-7.41 (m, 2H), 7.29 (d, 1H), 7.05-6.98 (m, 2H), 6.87 (t, 1H), 4.83 (d, 1H), 4.66(t, 1H), 4.09(t, 2H), 3.55(s, 3H), 3.31(t, 2H), 3.02(t, 2H), 2.85-2.75(m, 2H), 1.91(s, 3H), 1.30-1.13(m, 12H).

[0578] 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

[0579] Procedure: Example 7 was prepared by deprotection of intermediate (55) using the procedure for Example 1. Yield: 35.0 mg, 98.00%. 1H NMR (d6-DMSO, 400MHz) δ8.95 (s, 1H), 8.19 (brs, 3H), 8.15 (s, 1H), 8.07 (d, 1H), 8.00 (d, 1H), 7.55 (t, 1H), 7.14 (d, 1H), 6.96 ( t, 1H), 4.66 (s, 1H), 4.13 (t, 2H), 3.62 (s, 3H), 3.44 (t, 2H), 3.19 (s, 2H), 2.88-2.81 (m, 2H), 2.02 (s, 3H), 1.28 (d, 3H); LC-MS MH+438, HCOOH:ACN, Rt=1.22min, 3min run; HPLC RT(A2) 6.53min.

[0580] 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

[0581]

[0582] Step 1 - Intermediate (57): 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid

[0583] Procedure: To a stirred solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester (intermediate (56)) (10.0 g, 40.486 mmol) in THF (112 ml) and water (28 ml) was added ethanol (6 ml). Then LiOH.HO (3.401 g, 80.972 mmol) was added in batches at 0 ° C and the resulting mixture was stirred at RT for 16 h. After checking TLC, it showed that the desired product was formed. The reaction mixture was then distilled under vacuum. The crude reaction mixture was acidified by 6N 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. 1 H NMR (400MHz, DMSO-d6) δ 12.73 (bs, 1H), 3.84 (s, 3H), 2.26 (s, 3H).

[0584] Step 2-Intermediate (58)-4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxamide

[0585] 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 for 3 h at RT. Thereafter, the reaction mixture was evaporated under N2 atmosphere. The acid chloride was then dissolved in THF and slowly added to ammonia solution 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 =1.45min, 3min operation; 1 H NMR (400MH z, DMSO-d6) δ7.38 (s, 1H), 7.22 (s, 1H), 3.81 (s, 3H), 2.24 (s, 3H).

[0586] Step 3-Intermediate (59): 4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonitrile

[0587] 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 stirred at RT for 2 h. Thereafter, the volatiles were evaporated under N2 atmosphere and quenched with saturated sodium bicarbonate solution. The reaction mixture was diluted with ethyl acetate, the organic layer was washed with brine solution and separated, dried over sodium sulfate and concentrated in vacuo. The crude was then purified by column chromatography (by using 100-200 silica gel and eluting with 10% ethyl acetate / hexane) to give 4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonitrile (59) (5.5 g, 85.63%). 1 H NMR (400MHz, DMSO-d6) δ3.89 (s, 3H), 2.29 (s, 3H).

[0588] Step 4-Intermediate (60): 1,5-dimethyl-4-vinyl-1H-pyrazole-3-carbonitrile

[0589] 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 vinyl stannane (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 product formation with complete consumption of the 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 compound was purified by column chromatography (silica gel, 100-200 mesh) (eluted 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 =1.68min, 3min operation; 1 H NMR (400MHz, CDCl3) δ6.60 (dd, 1H), 5.73 (d, 1H), 5.35 (d, 1H), 3.82 (s, 3H), 2.31 (s, 3H).

[0590] Step 5-Intermediate (61): 4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carbonitrile

[0591] 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 h. 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, dissolved in ethanol (50.0 ml), sodium borohydride (1.448 g, 39.141 mmol) was added portionwise under ice-cooling. The reaction mixture was stirred at 0°C for 30 min. After completion of the reaction, the mixture was quenched with sodium bicarbonate solution and diluted with ethyl acetate, washed with water, brine, concentrated in vacuo to give a crude material, which was purified by combi flash 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, 3 min run; 1 H NMR (400MHz, DMSO)d 4.72 (bs, 1H), 3.79 (S, 3H) 3.47 (t, 2H) 2.58 (t, 2H), 2.22 (s, 3H).

[0592] Step 6-Intermediate (62) ((6-(2-(2-(3-cyano-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(methyl)carbamic acid tert-butyl ester

[0593] Procedure: Intermediate (62) was prepared by coupling intermediate 61 and 13 using the procedure used for intermediate (14). Yield: 260 mg, 37.3%; 1 H NMR (d6-DMSO, 400MHz) δ8.43 (bs, 1H), 7.61 (s, 1H), 7.53 (d, 1H), 7.34 (t, 1H), 7.20 (d, 1H), 7.13-7.07 (m, 1H), 6.86 (t, 1H), 4.75 (s, 2H), 4 .15 (t, 2H), 3.68 (s, 3H), 2.93-2.82 (m, 2H), 2.66 (s, 3H), 1.93 (bs, 3H), 1.32 (s, 9H); LCMS (HCOOH:ACN): M+H=519.58, Rt=1.55min, 3min run.

[0594] 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

[0595] Procedure: Intermediate (63) was prepared from intermediate (62) by addition of isopropyl MgBr using the same procedure used for the synthesis of intermediate (23). Yield: 450 mg, 75.19%.

[0596] 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

[0597] Procedure: Intermediate 289 was synthesized by deprotection of intermediate (63) using the procedure for intermediate (20). Yield: 250 mg, 66.01%; 1 H NMR (d6-DMSO, 400MHz) δ9.23 (bs, 2H), 9.03 (s, 1H), 8.20 (s, 1H), 7.88 (s, 2H), 7.62 (t, 1H), 7.17 (d, 1H), 6.98 (t, 1 H), 4.71 (s, 2H), 4.10 (t, 2H), 3.77 (s, 3H), 3.66-3.61 (m, 1H), 3.02 (t, 2H), 2.63 (s, 3H), 2.04 (s, 3H), 1.02 (d, 6H).

[0598] 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

[0599] Procedure: Intermediate (290) was prepared by reductive amination of intermediate (289) using the procedure for the synthesis of (274). Yield: 7 mg, 3.65%; 1H NMR (d6-DMSO, 400MHz) δ8.42 (s, 1H), 7.51 (d, 1H), 7.47 (s, 1H), 7.38 (t, 1H), 7.22 (d, 1H), 7.07-7.01 (m, 1H ), 6.88-6.81(m, 1H), 4.05(t, 2H), 3.75-3.58(m, 6H), 2.98(t, 2H), 2.11(s, 6H), 1.84(s, 3H), 1.01(d, 6H).

[0600] 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

[0601]

[0602] 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 for the synthesis of Example 2. Yield: 13 mg, 32.37%; 1 H NMR (d6-DMSO, 400MHz) δ8.46 (s, 1H), 7.53 (d, 1H), 7.47 (s, 1H), 7.40 (t, 1H), 7.30 (d, 1H), 7.01 (d, 1H), 6.85 (t, 1H), 4.82 (d, 1 H), 4.11-3.94(m, 3H), 3.70(s, 2H), 3.53(s, 3H), 2.88-2.71(m, 2H), 2.12(s, 6H), 1.98-1.81(m, 4H), 0.91(d, 3H), 0.63(d, 3H).

[0603] 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

[0604]

[0605] Step 1-Intermediate (74): 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)-N-(4-methoxybenzyl)methanamine

[0606] 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 to give 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)-N-(4-methoxybenzyl)methanamine (74) (2.2 g, 47.66%). LC-MS MH + 345.6, NH4Oac:ACN, R t =3.43min, 5min running.

[0607] Step 2-Intermediate (75) tert-butyl N-({6-bromoimidazo[1,2-a]pyridin-3-yl}methyl)-N-[(4-methoxyphenyl)methyl]carbamate

[0608] 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%; 1 H NMR (d6-DMSO, 400MHz) δ8.62 (bs, 1H), 7.63-7.47 (m, 2H), 7.35 (d, 1H), 7.0 3(d, 2H), 6.79(d, 2H), 4.72(s, 2H), 4.20(s, 2H), 3.70(s, 3H), 1.46(s, 9H).

[0609] LCMS (HCOOH:ACN): M+H = 446.33 and 448.28, Rt = 1.73 min, 3 min run.

[0610] Step 3-Intermediate (76): tert-butyl ((6-(3,4-difluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)(4-methoxybenzyl)carbamate

[0611] Procedure: Intermediate (76) was prepared by coupling intermediate (74) and (5) using the procedure as used for intermediate (13). Yield: 1.4 g, 73.96%; LCMS (HCOOH:ACN): M+H=496.3, Rt=2.07 min, 3 min run.

[0612] Step 4-Intermediate (77) 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 ethyl ester

[0613] Procedure: Intermediate (77) was synthesized by coupling intermediate (76) and (7) using the procedure as used for intermediate (14). Yield: 200 mg, 35.9%; LCMS (HCOOH:ACN): M+H=690.29, Rt=1.97 min, 3 min run.

