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

Abstract

The present invention relates to compounds of Formula (I) and related aspects.

Description

Technical Field

[0001] This invention relates to compounds of formula (I) and their salts, which have activity as inhibitors of N-myristoyltransferase (NMT), particularly the human form of NMT. ​​The invention also relates to the use of said compounds as medicines, particularly in the prevention or treatment of diseases or conditions in which inhibition of N-myristoyltransferase provides a therapeutic or preventative effect. These diseases include proliferative diseases (such as B-cell lymphoma and leukemia) and viral infections (such as human rhinovirus, HIV, poliovirus, foot-and-mouth disease, enterovirus 71, and poxvirus infections). Microbial infections (e.g., protozoan infections such as malaria and leishmaniasis) and fungal infections can also be treated. Background Technology

[0002] N-Myristyltransferase (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. Gordon, J. Biol. Chem., 2001, 276(43): p. 39501-39504). N-myristylation of NMT follows an ordered Bi-Bi mechanism. Before binding to the protein substrate, Myr-CoA binds NMT in a first NMT binding pocket (Rudnick, DA, C.M., W. C., W. J., Rocque et al., J. Biol. Chem., 1991, 266(15): p. 9732-9739). The bound myr-CoA promotes the opening of a second binding pocket for binding the protein substrate. After binding to a protein substrate, myristic acid is transferred to the protein substrate via a nucleophilic addition-elimination reaction, ultimately releasing CoA and myristic-acylated protein.

[0003] There are two types of human NMT: human NMT1 (HsNMT1) and human NMT2 (HsNMT2). Inhibition of human NMT has been proposed as a target for the treatment or prevention of various diseases or conditions, such as hyperproliferative disorders (e.g., cancers, such as human colorectal cancer, gallbladder cancer, brain tumors, and lymphomas such as B-cell lymphoma) (Resh MD. 1993. Biochem. Biophys. Acta 1115, 307-22; Bertiaume LG, Beuachamp E, WO 2017011907) 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), human rhinovirus (formally abbreviated as HRV) (Davis MP, Bottley, G, Beales LP, Killington, RA, Rowlands). DJ,Tuthill,TJ,2008Journal ofVirology 82 4169-4174;Mousnier A,Bell AS,Swieboda DP,Morales-Sanfrutos J,Perez-Dorado I,Brannigan JA,Newman J,Ritzefeld M,Hutton,JA,Guedan A,Asfor AS,Robinson,SW,Hopkins-Navratilova I,Wilkinson AJ,Johnston SL,Leatherbarrow RJ,Tuthill TJ,Solari R,Tate EW 2018Nature Chemistry 10(6)599-606),Corbic RamljakI,Stanger J,Real-Hohn A.Dreier D,Wimmer L.,Redlberger-Fritz M,Fischl W,Klingel K,Mihovilovic MD,Blaas D.Kowalski H,PLOS Pathogens 14(8):e1007203) and dengue virus 2019 Microbiology e00831 Suwanmanee S., Mahakhunkijcharoen Y., Ampawong,S.,Leaungwutiwong P.,Missé,D,Luplertlop,N.Because NMTs play a crucial role in protein transport, mediating protein-protein interactions, stabilizing protein structure, and signal transduction in living systems, inhibiting NMT enzymes has the potential to disrupt multi-protein pathways. This is an attractive property that could reduce the risk of developing drug resistance in the treatment or prevention of diseases such as hyperproliferative disorders and microbial infections.

[0004] Biochemical analysis showed that the myr-CoA binding site was highly conserved, but the peptide binding specificity differed between humans and fungi and parasites with NMT (Johnson, DR, RSBhatnagar, JIGordon et al., Annu. Rev. Biochem., 1994. 63: p. 869-914.). Therefore, NMT can be considered a potential target for developing selective non-peptide inhibitors.