[0614] 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

[0615] Procedure: Intermediate (78) was synthesized by hydrolysis of intermediate (77) using the procedure for intermediate (15). Yield: 900 mg, 93.71%; LCMS (HCOOH:ACN): M+H=662.6, Rt=2.02 min, 3 min run.

[0616] 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

[0617] Procedure: Intermediate (79) was synthesized by amidation of intermediate (78) using the same procedure used for intermediate (16). Yield: 430 mg, 44.83%; 1H NMR (d6-DMSO, 400MHz) δ8.42 (bs, 1H), 7.60 (bs, 1H), 7.53 (d, 1H), 7.27 (d, 2 H), 7.17(bs, 1H), 7.07(d, 2H), 6.80(d, 2H), 4.73(s, 2H), 4.19(s, 2H), 3.95( t, 2H), 3.69 (s, 3H), 3.62 (s, 3H), 3.59 (s, 3H), 3.16 (s, 3H), 2.72 (t, 2H), 1. 87 (s, 3H), 1.35 (s, 9H); LCMS (HCOOH:ACN): M+H=705.4, Rt=2.16min, 3min run.

[0618] Step 7-Intermediate (80): 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)(4-methoxybenzyl)carbamate

[0619] Procedure: Intermediate (8) was synthesized from intermediate (79) by addition of tBu using the same procedure as intermediate (17). Yield: 200 mg, 46.66%. 1 H NMR (d6-DMSO, 400MHz) δ8.41 (bs, 1H), 7.60 (bs, 1H), 7.52 (d, 1H), 7.26 (d , 2H), 7.17(bs, 1H), 7.06(d, 2H), 6.80(d, 2H), 4.72(s, 2H), 4.18(s, 2H), 3.93 (t, 2H), 3.69 (s, 3H), 3.67 (s, 3H), 2.81 (t, 2H), 1.89 (s, 3H), 1.34 (s, 9H), 1.20 (s, 9H); LCMS (HCOOH:ACN): M+H=702.78, Rt=1.87min, 3min operation.

[0620] 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

[0621] Procedure: Intermediate (81) was synthesized by reducing intermediate (80) using the same procedure as intermediate (21). Yield: 140 mg, 69.75%; 1H NMR (d6-DMSO, 400MHz) δ8.44 (bs, 1H), 7.65-7.52 (m, 2H), 7.37 (d, 1H), 7.31-7.18 (m, 2H), 7.08 (d, 2H), 6.81 (d, 2H), 4.73 (s, 2H), 4.60 (d, 1H), 4.18 (s, 2H), 4.07 (d , 1H), 3.96-3.79 (m, 2H), 3.70 (s, 3H), 3.52 (s, 3H), 2.81-2.71 (m, 1H), 1.80 (s, 3H), 1.36 (s, 9H), 0.74 (s, 9H); LCMS (HCOOH:ACN): M+H=704.76, Rt=1.76 min, 3 min running.

[0622] 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

[0623] Procedure: At 0 ° C, to a stirred solution of intermediate (81) (130 mg, 0.185 mmol) in acetonitrile (2.7 ml), ceric ammonium nitrate (202.573 mg, 0.37 mmol) dissolved in water (0.3 ml) was added. The reaction mixture was stirred for 1 h at the same temperature. The reaction mixture was checked by TLC and LCMS 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 under vacuum to obtain a 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, 3 min run.

[0624] 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

[0625] Procedure: Example 17 was synthesized by deprotection of intermediate (82) using the same procedure as used for Example 9 (Isomer 1). Yield: 22 mg, 66.31%; 1 H NMR (d6-DMSO, 400MHz) δ9.18 (s, 1H), 8.95-8.77 (m, 3H), 8.35 (s, 1H), 8.08 (d , 1H), 7.97(d, 1H), 7.58(t, 1H), 7.48-7.35(m, 1H), 4.77(s, 2H), 4.12(s, 1H), 4.03-3.94(m, 2H), 3.63(s, 3H), 2.91-2.78(m, 1H), 2.72-2.61(m, 1H), 2.03(s , 3H), 0.77 (s, 9H); LCMS (HCOOH:ACN): M+H=484.38, Rt=1.51min, 3min run; HPLC RT(A3)3.84min.

[0626] 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

[0627]

[0628] Step 1 - Intermediate (83): 1,5-dimethyl-1H-pyrazole-3-carboxylic acid

[0629] Procedure: To a solution of ethyl 1,5-dimethyl-1H-pyrazole-3-carboxylate (intermediate (2)) (20.0 g, 118.984 mmol) in THF: water (4: 1) (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 hr. 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) (16 g, 99%) as a light yellow solid. 1 H NMR (400MHz, DMSO)d 12.42 (s, 1H), 6.45 (s, 1H), 3.77 (s, 3H), 2.25 (s, 3H).

[0630] Step 2-Intermediate (84): N-methoxy-N,1,5-trimethyl-1H-pyrazole-3-carboxamide

[0631] 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 h. TLC was checked, which showed product formation. The reactant 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 N-methoxy-N,1,5-trimethyl-1H-pyrazole-3-carboxamide (84) (15.0 g, 69.05%) as a light yellow solid. 1 H NMR (400 MHz, DMSO) d 6.41 (s, 1H), 3.76 (s, 3H), 3.67 (s, 3H), 3.32 (s, 3H), 2.26 (s, 3H); LCMS (NH4Oac:ACN): M+H=184, Rt=2.17 min, 5 min run.

[0632] Step 3 - Intermediate (85): 1-(1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one

[0633] 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 tert-butyl lithium (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 hrs. TLC was checked, which showed product formation, and the reaction mixture was quenched with saturated NH4Cl solution. The reaction mixture was diluted with ethyl acetate and washed with water, brine solution. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by combiflash chromatography using 5% MeOH in DCM to afford 1-(1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (85) (6.0 g, 40.63%) as a light yellow solid. 1H NMR (400 MHz, DMSO) d 6.45 (s, 1H), 3.79 (s, 3H), 2.25 (s, 3H), 1.31 (s, 9H); LCMS (HCOOH:ACN): M+H=181, Rt=1.86 min, 3 min run.

[0634] Step 4 - Intermediate (86): 1-(4-bromo-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one

[0635] Procedure: N-bromosuccinimide (6.191 g, 34.975 mmol) was added in batches 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) under ice-cold conditions. The resulting reaction mixture was stirred at RT for 16 hr. TLC and LCMS were checked, which showed product formation. 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) (8.0 g, 92.68%) as a yellow solid compound, which was used in the next step without purification. 1 HNMR (400 MHz, DMSO) d 3.86 (s, 3H), 2.25 (s, 3H), 1.30 (s, 9H); LCMS (NH4Oac:ACN): M+H=259, Rt=3.59 min, 5 min run.

[0636] Step 5 - Intermediate (87): 1-(1,5-dimethyl-4-vinyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one

[0637] 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 tributyl vinyl tin (17.2 ml, 54.257 mmol) at room temperature. Argon was then purged through the reaction mixture for 15 min and Pd(PPh3)4 (3.133 g, 2.713 mmol) was added. The reaction mixture was stirred at 110°C for 16 hr. TLC was checked, which showed that the starting material was consumed and the desired product was formed. The reaction mixture was then diluted with ethyl acetate and washed with potassium fluoride solution, the precipitate was filtered through cintre and 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-hexanes to give 1-(1,5-dimethyl-4-vinyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (87) (5.0 g, 89.35%). 1 H NMR (400 MHz, DMSO) d 6.96-6.89 (m, 1H), 5.29-5.20 (m, 2H), 3.82 (s, 3H), 2.31 (s, 3H), 1.30 (s, 9H); LCMS (HCOOH:ACN): M+H=207, Rt=2.19 min, 3 min run.

[0638] Step 6 - Intermediate (88): 2-(1,5-dimethyl-3-pivaloyl-1H-pyrazol-4-yl)acetaldehyde

[0639] 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. 1H NMR (400 MHz, DMSO) d 9.49 (s, 1H), 3.82 (s, 3H), 3.65 (s, 2H), 2.17 (s, 3H), 1.30 (s, 9H); LCMS (NH4Oac:ACN): M+H=223, Rt=1.86 min, 3 min run.

[0640] Step 7-Intermediate (89): 1-(4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one

[0641] 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) in portions under ice-cold conditions. The reaction mixture was stirred at 0 °C for 30 min. After completion of the reaction, the mixture was quenched with sodium bicarbonate solution and diluted with ethyl acetate, washed with water, brine, concentrated in vacuo to give the crude. This batch was purified by combi flash 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. 1 H NMR (400 MHz, DMSO) d 4.46 (t, 1H), 3.77 (s, 3H) 3.36 (t, 2H), 2.69 (t, 2H), 2.17 (s, 3H), 1.30 (s, 9H); LCMS (HCOOH:ACN): M+H=225, Rt=1.81 min, 3 min run.