[0005] NMT fungal and mammalian enzymes from various sources have been well characterized, see, for example, the following references: *Saccharomyces cerevisiae* (Duronio, RJ, DATowler, R.O. Heuckeroth et al., Science, 1989, 243(4892): p.796-800), *Candida albicans* (Wiegand, RC, C. Carr, J. C. Minnerly et al., J. Biol. Chem., 1992, 267(12): p.8591-8598), and *Cryptococcus neoformans* (Lodge, J.K., RL. Johnson, R.A. Weinberg et al., J. Biol. Chem., 1994, 269(4): p.2996-3009), human NMT1 (McIlhinney, R.A. J. and K. McGlone, Exp. Cell. Res., 1996, 223: pp. 348-356) and human NMT2 (Giang, DK and BFCravatt, J. Biol. Chem., 1998, 273: pp. 6595-6598).

[0006] NMT has also been characterized in protozoan parasites. For example, see the following references: Plasmodium falciparum (Pf) (Gunaratne, RS, M. Sajid, ITLing et al., Biochem.J., 2000.348:p.459-463), Plasmodium vivax (Pv), Leishmania major (Lm) (Price, HP, MR Menon, C. Panethymitaki et al., J. Biol. Chem., 2003.278(9):p.7206-7214.), Leishmania donoris (Lm) donovani (Ld) (Branningan, JA, BASmith, Z. Yu et al., J. Mol. Biol., 2010. 396: p. 985-999) and Trypanosoma brucei (Tb) (Price, HP, MR Menon, C. Panethymitaki et al., J. Biol. Chem., 2003. 278(9): p. 7206-7214.).

[0007] Several myristoylated proteins have been observed in protozoa, and their functions have been determined. These proteins and the processes they participate in suggest that N-myristoylation may play a role in multiple pathways of parasitic biology. Therefore, inhibiting myristoylation could disrupt multiple pathways. Consequently, the likelihood of developing resistance should be lower than with some other targets. To date, only one NMT subtype has been found in each protozoan organism studied. If there is indeed only one subtype, this would also help reduce the likelihood of resistance development.

[0008] As mentioned above, there are two binding pockets in NMT: one is the myr-CoA binding pocket, and the other is the peptide binding pocket. Most NMT inhibitors reported to date target the peptide binding pocket. Most NMT inhibitors developed to date target fungal N-myristyltransferase.

[0009] Compounds with NMT inhibitory activity have been disclosed, see, for example, WO00 / 37464 (Roche), WO2010 / 026365 (University of Dundee), WO2013 / 083991 (Imperial Innovations Limited), WO2017 / 001812 (Imperial Innovations Limited), WO2020 / 128473 (Imperial College Innovations Limited) and WO2020 / 128475 (Imperial College Innovations Limited).

[0010] In addition, Bell et al. published the results of a high-throughput screening study to identify NMT inhibitors, and disclosed that compounds PF-03531814 (1-(5-chloro-2-{[2-(dimethylamino)ethyl]amino}pyrimidin-4-yl)-N-[(5-methylpyrazin-2-yl)methyl]azacyclobutane-3-carboxamide) and PF-03531549 (1-(5-chloro-2-{[2-(dimethylamino)ethyl]amino}pyrimidin-4-yl)-N-[(2,4-difluorophenyl)methyl]azacyclobutane-3-carboxamide) exhibit selective activity against Plasmodium falciparum NMT relative to two human NMTs (PLoS Neglected Tropical Diseases 2012, 6, e1625).

[0011]

[0012] There is still a need in the field for other compounds that have inhibitory activity against N-myristoyltransferase, especially the human form of N-myristoyltransferase. Invention Overview

[0014] Compounds of formula (I), or pharmaceutically acceptable esters, amides, carbamates, or salts thereof, including salts of such esters, amides, or carbamates:

[0015]

[0016] in:

[0017] n1 is 1 or 2; n2 is 1 or 2;

[0018] X 1 Selected from CR x and N;

[0019] When it exists, R xSelected from hydrogen, halogens, and -C atoms optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, -OCH3 and -OCF3;

[0020] R 1 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogens, -CH3, -OCH3, and -OCF3;

[0021] R 2 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogens, -CH3, -OCH3, and -OCF3;

[0022] Or R 1 and R 2 They connect together to form C along with the atoms they are connected to. 3-6 Cycloalkyl or a 3- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 3 to 6-membered non-aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogen, -OH, -CH3, -OCH3 and -OCF3;