[0642] 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

[0643] 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 hr. TLC and LCMS showed product formation and the reaction mixture was diluted with ethyl acetate and washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by combiflash using 5% MeOH-DCM to afford 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) (3.0 g, 49.05%) as a brown sticky gum. 1 H NMR (400MHz, DMSO)d 8.50-8.42(brs, 1H), 7.62(s, 1H), 7.53(d, 1H), 7.30-7.15(m, 3H), 4.76(s, 2H), 3.92(t, 2H), 3.67(s, 3H), 2.81 (t, 2H), 2.67 (s, 3H), 1.86 (s, 3H), 1.32 (s, 9H), 1.19 (s, 9H); LCMS (HCOOH:ACN): M+H=596, Rt=1.75min, 5min run.

[0644] 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

[0645] 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 h. After completion of the reaction, the solvent was evaporated, diluted with DCM and washed with sodium bicarbonate solution, water, 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 afford 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%). 1 H NMR (400MHz, DMSO)d 8.55-8.45(brs, 1H), 7.63(s, 1H), 7.60(d, 1H), 7.38(d, 1H), 7.35-7.25(brs, 2 H), 4.78 (s, 2H), 4.60 (d, 1H), 4.07 (d, 1H), 3.92-3.88 (m, 1H), 3.84-3.78 (m, 1H) , 3.52 (s, 3H), 2.80-2.70 (m, 1H), 2.68 (s, 3H), 2.60-2.52 (brs, 1H), 1.78 (s, 3H), 1.34 (s, 9H), 0.74 (s, 9H); LCMS (NH4Oac:ACN): M+H=598, Rt=3.75min, 5min running.

[0646] 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

[0647] 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 2M HCl in diethyl ether (40.0 ml) at 0°C. The reaction mixture was stirred at rt for 3 h. TLC and LCMS showed consumption of starting material. The reaction mixture was evaporated under reduced pressure to give the crude. The crude 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 (HCl salt) (1.04 g, 96.93 mmol, 49%) as a light yellow solid. 1 H NMR (400MHz, DMSO)d 10.02-9.96(brs,2H),9.26(s,1H),8.44(s,1H)8.08(d,1H),7.98(d,1H) ,7.64(t,1H),7.46-7.40(m,1H),4.75(s,3H),4.16(s,1H),3.97(t,2H), 3.71 (s, 3H), 2.87-2.80 (m, 1H), 2.72-2.65 (m, 1H), 2.60 (s, 3H), 2.09 (s, 3H), 0.76 (s, 9H); LCMS (HCOOH:ACN): M+H=498, Rt=2.54min, 5min run; HPLC RT(B3)8.739min.

[0648] 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

[0649] Example 20 was prepared by the same route as Example 21 starting with tert-butyl N-({6-bromoimidazo[1,2-a]pyridin-3-yl}methyl)-N-[(4-methoxyphenyl)methyl]carbamate to produce two amine protecting groups which were cleaved sequentially using the same procedure used for Example 17 to give 60 mg (49%) of Example 20. 1H NMR (d6-DMSO, 400MHz) δ8.54 (s, 1H), 7.55 (d, 1H), 7.47 (s, 1H) 7.31 (m, 3H), 4.66 (brds, 1H) 4.07 (s, 2H), 3.95 (t, 2H), 2.83 (m, 2H), 2.40 (brds, 1H), 1.81 (s, 3H), 1.28 (s, 6H); LCMS (HCOOH:ACN): M+H=456.30., Rt=1.471min, 3min run; HPLC RT(A4)5.672min.

[0650] 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

[0651] Example 22 was prepared starting from the corresponding ({6-bromoimidazo[1,2-a]pyridin-3-yl}methyl)(ethyl)amine by the same route as Example 18. The final deprotection step afforded Example 22 (466 mg, 55%). 1 H NMR (d6-DMSO, 400MHz) δ8.51 (s, 1H), 7.54 (d, 1H), 7.48 (s, 1H), 7.43 (t, 1H), 7.32 (d, 1H) 7.05 (d, 1H), 6.878 (t, 1H), 4.80 (s, 1 LC-MS MH+466, NH4Oac:ACN, Rt=1.61min, 3min run; HPLC RT(A6)5.257min.

[0652] 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

[0653] Example 22 was prepared starting from intermediate (28) by the same route as Example 24. Final step deprotection gave 38 mg, 66% of Example 25. 1H NMR (d6-DMSO, 400MHz) δ8.55 (s, 1H), 7.56 (d, 1H), 7.51 (s, 1H), 7.31 (m, 3H), 4.72 (s, 1H), 4.03 (s, 2H ), 3.94(m, 2H), 3.88(m, 1H), 3.53(s, 3H), 2.72(t, 2H), 2.26(s, 3H), 0.84(d, 3H), 0.52(d, 3H); LC-MS MH+484.36, FA:ACN, Rt=1.52min, 3min run; HPLC RT(B1)9.062min.

[0654] Synthetic Antibody Drug Conjugate (ADC) Example 1 - Trastuzumab-NMT Inhibitor ADC

[0655] Synthetic drug conjugate 1: (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-(3-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}propionamido)propionamido]phenoxy)-3,4-dihydroxy-2-methylcyclohexane-1-carboxylic acid (as hydrate)

[0656]

[0657] Step 1: To a solution of (1S,2R,3S,4R,5R)-5-[2-(3-{[(9H-fluoren-9-yloxy)carbonyl]amino}propionamido)-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 purified directly 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}propionamido)phenoxy)-2,3,4-trihydroxycyclohexane-1-carboxylic acid (ADC intermediate 2) (107 mg) as a white solid after lyophilization.

[0658] 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}propionamido)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 (1 N, aq., 0.5 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 8 h. 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) (TFA salt, 42 mg) as a white solid after lyophilization.

[0659] Step 3: To a solution of (1S,2R,3S,4R,5R)-5-[2-(3-aminopropionamido)-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 purified directly 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}propionamido)phenoxy)-2,3,4-trihydroxycyclohexane-1-carboxylic acid hydrate (drug conjugate 1) (36 mg) as a white solid after lyophilization.

[0660] Preparation of ADC Example 1 - Trastuzumab-NMT Inhibitor ADC (DAR 5)

[0661] Trastuzumab was purchased and reconstituted to obtain a 25mg / mL solution. 5% v / v of 500mM Tris, 25mM EDTA (pH 8.5) was added to adjust the pH, followed by reduction and conjugation. 2.5 molar equivalents of TCEP (tris (2-carboxyethyl) phosphine) were added relative to the antibody from a 10mM mother liquor in water, and the antibody was reduced for 90 minutes. 8 molar equivalents of drug conjugate 1 were added from a 10mM mother liquor in DMA (dimethylacetamide), and the reduced antibody was conjugated for 60 minutes. 8 molar equivalents of NAC (N-acetylcysteine) were added from a 10mM mother liquor in water to quench unreacted drug conjugate 1, and it was reacted for 20 minutes. The conjugate was purified by preparative SEC (size exclusion chromatography) using a Superdex200PG column equilibrated in PBS. Protein-containing fractions were pooled and subjected to final filtration through appropriately sized 0.2 μm PES filters (Chromatograph Direct / FIL-S-PES-022-13-100-S) under laminar flow class A. The final product was sampled for the following QC tests: determination of monomer and [ADC] mg / ml by SEC HPLC, determination of average DAR (drug to antibody ratio) by PLRP-HPLC (polymeric reverse phase HPLC), determination of residual NMT inhibitor 1 by RP-HPLC, and determination of endotoxin by Endosafe kinetic chromogenic assay.

[0662] ADC Example 3 was prepared using the same method described for ADC Example 1, except that saccituzumab was used as the antibody instead of trastuzumab.

[0663] ADC Example 4 was prepared using the same method described for ADC Example 1, except that ifinatumomab was used as the antibody instead of trastuzumab.

[0664] Preparation of ADC Example 5

[0665] Preparation of ADC Example 5 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:

[0666]

[0667] Wherein steps 1 to 3 are as described for drug conjugate 1.

[0668] Herceptin (trastuzumab) was purchased and reconstituted to obtain 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, followed by reduction and conjugation. 2.55 molar equivalents of TCEP (tris (2-carboxyethyl) phosphine) were added relative to the antibody from a 5 mM mother solution in water, and the antibody was reduced for 120 minutes. Prior to conjugation, the reduced mAb was diluted 1 / 3 with PBS. 8 molar equivalents of drug conjugate 2 were added from a 10 mM mother solution in DMA (dimethylacetamide), and the reduced antibody was conjugated for 90 minutes. 8 molar equivalents of NAC (N-acetylcysteine) were added from a 100 mM mother solution in water to quench unreacted drug conjugate 2, and allowed to react for 20 minutes. The conjugate was buffer exchanged into PBS using G25 resin (NAP25 column), then given activated carbon with 1mg carbon: 1mg ADC ratio, and incubated overnight at room temperature on a roller mixer with 10rpm. The conjugate was then spun down at 4000xG for 15 minutes to precipitate activated carbon, and the supernatant (ADC) was taken out and filtered through a 0.2μm PES filter. The Amicon15 device was then used to further purify and concentrate the conjugate by diafiltration, wherein the PBS (pH7.4) of 6x diafiltration volume (DV) was used in buffer exchange. The conjugate was then finally filtered by a 13mm 0.2μm PES filter (chromatography direct type / FIL-S-PES-022-13-100-S) under a grade A laminar flow, then prepared in 0.02% PS80. The final product was sampled for the following QC tests: monomer and [ADC] mg / ml by SEC HPLC, mean DAR by PLRP, residual NMT inhibitors by RP-HPLC, and endotoxin by Endosafe.