[0023] R 3 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -OH, -CH3, -OCH3 and -OCF3;

[0024] Or R 1 and R 3 These atoms are linked together to form a 3- to 6-membered nonaromatic heterocyclic group containing one N heteroatom, wherein the 3- to 6-membered nonaromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens, -CH3, -OH, -OCH3, and -OCF3; X 2 Selected from CR 4 and N;

[0025] When it exists, R 4 Selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from halogens, -OH, -OCH3, -OCF3, and -NR. a R b ;

[0026] R 5a and R 5d The methyl group is independently selected from hydrogen; halogen; methyl group optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3; and methoxy group optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3;

[0027] R 5b and R 5c Independently selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3;

[0028] Or R 5b and R 5c They are linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from S, O and N, wherein the 6-membered aryl group or the 5- or 6-membered aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3.

[0029] R 6 Selected from hydrogen and methyl;

[0030] When they exist, each R 7 -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, -OCH3 and -OCF3;

[0031] R 8 Selected from hydrogen; halogen; -OH; -CN; -C optionally substituted with 1, 2 or 3 substituents. 1-4Alkyl group, each substituent independently selected from halogens, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; -C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -CH3, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; -C groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkenyl group, each substituent independently selected from halogen, -OH, -CN, and methoxy group optionally substituted with 1, 2, or 3 halogens; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, CN and methoxy group optionally substituted with 1, 2 or 3 halogens;

[0032] R 9 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; or

[0033] R 8 and R 9 They connect together to form 6-membered aryl groups and C atoms together with the atoms they are attached to. 5-6 Cycloalkyl or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N, O, and S, wherein the 6-membered aryl group, C 5-6 The cycloalkyl or 5- to 6-membered aromatic heterocyclic group is optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens; -OH; -CN; -C optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from -halogen, -OH and methoxy group optionally substituted with 1, 2 or 3 halogens; p is 0, 1 or 2;

[0034] Z is a 5- to 13-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 13-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents, each substituent being independently selected from halogens; -C optionally substituted with 1, 2, or 3 substituents 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl group; -OC group optionally substituted with 1, 2 or 3 substituents. 1-6Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; NR c R d ; and C substituted with one, two or three substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -OH, and -OC optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; or when two substituents are in adjacent ring positions, they can be linked together to form a C1 ring with the atoms to which they are linked. 3-6 Cycloalkyl or a 4- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 4- to 6-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C is optionally substituted with one, two, or three substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl;

[0035] R c and R d Independently selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and C4 groups optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3;

[0036] Or Z is -NR 10 R 11 ,in

[0037] R 10 Selected from hydrogen and -C 1-4 Alkyl; and

[0038] R 11 It is a 5- to 10-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 10-membered non-aromatic heterocyclic group is optionally substituted by 1, 2, 3, or 4 substituents, said substituents being independently selected from halogens; -OH; -C optionally substituted by 1, 2, or 3 substituents. 1-6Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; and

[0039] When they exist, each R a and R b Independently selected from hydrogen and -C 1-4 alkyl.

[0040] The present invention also provides compounds of formula (I), or pharmaceutically acceptable esters, amides, carbamates, or salts thereof, including salts of such esters, amides, or carbamates:

[0041]

[0042] in:

[0043] n1 is 1 or 2; n2 is 1 or 2;

[0044] X 1 Selected from CR x and N;

[0045] When it exists, R x Selected from hydrogen, halogens, and -C atoms optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, -OCH3 and -OCF3;

[0046] R 1 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogens, -CH3, -OCH3, and -OCF3;

[0047] R 2 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogens, -CH3, -OCH3, and -OCF3;

[0048] Or R 1 and R 2They connect together to form C along with the atoms they are connected to. 3-6 Cycloalkyl or a 3- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 3 to 6-membered non-aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogen, -OH, -CH3, -OCH3 and -OCF3;

[0049] R 3 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -CH3, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -OH, -OCH3 and -OCF3;

[0050] Or R 1 and R 3 These groups are linked together to form a 3- to 6-membered nonaromatic heterocyclic group containing one N heteroatom, wherein the 3- to 6-membered nonaromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens, -OH, -CH3, -OCH3, and -OCF3; X 2 Selected from CR 4 and N;

[0051] When it exists, R 4 Selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3 and -OCF3; and -NR a R b ;

[0052] R 5a and R 5d The methyl group is independently selected from hydrogen; halogen; methyl group optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3; and methoxy group optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3;

[0053] R 5b and R 5c Independently selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; -OC group optionally substituted with 1, 2, or 3 substituents. 1-4Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3;

[0054] Or R 5b and R 5c They are linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from S, O and N, wherein the 6-membered aryl group or the 5- or 6-membered aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3.

[0055] R 6 Selected from hydrogen and methyl;

[0056] When they exist, each R 7 -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, -OCH3 and -OCF3;

[0057] R 8 Selected from hydrogen; halogen; -OH; -CN; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; -C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -CH3, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; -C groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkenyl group, each substituent independently selected from halogen, -OH, -CN, and methoxy group optionally substituted with 1, 2, or 3 halogens; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, CN and methoxy group optionally substituted with 1, 2 or 3 halogens;

[0058] R 9 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; or

[0059] R 8 and R 9These groups are linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N, O, and S, wherein the 6-membered aryl group or the 5- or 6-membered aromatic heterocyclic group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens; -OH; -CN; -C optionally substituted with one, two, or three substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent being independently selected from -halogen, -OH and methoxy group optionally substituted with 1, 2 or 3 halogens;

[0060] p is 0, 1, or 2;

[0061] Z is a 5- to 13-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein the 5- to 10-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents, each substituent being independently selected from halogens; -C optionally substituted with 1, 2, or 3 substituents 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl;

[0062] Or Z is -NR 10 R 11 ,in

[0063] R 10 Selected from hydrogen and -C 1-4 Alkyl; and

[0064] R 11 It is a 5- to 10-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 10-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents, each substituent being independently selected from halogens; -OH; -C optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; and

[0065] When they exist, each R a and R b Independently selected from hydrogen and -C 1-4 alkyl.

[0066] The compounds of the present invention have been surprisingly found to possess activity as inhibitors of N-myristyltransferase, and in particular, they have been found to be highly effective inhibitors of human N-myristyltransferase 1. The compounds of the present invention have also been surprisingly found to have good metabolic stability. These advantages are intended to make the compounds of the present invention particularly useful for the treatment and prevention of diseases in which inhibition of N-myristyltransferase provides therapeutic or preventative effects, such as hyperproliferative diseases (e.g., B-cell lymphoma and leukemia), viral infections (e.g., human rhinovirus, HIV, poliovirus, foot-and-mouth disease, enterovirus 71 infection, and poxvirus infection). These compounds can also be used for the prevention or treatment of, for example, protozoan infections (e.g., malaria and leishmaniasis) and fungal infections.

[0067] The present invention also provides pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable carriers.

[0068] The present invention also provides compounds of the present invention for use as medicines or pharmaceutical compositions of the present invention.

[0069] The present invention also provides compounds or pharmaceutical compositions of the present invention for the prevention or treatment of diseases or conditions in which inhibition of N-myristyltransferase provides therapeutic or preventive effects.

[0070] The present invention also provides the use of the compounds of the present invention in the preparation of medicaments for the prevention or treatment of diseases or conditions in which inhibition of N-myristoyltransferase provides therapeutic or preventive effects.

[0071] The present invention also provides a method for treating or preventing diseases or conditions in mammals in which inhibition of N-myristoyltransferase provides therapeutic or preventative effects, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition of the present invention.

[0072] The present invention also provides a kit comprising: (a) a first pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier; and (b) a second pharmaceutical composition comprising an additional therapeutic agent, suitably another N-myristyltransferase inhibitor, and a pharmaceutically acceptable carrier.

[0073] Brief description of the attached figures

[0074] Figure 1 (a) shows the metabolic activity of the P-493-6 cell line treated with the compound 3 of the examples at the indicated concentration for 72 hours, inducing different levels of c-MYC expression. Figure 1 (b) shows the metabolic activity of the P-493-6 cell line treated with the compound 2 of the example at the indicated concentration for 72 hours, inducing different levels of c-MYC expression.