[0669] Preparation of ADC Example 6

[0670] ADC Example 6 was prepared using the same method as described for ADC Example 1, except that Drug Conjugate 3 was used, wherein the linker used was GGFG.

[0671] Structure of drug conjugate 3:

[0672]

[0673] It can be prepared using the same method as drug conjugate 1.

[0674] Biological Examples

[0675] Biological Example 1: HsNMT1 IC 50

[0676] Based on the detection of CoA by 7-diethylamino-3-(4-maleimido-phenyl)-4-methylcoumarin, the IC values ​​of certain example compounds and comparative compound 1 against human NMT1 (HsNMT1) were measured using a sensitive fluorescence-based assay. 50 Values ​​as described in Goncalves, V. et al., Analytical Biochemistry, 2012, 421, 342-344 and Goncalves, V. et al., J. Med. Chem, 2012, 55, 3578.

[0677] Results: HsNMT1 IC of some of the examples of the present invention and comparative compound 1 50 The values ​​are shown in the following Table 1. The results indicate that the Test Example compounds of the present invention are highly effective inhibitors of human NMT.

[0678] Biological Example 2: Cytotoxicity in the SU-DHL-10 cell line

[0679] Certain example compounds of the invention and comparative compound 1 were tested in the SU-DHL-10 cell line (human B-cell lymphoma). Compounds showing efficacy in this assay are expected to be useful as agents for treating or preventing hyperproliferative disorders such as cancer.

[0680] Cells were seeded in 96-well microplates and treated with 9 increasing concentrations of compounds or cisplatin (as a positive control) in technical triplicate. The IC values ​​of the test compounds and cisplatin were determined after 72 h of treatment in each cell line. 50 .

[0681] 1. On day 1, 90 μL of various cell suspensions with cell numbers ranging from 5000 to 8000 cells / well were inoculated into the wells of a 96-well plate (Corning). The number of cells to be inoculated was determined in advance.

[0682] 2. Place all 96-well plates containing cells in an incubator at 37°C and 5% CO2 overnight.

[0683] 3. On day 2, observe the cells under a microscope to ensure that the cells treated with vehicle control are in good condition.

[0684] 4. Prepare a dilution series of test compounds and cisplatin at 10X desired final concentration. Add 10 μL / well of 10X compound solution to the corresponding plate. The final volume for all plates is 100 μL / well. The final DMSO concentration is 0.1%.

[0685] 5. On day 5 (after 72 hours incubation), add 50 μL of CTG reagent to each well.

[0686] 6. Mix the contents on an orbital shaker for 5 minutes to promote cell lysis.

[0687] 7. Incubate the plate at room temperature for 10 minutes to allow the luminescent signal to stabilize.

[0688] Luminescence was recorded using an EnVision Multi Label Reader. Data analysis was performed using GraphPadPrism 8.0.

[0689] To calculate IC 50 Concentration response curves were generated using a nonlinear regression model with a sigmoidal concentration response. The formula used to calculate the % viable cells is shown below, and the IC was automatically generated by GraphPad Prism 8.0. 50 .

[0690]

[0691] (lum Test Article = luminescence in test article treated wells; Lum Untreated = luminescence in vehicle treated wells; Lum Medium Control = luminescence in wells containing medium only and no cells; Lum Untreated-lum Medium Control was set to 100%)

[0692] Results: The IC values ​​of some of the compounds of the present invention are provided in Table 1 below. 50 Table 1 also shows the IC values ​​of comparative compound 1. 50 The results indicate that the test compounds of the present invention exhibit potent cytotoxic activity. Many of the example compounds are significantly more potent than comparative compound 1.

[0693] Table 1: Results of Biological Examples 1 and 2

[0694]

[0695]

[0696] Biological Example 3: Cytotoxicity in Additional Cell Lines

[0697] As described in Biological Example 2, the effect of comparing Compound 1 and certain Example compounds on the survival rate 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 cancer), DU4475 (human breast cancer), LU2511 (human lung large cell undifferentiated carcinoma), LU0884 (human lung squamous cell carcinoma), Panc-1 (human pancreatic cancer), MCF-7 (human breast cancer), SW480 (human colon adenocarcinoma) and HCC1806 (human ductal carcinoma)) was analyzed using standard CellTiter-Glo assay (CTG, Promega). It is expected that compounds that show efficacy in these assays can be used as agents for the treatment or prevention of hyperproliferative disorders (such as cancer).

[0698] Results: The IC values ​​of some of the compounds of the present invention are provided in Table 2 below. 50 Table 2 also shows the IC values ​​of comparative compound 1. 50 value. Figures 1A to 2B The inhibition percentage values ​​of certain example compounds, comparative compound 1 and cisplatin (as a control) tested in certain analyses listed above are shown. The results indicate that the test compounds of the present invention exhibit potent cytotoxic activity in different cell lines. In different cell lines, the tested example compounds are more potent than comparative compound 1.

[0699] Table 2: IC of comparative compound 1 and certain example compounds 50 value

[0700]

[0701]

[0702] Biological Example 4: Mouse Xenograft Model

[0703] In the subcutaneous xenograft DOHH-2 lymphoma model, 10 6-8 week old female CB17 / SCID mice were used to evaluate the in vivo efficacy of certain example compounds. Each mouse was subcutaneously inoculated in the right anterior region with DOHH-2 tumor cells (5×10 6 ), for tumorigenesis. When the average tumor size reaches about 100-150mm 3After 1 , test compound administration was started. Compounds were administered IP (vehicle 10 mM sodium phosphate + 0.2% Tween-80 (pH 7.4)) or orally (vehicle 15 Na2HPO4 buffer (10 mM) (pH 4.5) + 0.2% tween 80). Tumor volume was measured in two dimensions using calipers and expressed in mm using the following formula: 3 Volume is expressed as: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension) and W is the tumor width (the longest tumor dimension perpendicular to L).

[0704] Example 21 (12.5 or 25 mg / kg) was orally administered to mice once a day for 9 consecutive days ( Figure 3 Example 5 (7 or 20 mg / kg) was administered intraperitoneally in a cycle consisting of three days of once daily (QD) administration, followed by a three-day dosing-free period, followed by an additional three days of QD dosing ( Figure 4 Example 12 (0.7 or 2 mg / kg) was administered intraperitoneally in a cycle consisting of three days of QD administration, followed by a three-day dosing-free period, followed by an additional three days of QD administration ( Figure 5 In a separate study, Example 12 was administered at 2 mg / pk in a cycle consisting of two days of QD administration followed by a four-day or six-day dosing-free period, and the cycle was repeated three times ( Figure 6 ).

[0705] The protocol and any one or more modifications or procedures involving the care and use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of CrownBio before implementation. During the study, the care and use of animals were performed in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) guidelines.

[0706] result: Figures 3 to 6 It was shown that the intraperitoneal administration of Examples 5 and 12 and the oral administration of Example 21 resulted in a significant reduction in tumor volume or a reduction in the growth of tumor volume when compared to the vehicle. The results confirmed that the high in vitro potency of the Example compounds tested in Biological Examples 2 and 3 (especially Examples 12 and 21) was converted into high in vivo potency.

[0707] Therefore, it is expected that the tested example compounds will be useful as pharmaceuticals, in particular for the treatment of hyperproliferative disorders such as cancer.

[0708] Biological Example 5: Caco-2 Cell Permeability Analysis

[0709] Certain Example compounds and Comparative Example 1 were tested for apical to basal (AB) and basal to apical (BA) permeability in Caco-2 cells.

[0710] Cell culture: Caco-2 cells were grown in 96-well plates in HBSS buffer containing 10 mM HEPES for 10 days. 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.

[0711] Cell seeding: cells were seeded at 18750 cells / well (membrane area = 0.0804 cm 2 ) were seeded in a 96-well plate.

[0712] AB assay: 75 μl of cell suspension was diluted with 2.5 × 10 5 Add 40 ml of medium to the feed plate. Place the plate in an incubator (37°C, 5% CO2 and controlled humidity). Grow Caco-2 cells for 10 days, changing the medium every other day.

[0713] BA analysis: 25 μl of cell suspension was diluted with 7.5 × 10 5 Cells / ml were added to the bottom side of the top well (keeping the plate upside down). The plate (inverted position) was placed in an incubator (37°C, 5% CO2 and 95% relative humidity) for 2 h. The front of the plate was facing up. 75 μl of culture medium was added to the top well, and 40 ml of culture medium was added to the feed tray.

[0714] Permeability analysis: The top and base wells were washed with buffer (pH 7.4) and 250 μl of buffer was added to the wells of the base plate. 75 μl of compound solution (2 μM, dissolved in water with 1% DMSO) was transferred to the top wells (n=2). The top plate was placed on the base plate. The lid was closed to prevent evaporation. The assembly was incubated at 37°C for 2.5 h (without shaking) under 5% CO2 and 95% relative humidity. After incubation, the top plate was separated from the base plate. Aliquots were taken from the receptor wells and donor wells, diluted and quantified together with the initial donor sample using LC-MS / MS.