[0075] Figure 2 (a) shows the metabolic activity of the Shep-ER-MYCN cell line treated with the compound 3 of the examples at the indicated concentrations for 72 hours, with and without induction of MYCN. Figure 2 (b) shows the metabolic activity of the Shep-ER-MYCN cell line treated with the compound 2 of the examples at the indicated concentrations for 72 hours, with and without inducing MYCN.

[0076] Figure 3 (a) shows the metabolic activity of the SKNAS-ER-MYCN cell line treated with the compound 3 of the examples at the indicated concentrations for 92 hours, with and without inducing MYCN. Figure 3 (b) shows the metabolic activity of the Shep-ER-MYCN cell line treated with the compound 2 of the examples at the indicated concentrations for 72 hours, with and without inducing MYCN.

[0077] Figure 4 The in vivo therapeutic efficacy (percentage reduction in parasite load) of three different doses of Compound 3 of the present invention against Plasmodium falciparum up to day 7 post-infection was shown compared with standard treatment (chloroquine) and control mice (details of the mouse malaria model are provided in section (g) of “Details of Biological Assays and Results” below).

[0078] Figure 5a The therapeutic efficacy (tumor size reduction) of Compound 2 of Example compared to the carrier was demonstrated when administered orally in a subcutaneous xenograft DOHH-2 lymphoma model using female 6-8 week old CB17 / SCID mice. Figure 5b The therapeutic efficacy of Compound 2 of Example compared to the carrier was demonstrated when administered intraperitoneally in a subcutaneous xenograft DOHH-2 lymphoma model using female 6-8 week old CB17 / SCID mice. Figure 5c Example 129 demonstrates the therapeutic efficacy compared to the carrier when administered intraperitoneally in a subcutaneous xenograft DOHH-2 lymphoma model using female 6-8 week old CB17 / SCID mice. Invention Details

[0080] This invention provides compounds as NMT inhibitors. The term "NMT inhibitor" as used herein is intended to cover any part that binds to NMT and inhibits its activity. The inhibitor can be a competitive or partially competitive inhibitor. The inhibitor can bind to NMT at the myr-CoA binding pocket or peptide binding pocket (or inhibit NMT via another mechanism). The compounds of this invention suitably bind to and inhibit NMT via the peptide binding pocket.

[0081] definition

[0082] Unless otherwise limited in specific circumstances, the following definitions apply to the terminology used throughout this specification.

[0083] As used herein, the term "alkyl" refers to both straight-chain and branched saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, pentyl, and hexyl. Among unbranched alkyl groups, suitable choices are methyl, ethyl, n-propyl, isopropyl, and n-butyl, for example, methyl, ethyl, n-propyl, and n-butyl. Among branched alkyl groups, references may be made to isopropyl, tert-butyl, isobutyl, 1-ethylpropyl, and 1-ethylbutyl, for example, tert-butyl, isobutyl, 1-ethylpropyl, and 1-ethylbutyl.

[0084] As used herein, the term "alkoxy" (e.g., methoxy) refers to an O-alkyl group (e.g., O-methyl), where "alkyl" is as described above. Examples of alkoxy groups include methoxy and ethoxy. Other examples include propoxy and butoxy.

[0085] As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group having at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl, propenyl, butenyl, pentenyl, and hexenyl. Suitable alkenyl groups include vinyl, 1-propenyl, 2-propenyl, and but-2-enyl.

[0086] As used herein, the term "cycloalkyl" refers to a saturated group in a cyclic system. A cycloalkyl group can be monocyclic or bicyclic. A bicyclic group can be, for example, fused or bridged. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of bicyclic cycloalkyl groups include bicyclic octane, bicyclic nonane, bicyclic decane (naphthane), and bicyclic octane. Another example of a cycloalkyl group is adamantane. Suitable examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Other examples of monocyclic cycloalkyl groups are cycloheptyl and cyclooctyl. Examples of bicyclic cycloalkyl groups include bicyclic [2.2.1]hept-2-yl. Suitably, a cycloalkyl group is monocyclic. Cycloalkyl groups, for example, C 3-6 Cycloalkyl groups can be attached to the rest of the molecule via a single carbon atom, for example:

[0087]

[0088] Or it can be linked to the rest of the molecule via bonds, for example:

[0089]

[0090] The dashed lines indicate connections to the rest of the compound.