[0715] Membrane integrity test: The solution in the top well was discarded by inverting the plate and soaking it on a tissue. 250 μl of buffer (pH 7.4) was added to each well of the base plate, and 75 μl of Lucifer Yellow (LY; 0.1 mg / ml) in buffer (pH 7.4) was added to the wells of the top plate. The top plate was placed on the base plate and a lid was used to prevent evaporation. The assembly was incubated at 37°C for 1 h (without shaking) under 5% CO2 and 95% relative humidity conditions. The top plate was separated from the base plate. The fluorescence (excitation: 432 nm, emission: 530 nm) of an aliquot (100 ul) was measured from the base well. The fluorescence of 100 μl of buffer (pH 7.4) and 100 μl of LY (0.1 mg / ml) was also measured. Holes with more than 1% fluorescence intensity relative to 0.1 mg / ml LY were considered non-integrated membranes. The permeability calculation did not take into account the holes (if any).

[0716] Calculation: Drug was detected and quantified by LC-MS / MS. The data generated was in 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

[0717] Results: The results of the analysis are shown in Table 3 below. The results indicate that many of the tested Example compounds are more permeable to cells than Comparative Compound 1 in this analysis. Therefore, it is expected that the tested Example compounds or at least some of them have better bioavailability than Comparative Compound 1.

[0718] Biological Example 6: Rat Hepatocyte Half-Life

[0719] In a metabolic analysis using mouse- and rat-derived hepatocytes, the metabolic stability of certain Example compounds and Comparative Compound 1 was tested. Compounds having good metabolic stability in this analysis are expected to be particularly useful as agents for preventing and / or treating cancer due to their long half-lives in human patients.

[0720] 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 a 100 μM stock solution, followed by further dilution with pH 7.4 Krebs-Henseleit buffer (supplemented with CaCl2, NaHCO3, HEPES, fructose, and glycine) to provide a 2 μM working solution. 25 μL of the working solution was incubated at 37°C and incubated with 25 μL of a rat or mouse hepatocyte suspension (containing 1×10 6 Cells / mL) were treated and incubated at 37°C with 5% CO2 level at 95% relative humidity. The wells were incubated for appropriate time (0, 15, 30, 45, 60 and 75 min) and then quenched with 250 μL of acetonitrile containing reference standards (diltiazem, 7-ethoxycoumarin and propranolol). The plate was shaken, ultrasonicated for 5 min, and then cooled to 4°C until all sampling was completed. All plates were centrifuged for 20 min at 4000 rpm to precipitate the debris. 110 μL of supernatant was diluted with 110 μL of water and quantified using LC-MS / MS.

[0721] The results were used to calculate the remaining percentage of the test compound at time point t = 100 x ~ [(AUC at time point t) / (AUC at T = 0)]. A linear regression curve was fit to the natural logarithm (ln) of AUC versus time. T-half (min) = 0.693 / slope

[0722] Results: The results of Biological Example 6 are shown in Table 3 below. The results indicate that certain Example compounds exhibit lower metabolic stability than Comparative Compound 1. It is expected that the combination of high in vitro and in vivo potency (as outlined in Biological Examples 2 to 4) and lower metabolic stability makes the compounds of the invention, or at least some of them, more suitable for certain applications, such as payloads for antibody drug conjugates, than Comparative Compound 1.

[0723] Table 3: Results of Biological Examples 5 and 6

[0724]

[0725]

[0726] Biological Example 7: Orthotopic Breast Cancer Xenograft Model

[0727] One day before tumor inoculation, NOD / SCID mice were implanted subcutaneously with estrogen pellets (17β-estradiol, 60-day release, 0.36 mg) in the right flank. Then, on day -8, each mouse was injected with 1×10 7Live BT474 breast cancer cells were resuspended in 0.2 mL of phosphate buffered saline mixed with Matrigel (1:1). On day 0 of the study, when the average tumor volume was 149.78 mm 3 , mice were assigned to treatment groups.Dosing was started the next day, and trastuzumab, embodiment 12 or ADC embodiment 1 were intravenously administered to all animals.The study was terminated on the 35th day of the study.Once a week, for four weeks, mice were administered with vehicle alone (Group 1), 2.5mg / Kg trastuzumab (Group 2), 5mg / Kg trastuzumab (Group 3), 2.5mg / Kg ADC embodiment 1 (Group 4) or 5mg / Kg ADC embodiment 1 (Group 5), or 2mg / Kg embodiment 12 (administered for 2 days, then discontinued for 5 days) (Group 6). Each group included 10 mice.The tumor volume of mice was measured three times per week, and the formula 0.5 (LxW) was used to calculate the tumor volume of mice. 2 ) to calculate tumor volume. Figure 7 and Figure 8 The mean tumor volume (+SEM) for each study group at each measurement is shown in the , plotted as the Last Observation Carried Forward. Statistical analysis of tumor readings for Groups 1, 2, 3, 4, and 5 was performed using two-way ANOVA until study day 23 (after which >50% of the animals were lost within one study group; Group 2), or a mixed effects model was fitted when the group median was missing (PRISMGraphPad Software). Statistical analysis of Group 6 was performed until Day 12 (at which time the study was terminated due to significant weight loss observed). One mouse in Group 5 was identified as an outlier (5% confidence level) at all time points using ROUT outlier analysis in GraphPad Prism and was therefore excluded from the analysis.

[0728] Tumor growth inhibition, ΔTGI % = ((mean(C)-mean(C0))-(mean(T)-mean(T0))) / (mean(C)-mean(C0))×100%, where T is the mean tumor volume on the measurement day and T0 is the mean tumor volume of the treatment group on study day 0. C is the mean tumor volume of the control group 1 mice on the measurement day and C0 is the mean tumor volume on study day 0.

[0729] During the study, body weights were measured three times per week for all animals. Animals were given DietGel throughout the study. The average body weights of each group during the dosing period are presented in Fig. 9 and Fig.10 middle.

[0730] result

[0731] The results of treatment with trastuzumab alone or ADC Example 1 on tumor size are plotted as percent tumor growth inhibition in Table 4 and are presented in Table 4. Figure 7 and Figure 8 The tumor volume (mm 3 ). Figure 7 and Figure 8 Also shown are tumor volumes for mice treated with Example 12 alone, but this study was terminated early due to significant weight loss observed in the treatment group.

[0732] Table 4: Tumor Growth Inhibition

[0733]

[0734] Mice treated with 2.5 mg / kg ADC Example 1 (Group 4) had significantly reduced tumor volume ( 1.34 × 10 cells / mL) compared to animals treated with 2.5 mg / kg trastuzumab (Group 2; p<0.0001). Figure 7 In addition, 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 5.0 mg / kg ADC Example 1 (Group 5) had significantly reduced tumor volume compared to mice treated with 2.0 mg / kg Example 12. Mice treated with 2.0 mg / kg Example 12 (Group 6) had reduced tumor volume (see Table 4). Figure 7 and Figure 8 ), but the study was stopped on day 13 due to significant weight loss observed in this study group. ADC Example 1 dosed at 2.5 mg / kg was approximately equivalent to Example 12 at this time point (Group 4, see Figure 7 ), but 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 dosed at 2.5 mg / kg was approximately 1 / 100 of that of Example 12 administered alone, meaning that ADC Example 1 was approximately 100 times more potent than Example 12 in vivo.

[0735] The effect of treatment with trastuzumab alone, Example 12 alone, or ADC Example 1 on the body weight of mice is shown in Fig. 9 and Fig.10There was no significant difference between mice treated with trastuzumab or ADC Example 1 and vehicle control, while the body weight of mice in Group 6 (Example 12) decreased significantly ( Fig. 9 and Fig.10 ), and then the study was terminated early due to the observation of significant weight loss.

[0736] Biological Example 8: Gastric Cancer Xenograft Model

[0737] The purpose of this study was to preclinically evaluate the in vivo therapeutic efficacy of an antibody-drug conjugate (ADC Example 1) in the treatment of the subcutaneous NCI-N87 human gastric xenograft model in female BALB / c nude mice.

[0738] In this study, 143 mice were inoculated subcutaneously in the right flank region with 1 × 10 7 Live NCI-N87 tumor cells resuspended in 0.1 mL of PBS mixed with Matrigel (1:1) were used for tumorigenesis. On study day 0, when the average tumor volume was 168.08 mm 3 102 mice were assigned to 9 treatment groups. Dosing was started the next day, and the animals were intravenously administered vehicle control, trastuzumab, ADC Example 1, de trastuzumab and isotype control antibodies conjugated to NMT inhibitor 1 (isotype control). The study was terminated on the 28th day of the study. Once a week for two weeks, mice were administered 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 de trastuzumab (Group 6), 5 mg / Kg de trastuzumab (Group 7) or 5 mg / Kg isotype control antibody (Group 8).

[0739] Table 5: Summary of dosing regimen

[0740]

[0741] The tumor volume of mice was measured three times a week and calculated using the formula 0.5(LxW2). Fig.11 and Fig.12 The mean tumor volume (+SEM) for each study group at each time of measurement is shown in .

[0742] 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 measurement day, and T0 is the mean tumor volume on study day 0. C is the mean tumor volume of the control group 1 mice on the measurement day and C0 is the mean tumor volume on study day 0.

[0743] During the study, body weights were measured three times per week for all animals. Animals were given DietGel throughout the study. The average body weights of each group during the dosing period are presented in Fig.13A (2.5mg / kg) and Fig. 13B (5mg / kg).

[0744] result

[0745] Significant weight loss (>10%) was observed in 3 / 10 animals in Group 1 (vehicle control); one animal in Group 2 (2.5 mg / Kg trastuzumab) and one animal in Group 3 (5 mg / Kg trastuzumab); all mice regained weight by the next measurement. No significant weight loss was observed in any other group.

[0746] When compared to vehicle alone (Group 1), there was a significant reduction in tumor volume in mice treated with trastuzumab, ADC Example 1, and detrastuzumab at all concentrations (2.5 mg / kg or 5 mg / kg) (p<0.0001). The isotype control ADC (Group 8; p=0.7935) showed no significant difference compared to vehicle alone (Group 1).

[0747] Compared with mice treated with trastuzumab 2.5 mg / kg (Group 2), mice treated with trastuzumab 5 mg / kg (Group 3; p<0.0001) and ADC Example 1 5 mg / kg (Group 5; p<0.0001) showed a significant reduction in tumor volume. Compared with Group 2 (trastuzumab 2.5 mg / kg), mice treated with de trastuzumab 2.5 mg / kg (Group 6; p<0.0001) and isotype control-ADC (Group 8; p<0.0001) showed significantly higher tumor volumes. ADC Example 1 2.5 mg / kg (Group 4; p=0.8757) and de trastuzumab 5 mg / kg (Group 7; p=0.9965) were not significantly different from trastuzumab 2.5 mg / kg (Group 2).

[0748] Mice treated with ADC Example 1 5 mg / kg (Group 5; p<0.0001) showed a significant reduction in tumor volume compared to trastuzumab 5 mg / kg (Group 3). There was no significant difference between Group 3 (trastuzumab 5 mg / kg) and Group 4 (ADC Example 1 2.5 mg / kg). In addition, all other groups (Groups 6-8) had significantly higher tumor volumes compared to Group 3 (trastuzumab 5 mg / kg).

[0749] Mice treated with ADC Example 1 5 mg / kg (Group 5; p<0.0001) showed a significant reduction in tumor volume compared to ADC Example 1 2.5 mg / kg (Group 4). There was no significant difference between Group 4 and Group 7 (detrastuzumab 5 mg / kg, p=0.9932). In addition, all other groups (Groups 6 and 8) had significantly higher tumor volumes compared to Group 4 (ADC Example 1 2.5 mg / kg).

[0750] Group 5 mice treated with ADC Example 1 5 mg / kg had significantly lower tumor volumes compared to all other groups (p<0.0001).

[0751] Mice treated with 5 mg / kg of trastuzumab (Group 7; p<0.0001) showed a significant reduction in tumor volume compared to 2.5 mg / kg of trastuzumab (Group 6). Group 8 showed significantly higher tumor volume compared to Group 6 (p<0.0001).

[0752] Mice treated with isotype control-ADC (Group 8; p<0.0001) had significantly higher tumor volumes compared to Group 7 (trastuzumab 5 mg / kg).

[0753] Increased tumor growth inhibition (TGI) compared to the vehicle group (Group 1) was evident in all treatment groups except Group 8. When comparing tumor growth inhibition across all treatment groups, treatment with 5.0 mg / kg ADC Example 1 (Group 5; TGI = 224.01%) was the most effective.

[0754] TGI = (mean tumor volume of vehicle group - mean tumor volume of treatment group) / (mean tumor volume of vehicle group - mean initial tumor volume) × 100

[0755] Biological Example 9: LNCaP Prostate Cancer Xenograft Model

[0756] The purpose of this study was to evaluate the efficacy of ADC Example 4 in male NOD SCID mice bearing LNCaP tumors.

[0757] A total of 84 male NOD SCID mice, 5-8 weeks old and weighing 25-30 g, were used for the study. 7 LNCaP tumor cells with a 78% survival rate and approximately 70% to 80% confluence were implanted subcutaneously into the flank of male NOD SCID mice. When tumors reached approximately 80-100 mm 3 At 4 hr, animals were assigned to treatment groups, with 10 mice per group assigned to each group with similar means and distribution of tumor volumes as shown in Table 6 below. Mice were treated with vehicle alone, unconjugated ifinatumomab, ifinatumomab-derutec (ifinatumomab-DXd), or ADC Example 4.

[0758] Table 6: Dosing regimen for Biological Example 11

[0759] Group n treat dose way Dosing frequency 1 10 Vehicle (PBS + 0.02% PS80) - IV Q7D (three total doses) 2 10 Ifinatumomab 10mg / kg IV Q7D (three total doses) 3 10 Ifinatumomab 5mg / kg IV Q7D (three total doses) 4 10 Ifinatumomab-DXd 10mg / kg IV Q7D (three total doses) 5 10 Ifinatumomab-DXd 5mg / kg IV Q7D (three total doses) 6 10 ADC Example 4 10mg / kg IV Q7D (three total doses) 7 10 ADC Example 4 5mg / kg IV Q7D (three total doses)

[0760] Observation duration: 35 days.

[0761] Dosing volume: 5 mL / kg for all IV doses

[0762] During the course of the study, no adverse reactions were observed at any dose, and the mean body weight in each group remained within 10% of the pre-treatment level ( Fig.15 ).

[0763] Cases of subjects losing >10% of body weight were observed at various time points in the study. Three weeks after the first animal entered treatment, DietGel was provided to all mice to improve weight loss. No animals were euthanized prematurely due to weight loss, and these cases of weight loss were likely related to tumor burden.

[0764] On day 28 of the study, animals receiving three Q7D doses of 10 mg / kg of ADC Example 4 showed significantly higher mean body weights than animals receiving vehicle control treatment (one-way ANOVA, Dunnett's p=0.0046). At this time point, no other treatment group was significantly different from vehicle in body weight.

[0765] Two animals were terminated early due to welfare issues. The first was euthanized on day 26 of treatment with 10 mg / kg ifinatumomab, and the second was euthanized on day 33 of treatment with 5 mg / kg ifinatumomab-DXd. Both animals were euthanized primarily due to wheezing. Large spontaneous thymoma was documented at necropsy for each animal.

[0766] Tumors in the vehicle-treated group grew steadily during the study, reaching 752 ± 89.4 mm on day 28 of the study. 3 The average volume of

[0767] On day 28, treatment with 10 mg / kg or 5 mg / kg of ifinatumomab had no significant effect on LNCaP tumor volume, and animals receiving this therapy showed tumor growth curves very similar to those of animals treated with vehicle alone ( Fig.14 , Table 7).

[0768] Treatment with 10 mg / kg of ifinatumomab-DXd significantly reduced the mean volume of LNCaP tumors by day 28 compared to vehicle controls. Animals receiving this therapy showed a significantly lower tumor growth rate than control animals. At a dose of 5 mg / kg, ifinatumomab-DXd slowed the growth of LNCaP tumors to a lesser extent ( Fig.14 , Table 7).

[0769] All animals given 10 mg / kg ADC of Example 4 showed tumor regression within three weeks of starting treatment ( Fig.14 , Table 7). This therapy produced a significant reduction in mean tumor volume compared to vehicle starting on day 7 (Mann-Whitney). By day 28, each tumor had regressed to ≤ 25% of its volume at the start of treatment.

[0770] Likewise, animals receiving 5 mg / kg ADC Example 4 showed a significant reduction in tumor volume from day 7 to day 28 compared to the control group (Mann-Whitney ( Fig.14 , Table 7). By day 28, all animals except one showed lower tumor volumes than those recorded at the start of treatment.

[0771] Table 7. Comparison of tumor volumes among treatment groups .

[0772] Adjusted p values ​​calculated by Kruskal-Wallis test and Dunn's multiple comparisons relative to vehicle control.

[0773]

[0774]

[0775] Biological Example 10: VcaP Prostate Cancer Xenograft Model

[0776] The purpose of this study was to preclinically evaluate the in vivo therapeutic efficacy of ADC Example 4 in the treatment of the subcutaneous VcaP human prostate cancer xenograft model in non-castrated male CB17 / SCID mice.

[0777] In this study, 144 mice were inoculated subcutaneously in the right anterior flank region with 1×10 7Live VcaP tumor cells resuspended in 0.1 mL of PBS mixed with Matrigel (1:1) were used for tumorigenesis. On study day 0, when the average tumor volume was approximately 162.16 mm 3 80 mice were assigned to 8 treatment groups at 1:10 p.m. on day 1. Dosing was started the next day, and all animals were intravenously administered ADC Example 4, ifinatumomab-derutec (ifinatumomab-Dxd) or unconjugated ifinatumomab. All mice received two doses of the test agent on day 1 and day 8 of the study. The study was terminated on day 30 of the study.