[0091] The term "aryl" as used in this article refers to a carbocyclic aromatic ring system, such as phenyl.

[0092] As used in this article, the term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, or iodine. Fluorine, chlorine, and bromine are suitable, and fluorine and chlorine are particularly suitable.

[0093] As used herein, the term "heterocyclic group" (or heterocycle) refers to an aromatic or non-aromatic cyclic group of carbon atoms in which one to four carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). Heterocyclic groups (or heterocycles) can be, for example, monocyclic or bicyclic. In bicyclic heterocyclic groups (or heterocycles), there may be one or more heteroatoms in each ring, or one or more heteroatoms in only one ring. The heteroatoms may be S, O, or N, preferably O or N.

[0094] Examples of monocyclic non-aromatic heterocyclic groups (or heterocycles) include aziridine, aziridine butyl, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, aziridine heptyl and diazacyclic heptyl (e.g., 1,4-diazacyclic heptyl, 1,1-diazacyclic heptyl or 1,5-diazacyclic heptyl, preferably 1,4-diazacyclic heptyl).

[0095] Examples of bicyclic non-aromatic heterocyclic groups (or heterocycles) include diazabicycloheptyl (e.g., 3,6-diazabicyclo[3.2.0]heptyl), 1H-octahydropyrrolo[3,4-b]pyridyl, 2,5-diazabicyclo[2.2.1]heptyl, cis-octahydropyrrolo[3,4-b]pyridyl, cis-octahydropyrrolo[3,4-c]pyridyl, 3,7-diazabicyclo[3.3.1]nonyl, 2,6-diazaspiro[3.3]heptyl, octahydropyrrolo[3,2-b]pyrryl, 1,7-diazaspiro[4.4]nonyl, 1,8-diazaspiro[4.5]decyl, decahydro-2,7 -Naphthidyl, 2,8-diazaspiro[5.5]undecyl, 3,6-diazabicyclo[3.2.0]heptane, 2,8-diazaspiro[4.5]decyl, octahydropyrrolo[3,4-c]pyrrolyl, trans-octahydro-1H-pyrrolo[3,4-b]pyridyl, 2,6-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.5]decyl, 1,7-diazaspiro[3.5]nonyl, 1,6-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, (4aR,8aR)-decahydro-1,5-naphthidyl, 3,9-diazaspiro[5.5]undecyl, (3aS,6aS)-octahydropyrrolo[2,3-c]pyrrole, 2,9-diazaspiro[6.6]tridecyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, 9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonyl, cis-octahydropyrrolo[3,4-c]pyridyl, cis-decahydro-1,7-naphthidyl, 2,7-diazabicyclo[4.2.0]octyl, (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazinyl, 2,6- Diazaspiro[3.4]octyl, 1,9-diazaspiro[6.6]tetrazyl, (4aS,8aS)-decahydro-1,5-naphthidyl, trans-decahydro-1,7-naphthidyl, (1S,2S)-2,5-diazabicyclo[2.2.1]heptyl, trans-decahydro-1,7-naphthidyl, rac-(4aR,8aR)-octahydro-2H-pyrido[4,3-b]morpholinyl, decahydro-1,6-naphthidyl, octahydro-1H-pyrrolo[3,2-c]pyridyl, rac-(3aR,6aR)-octahydropyrrolo[2,3-c]pyrrolyl and decahydropyrrolo[3,2-c]azazolyl.

[0096] Examples of monocyclic aromatic heterocyclic groups (or heterocycles) include furanyl, thiophene, pyrrole, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiazolyl, pyridinyl, triazolyl, triazinyl, tetrazolyl, pyridazinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl.

[0097] Examples of bicyclic aromatic heterocyclic groups (or heterocycles) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiopheneyl, benzoimidazolyl, naphridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolo[4,5-b]pyridinyl, pyridopyrimidinyl, isoquinolinyl, and benzodioxazolyl.