[0778] Assign the 8 groups as follows:

[0779] Group 1 Vehicle Control

[0780] Group 2 Unconjugated Ifinatumomab 5 mpk

[0781] Group 3 Unconjugated Ifinatumomab 2.5 mpk

[0782] Group 4 Ifinatumomab-Drugtec 5 mpk

[0783] Group 5: Ifinatumomab-Drugtec 2.5 mpk

[0784] Group 6 ADC Example 4 10mpk

[0785] Group 7 ADC Example 4 5mpk

[0786] Group 8 ADC Example 4 2.5mpk

[0787] No significant weight loss was observed in any of the animals in the study ( Fig.17 ).

[0788] When compared to vehicle alone (Group 1), there was a significant reduction in tumor volume in mice treated with ADC Example 4 at all concentrations (Group 8, 2.5 mg / kg; Group 7, 5 mg / kg and Group 6; 10 mg / kg) (p<0.0001). Compared to vehicle alone (Group 1), Ifinatumab-Dxd 5 mg / kg (Group 4; p=0.0078) showed significantly higher tumor volume, while Ifinatumab-Dxd 2.5 mg / kg (Group 5; p=0.8127) and unconjugated Ifinatumab at both concentrations (Group 2; p=0.1104 and Group 3; p=0.6703) did not show significant differences compared to vehicle alone (Group 1), see Fig.16 .

[0789] 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 reduction in tumor volume 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 Fig.16 .

[0790] There was no significant difference in tumor volume between mice treated with Ifinatumomab-Dxd 2.5 mg / kg (Group 5) and Groups 2, 3, and 4 (unconjugated Ifinatumomab 5 mg / kg, unconjugated Ifinatumomab 2.5 mg / kg, Ifinatumomab-Dxd 5 mg / kg, respectively). Mice treated with Ifinatumomab-Dxd 5 mg / kg (Group 4) had significantly higher tumor volume compared to mice treated with unconjugated Ifinatumomab 5 mg / kg (Group 2, p=0.0002) and unconjugated Ifinatumomab 2.5 mg / kg (Group 3, p=0.0216), see Fig.16 .

[0791] Increased 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 (Group 6; ΔTGI = 114.03% and Group 7; ΔTGI = 114.69%) was most effective, see Table 8.

[0792] Table 8. Dosing regimen and results for Biological Example 10

[0793]

[0794] Biological Example 11: JIMT-1 Breast Cancer Xenograft Model

[0795] The purpose of this study was to preclinically evaluate the in vivo therapeutic efficacy of ADC Example 3 in the treatment of the subcutaneous JIMT-1 human breast xenograft model in female NOD / SCID mice.

[0796] In this study, 128 mice were inoculated subcutaneously in the right anterior flank region with 5 × 10 6 Live JIMT-1 tumor cells resuspended in 0.1 mL PBS were used for tumorigenesis. On study day 0, when the average tumor volume was approximately 160.66 mm 3At 4 pm, 80 mice were assigned to 8 treatment groups. Dosing began the next day, and all animals were intravenously administered ADC Example 3, gosartuzumab, or unconjugated sartuzumab.

[0797] The study was terminated on study day 60. The 8 groups were allocated as follows:

[0798] Group 1 Vehicle Control

[0799] Group 2 Unconjugated tacizumab 5 mpk

[0800] Group 3 Unconjugated taciturnumab 2.5 mpk

[0801] Group 4 Gosartuzumab 5 mpk (ADC Example 3, 5 mg / kg, added on days 27 and 34)

[0802] Group 5 Gosartuzumab 2.5 mpk (ADC Example 3, 5 mg / kg, added on day 27)

[0803] Group 6 ADC Example 3 10mpk

[0804] Group 7 ADC Example 3 5mpk

[0805] Group 8 ADC Example 3 2.5mpk

[0806] Significant weight loss (>10%) was observed in one animal in Group 7. No significant weight loss was observed in any other group in the study, see Fig. 20 and Fig.21 On study day 10, one animal in Group 2 was found dead.

[0807] There was a significant reduction in tumor volume in mice treated with ADC Example 3 at all concentrations (Group 8, 2.5 mg / kg; Group 7, 5 mg / kg and Group 6, 10 mg / kg) when compared to vehicle alone (Group 1) (p<0.0001). Both concentrations of gosartuzumab (Group 4, 5 mg / kg, p<0.0001; Group 5, 2.5 mg / kg, p=0.0348) showed a significant reduction in tumor volume when compared to vehicle alone (Group 1). There was a significant reduction in tumor volume for unconjugated sartuzumab in Group 2 (5 mg / kg, p=0.0028) when compared to vehicle alone (Group 1), but there was no significant difference in Group 3 (2.5 mg / kg, p=0.0586). Data for the 5 mg / kg and 10 mg / kg groups are shown in Fig.18 The data of the 2.5 mg / kg group are shown in Fig.19 middle.

[0808] 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 reductions in tumor volume compared to Group 8 (2.5 mg / kg) (p<0.0001).

[0809] Compared with unconjugated saccharituzumab Group 2 (5 mg / kg, p=0.0097) and Group 3 (2.5 mg / kg, p=0.0499), Group 4 gosartuzumab (5 mg / kg) showed a significant reduction in tumor volume, while Group 5 (gosartuzumab, 2.5 mg / kg) was not significantly different from Group 2 (p=0.8424) and Group 3 (p=0.9995). There was also no significant difference between the two concentrations of unconjugated saccharituzumab (Group 2 (5 mg / kg) and Group 3 (2.5 mg / kg)), p=0.9837. However, there was a significant difference between the two concentrations of gosartuzumab (Group 4 (5 mg / kg) and Group 5 (2.5 mg / kg)), p=0.3802.

[0810] Increased 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 (Group 6; ΔTGI = 121.55% and Group 7; ΔTGI = 122.04%) was most effective.

[0811] Since treatment with gosartuzumab was only partially effective in Group 4, additional doses of ADC Example 3 were administered intravenously at 5 mpk on study days 27 and 34. This resulted in a significant reduction in tumor volume compared to vehicle controls (see Fig.18 Group 5 also received a dose of ADC Example 3 (5 mpk intravenously) on study day 27 (see Fig.19 ), but no significant response was observed.

[0812] Table 9. Dosing regimen and results for Biological Example 11

[0813]

[0814] QW = Once a week

[0815] Conclusion: The results of Biological Examples 1 and 2 confirm that the test compounds of the present invention are highly effective inhibitors of human NMT1 and exhibit potent cytotoxic activity in cancer cell lines. Biological Example 3 confirms that the test compounds of the present invention exhibit potent activity in a range of different cancer cell lines. The results of Biological Example 4 confirm that the test compounds of the present invention reduce the increase in tumor volume, or significantly reduce tumor volume, when compared to the vehicle. Biological Example 5 confirms that the test compounds of the present invention show improved cell permeability compared to Comparative Compound 1. Biological Example 6 confirms that for certain purposes, the test compounds of the present invention have a better metabolic stability profile than Comparative Compound 1. Biological Example 7 confirms that the tested example compounds are effective payloads for ADCs and reduce tumor growth in an in vivo breast cancer xenograft model as ADCs without adverse effects on body weight. The results of Biological Example 8 further confirm that the tested example compounds are effective payloads for ADCs and reduce tumor growth in an in vivo gastric cancer xenograft model as ADCs without adverse effects on body weight.

[0816] The results of Biological Example 9 indicate 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 a significant reduction in tumor volume, unlike treatment with ifinatumab alone, which had no significant effect on tumor volume. ADC Example 4 also outperformed ifinatumab-DXd in both doses.

[0817] Results from Biological Example 10 indicate that in the VcaP human prostate cancer xenograft model, ADC Example 4 was well tolerated in mice at 2.5 mg / kg, 5 mg / kg and 10 mg / kg doses. ADC Example 4 reduced tumor volume more than ifinatumomab-Dxd and unconjugated ifinatumomab. In fact, using unconjugated ifinatumomab showed no significant difference compared to vehicle alone. Compared to the control, ADC Example 4 resulted in the most increased tumor growth inhibition, see Table 8.

[0818] Results from Biological Example 11 indicate that ADC Example 3 was well tolerated in mice at 2.5 mg / kg, 5 mg / kg, and 10 mg / kg doses in the JIMT-1 human breast xenograft model. Mice treated with all three concentrations of ADC Example 3 showed a significant reduction in tumor volume compared to all other treatment groups, as also shown by the ΔTGI results in Table 9, with ADC Example 3 resulting in the greatest increase in tumor growth inhibition.

[0819] Therefore, the compounds of the present invention are expected to be useful pharmaceuticals, particularly for the treatment or prevention of hyperproliferative disorders such as cancer.

[0820] Throughout this specification and the following claims, unless the context requires otherwise, the word 'comprise' and variations such as 'comprises' and 'comprising' will be understood to imply the inclusion of a stated 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.

[0821] All patents and patent applications mentioned herein are incorporated by reference in their entirety.

Claims

1. A compound of formula (I): in: R 1 is a group of formula OLA; L is -(CHR 12 ) m -; Each R 12 are independently H or C 1-4 Alkyl; m is 1, 2 or 3; A is: v is 0, 1, or 2; R 9a H, C 1-4 Alkyl or C 1-4 Haloalkyl; R 9b H, C 1-4 Alkyl or C 1-4 Haloalkyl; R 9c C 1-4 Alkyl or C 1-4 Haloalkyl; R 9d H, C 1-4 Alkyl or C 1-4 Haloalkyl; R 10 H, C 1-4 Alkyl or C 1-4 Haloalkyl; R 11 H, halogenated, 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 is independently F, Cl, Br, OCH3, OCF3 or C optionally substituted with up to 3 halogen groups 1-4 alkyl; Y is CH or C 1-4 alkyl; R 3 H or C 1-4 alkyl; R 4 H or C 1-4 alkyl; R 5 H or C 1-4 alkyl; R 6 H or C 1-4 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 the atoms therebetween form a bond between the atoms therebetween, or between the atoms therebetween and -(CHR a ) r - a 3- to 7-membered non-aromatic heterocyclic ring; or said R 7 Group and the R 5 The group and the atoms therebetween form a group consisting of the atoms therebetween and -(CHR a ) r -3 to 7 membered non-aromatic heterocyclic ring; r is 1, 2, 3, 4 or 5; and R a is hydrogen or methyl; or a salt and / or solvate thereof.

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

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

4. The salts and solvates according to claim 2, which are pharmaceutically acceptable solvates of pharmaceutically acceptable salts. The salt according to claim 2 , which is a pharmaceutically acceptable salt. The solvate according to claim 2 , which is a pharmaceutically acceptable solvate.

7. The compound of claim 1.

8. The compound, salt and / or solvate thereof as claimed in any one of claims 1 to 7, wherein each R 12 For H. 9 . The compound, salt and / or solvate thereof according to claim 1 , wherein m is 2. 10 . The compound, salt and / or solvate thereof according to claim 1 , wherein v is 0.

11. The compound, salt and / or solvate thereof according to any one of claims 1 to 10, wherein R 9c C 1-4 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, for example methyl, isopropyl or tert-butyl.

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

13. The compound, salt and / or solvate thereof according to claim 11, wherein R 9c It is isopropyl.

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

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

16. The compound, salt and / or solvate thereof according to any one of claims 1 to 14, wherein R 9d C 1-4 An alkyl group, such as a methyl group.

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

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

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

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

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

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

23. The compound, salt and / or solvate thereof as claimed in any one of claims 1 to 22, wherein at least one R 2 is halogenated, such as Cl, F or Br, such as Cl or F, especially F.

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

25. The compound, salt and / or solvate thereof as claimed in any one of claims 1 to 24, wherein R 3 For H.

26. The compound, salt and / or solvate thereof as claimed in any one of claims 1 to 25, wherein R 4 For H.

27. The compound, salt and / or solvate thereof as claimed in any one of claims 1 to 26, wherein R 5 For H.

28. A compound, a salt and / or a solvate thereof as claimed in any one of claims 1 to 26, wherein R 5 C 1-4 An alkyl group, such as a methyl group.

29. The compound, salt and / or solvate thereof as claimed in any one of claims 1 to 28, wherein R 6 For H.

30. The compound, salt and / or solvate thereof as claimed in any one of claims 1 to 28, wherein R 6 C 1-4 An alkyl group, such as a methyl group.

31. A compound, a salt and / or a solvate thereof as claimed in any one of claims 1 to 28, wherein R 5 is methyl and R 6 For H.

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

33. A compound, a salt and / or a solvate thereof according to any one of claims 1 to 32, which is a compound of formula (IA): in: 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, isopropyl or tert-butyl; R 9cb is H or methyl; R 10a is methyl; and R 11a is methyl; The condition is that when R 2a When H, R 9cb is H; or a salt and / or solvate thereof.

34. The compound, salt and / or solvate thereof as claimed in claim 33, wherein R 2a For F.

35. The compound, salt and / or solvate thereof as claimed in claim 33 or 34, wherein R 5a For H.

36. A compound, a salt and / or a solvate thereof as claimed in any one of claims 33 to 35, wherein R 6a It is methyl.

37. A compound, a salt and / or a solvate thereof as claimed in any one of claims 33 to 36, wherein R 9cb For H.

38. A compound, salt and / or solvate thereof as described in any one of claims 33 to 36, wherein R 9ca is tert-butyl and R 9cb For H.

39. A compound, salt and / or solvate thereof as described in any one of claims 33 to 36, wherein R 9ca is methyl and R 9cb It is methyl.

40. The compound, salt and / or solvate thereof as claimed in claim 1, which is a compound selected from the group consisting 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-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; or a salt and / or solvate thereof.

41. The compound, salt and / or solvate thereof according to claim 1, which is 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.

42. The compound, salt and / or solvate thereof according to claim 41, which is 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:

43. The compound, salt and / or solvate thereof according to claim 41, which is 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:

44. The compound, salt and / or solvate thereof according to claim 41, which is 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:

45. The compound, salt and / or solvate thereof according to claim 41, which is 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:

46. ​​The compound, salt and / or solvate thereof according to claim 1, which is 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.

47. The compound, salt and / or solvate thereof according to claim 46, which is 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:

48. The compound, salt and / or solvate thereof according to claim 46, which is 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:

49. The compound, salt and / or solvate thereof according to claim 46, which is 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:

50. The compound, salt and / or solvate thereof according to claim 46, which is 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:

51. A compound, salt and / or solvate thereof as described in any one of claims 1 to 39, wherein s is 2 and each R 2 For F.

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

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

54. A compound, pharmaceutically acceptable salt and / or solvate as claimed in claim 53 for use in the prevention or treatment of a disease or condition in which inhibition of N-myristoyl transferase provides a therapeutic or preventive effect.

55. Use of a compound, pharmaceutically acceptable salt and / or solvate as claimed in any one of claims 2 to 51 in the preparation of a medicament for the treatment or prevention of a disease or condition in which inhibition of human NMT provides a therapeutic or preventive effect.

56. A method for treating or preventing a disease or condition in a subject, wherein inhibition of human NMT provides a therapeutic or preventive effect in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound as described in any one of claims 2 to 51, a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier.

57. The compound for use, pharmaceutically acceptable salt and / or solvate of claim 54, the use of claim 55, or the method of claim 56, wherein the disease or condition 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. The compound for use, pharmaceutically acceptable salt and / or solvate, use or method of claim 57, wherein the disease or disorder is a hyperproliferative disorder, and wherein the hyperproliferative disorder is cancer.

59. A compound for use, a pharmaceutically acceptable salt and / or solvate, a use or a method as claimed in claim 58, wherein the cancer is colorectal cancer, gallbladder cancer, a brain tumor, a lymphoma (such as B-cell lymphoma or diffuse large B-cell lymphoma), a leukemia (such as AML) or a neuroblastoma.

60. The compound, pharmaceutically acceptable salt and / or solvate, use or method of claim 58, wherein the cancer is a hematological malignancy such as a lymphoma, in particular a B-cell lymphoma (e.g. high grade mantle zone lymphoma, follicular lymphoma, plasmablastic lymphoma, diffuse large B-cell lymphoma and Burkitt's lymphoma), a myeloma (such as multiple myeloma) or a leukemia (such as chronic lymphocytic leukemia, AML and B-acute lymphocytic leukemia) or a solid tumor (such as 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. A compound selected from the group consisting of: - Compound of formula (II) -Compound of formula (III): Where P is C 1-4 Alkyl or C 1-4 Alkoxy; -Compound of formula (V): - Compound of formula (VI) and - a compound of formula (VII) Where P is C 1-4 Alkoxy; or a salt thereof, such as a pharmaceutically acceptable salt, Among them, s, q, v, L, A, R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9a and R 9b As defined in claim 1.

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

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

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

66. The ADC of claim 63.

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

68. The ADC or salt thereof of claim 67, wherein the linker has formula (LII): in represents the point of attachment to a chain terminus (such as the N-terminus) or a functional group on an amino acid side chain of the antibody; and represents a point of attachment to a functional group of the compound, a salt or a solvate thereof according to any one of claims 1 to 51.

69. The ADC or salt thereof according to any one of claims 63 to 68, which has the formula: in: Ab is antibody; represents an NMT inhibitor, such as a compound of formula (I) as described in any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof; and p is an integer between 1 and 10.

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

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

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

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

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

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 medicament.

76. 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 treating or preventing a hyperproliferative disorder, such as cancer.

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

78. The drug conjugate or its salt and / or solvate as claimed in claim 77, wherein the linker is defined in claim 66, or its salt and / or solvate.

79. The drug conjugate, salt thereof and / or solvate thereof as claimed in claim 77 or 78, wherein the drug conjugate has formula (DC-1): or its salts and / or solvates, wherein It is a compound of formula (I) as claimed in any one of claims 1 to 51, a salt and / or a solvate thereof.

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