[0098] Other examples of bicyclic aromatic heterocyclic groups include those in which one ring is aromatic and the other is non-aromatic, such as dihydrobenzofuranyl, indanyl, dihydroindolyl, isoindolyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and benzozaheptanyl.

[0099] The compounds of the present invention

[0100] This invention provides compounds of formula (I) or pharmaceutically acceptable esters, amides, carbamates, or salts thereof, including salts of such esters, amides, or carbamates. The compounds of this invention are NMT inhibitors.

[0101] In one embodiment, a compound of formula (I) is provided as a pharmaceutically acceptable ester, amide, carbamate, or salt thereof. In one embodiment, the compound of formula (I) is provided as a pharmaceutically acceptable ester, amide, or carbamate salt thereof. In one embodiment, the pharmaceutically acceptable ester, amide, or carbamate of the compound of formula (I) is not a salt. In one embodiment, the compound of formula (I) is provided as a pharmaceutically acceptable ester. In one embodiment, the compound of formula (I) is provided as a pharmaceutically acceptable amide. In one embodiment, the compound of formula (I) is provided as a pharmaceutically acceptable carbamate. In one embodiment, the compound of formula (I) is provided as a pharmaceutically acceptable salt. In one embodiment, a compound of formula (I) is provided.

[0102] The inventors have discovered that compounds of formula (I) are inhibitors of human NMT, HsNMT1, and HsNMT2. In particular, data from this application show that said compounds are particularly potent inhibitors of human NMT1 because they have very low micromolar or nanomolar IC50 against human NMT1 (HsNMT1). 50 The values ​​(it has been well established that HsNMT1 and HsNMT2 are typically inhibited to the same extent by NMT inhibitor compounds (PLoS Neglected Tropical Diseases 6(4):e1625)). The inventors have also discovered that the compound of formula (I) is an inhibitor of Plasmodium vivax NMT.

[0103] To further test the potency of the compounds of the present invention, certain compounds were tested using eight different cancer cell lines in a metabolic activity assay. The compounds of the present invention inhibited metabolic activity in each metabolic activity assay and are therefore expected to serve as agents for the prevention and / or treatment of cancer, as they are inhibitors of human NMT1 and / or NMT2.

[0104] The EC50 of certain compounds of this invention against P. falciparum NMT was measured by measuring the amount of parasite DNA in human erythrocytes incubated with late-stage trophozoites of Plasmodium falciparum. 50 Values. Certain compounds of the present invention inhibited parasitic infections in cells in assays. The compounds of the present invention also showed a reduction in Plasmodium falciparum parasite load in mice implanted with human erythrocytes. As they are inhibitors of protozoan NMTs such as Pf NMT, the compounds of the present invention are expected to be used as drugs for the prevention and / or treatment of protozoan infections such as malaria.

[0105] The compounds of the present invention are not only effective but also exhibit good metabolic stability. The results of the following examples (e) and (f) demonstrate the rat hepatocyte half-life, rat IV half-life, and oral bioavailability of the compounds of various embodiments of the present invention.

[0106] The combination of the above properties makes the compounds of the present invention particularly suitable for use as pharmaceuticals, especially oral pharmaceuticals.

[0107] The compounds of this invention may contain a chiral (asymmetric) center or the molecule as a whole may be chiral. Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are all within the scope of this invention.

[0108] To avoid confusion, any embodiment of any feature of the compound of the present invention or more or more suitable aspects may be combined with any embodiment of another feature of the compound of the present invention or more or more suitable aspects to produce other embodiments.

[0109] The limitation of compounds of formula (I) in this article also applies to compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), (Im), (In), (Io), (Ip), and (Iq).

[0110] In the following embodiments and preferred embodiments, where the substituent in formula (I) is indicated as an optional substitution, the optional substituent may be attached to a available carbon atom, wherein the available carbon atom refers to a carbon atom attached to a hydrogen atom, i.e., a CH group, or the optional substituent may be attached to a available nitrogen atom, wherein the available nitrogen atom refers to a nitrogen atom attached to a hydrogen atom, i.e., an NH group. The optional substituent replaces the hydrogen atom attached to the carbon atom or the hydrogen atom attached to the nitrogen atom.

[0111] Suitable, in one embodiment, the relevant group is substituted. In another embodiment, the relevant group is unsubstituted.

[0112] In compounds of formula (I), n1 is 1 or 2, and n2 is 1 or 2. In some suitable embodiments, n1 is 1 and n2 is 1 or 2. In particularly suitable embodiments, n1 is 1 and n2 is 1. In such embodiments, compounds of formula (I) are compounds of formula (Ia):

[0113]

[0114] In the compound of formula (I), X 1 Selected from CR x And N. Appropriately, X 1 It is N. In such an embodiment, the compound of formula (I) is the compound of formula (Ib):

[0115]

[0116] In the compound of formula (I), when present, R x It can be selected from hydrogen, halogens, and -C atoms optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, -OCH3, and -OCF3. Suitably, R x Selected from hydrogen, halogens (suitably F or Cl), and -C optionally substituted with halogens (suitably F or Cl), -OCH3, or -OCF3. 1-4 Alkyl group. More appropriately, R x Selected from hydrogen, F, Cl and -C 1-4 Alkyl group. Even more appropriately, R x It is hydrogen.

[0117] In the compound of formula (I), R 1 It may be selected from hydrogen; -C may be optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6Cycloalkyl, each substituent independently selected from halogens, -CH3, -OCH3, and -OCF3; R 2 It may be selected from hydrogen; -C may be optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -CH3, -OCH3, and -OCF3; or

[0118] R 1 and R 2 They can connect together to form C along with the atoms they are connected to. 3-6 Cycloalkyl or a 3- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 3 to 6-membered non-aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogens, -OH, -CH3, -OCH3 and -OCF3.

[0119] In some suitable implementations, R 1 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3. More preferably, R 1 Selected from hydrogen and -C 1-4 Alkyl group. Even more appropriately, R 1 Selected from hydrogen and -C 1-3 Alkyl group. Even more appropriately, R 1 Selected from hydrogen and methyl. Even more appropriately, R 1 It is a methyl group.

[0120] In some suitable implementations, R 2 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3. More preferably, R 2 Selected from hydrogen and -C 1-4 Alkyl group. Even more appropriately, R 2 Selected from hydrogen and -C 1-3 Alkyl group. Even more appropriately, R 2 Selected from hydrogen and methyl. Even more appropriately, R 2 It is a methyl group.

[0121] In some suitable implementations, R 1 and R 2 Independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 substituents. 1-4Alkyl groups, each substituent independently selected from halogens, -OCH3, and -OCF3 (e.g., R...). 1 -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OCH3, and -OCF3, and R 2 -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OCH3, and -OCF3; or R 1 -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OCH3, and -OCF3, and R 2 It is hydrogen; or R 1 It is hydrogen and R 2 It is hydrogen). More appropriately, R 1 and R 2 Independently selected from hydrogen and -C 1-4 Alkyl (e.g., R) 1 It is -C 1-4 Alkyl and R 2 It is -C 1-4 Alkyl; or R 1 It is -C 1-4 Alkyl and R 2 It is hydrogen; or R 1 It is hydrogen and R 2 It is hydrogen). Or even more appropriately, R 1 and R 2 Independently selected from hydrogen and -C 1-3 Alkyl (e.g., R) 1 It is -C 1-3 Alkyl and R 2 It is -C 1-3 Alkyl; or R 1 It is -C 1-3 Alkyl and R 2 It is hydrogen; or R 1 It is hydrogen and R 2 It is hydrogen). Or even more appropriately, R 1 and R 2 Independently selected from hydrogen and methyl (e.g., R 1 It is methyl and R 2 It is methyl; or R 1 It is methyl and R 2 It is hydrogen; or R 1 It is hydrogen and R 2 It is hydrogen.

[0122] In some suitable implementations, R 1 -C is optionally substituted with 1, 2 or 3 substituents. 1-4Alkyl group, each substituent independently selected from halogen, -OCH3, and -OCF3; and R 2 -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3. More preferably, R 1 It is -C 1-4 Alkyl; and R 2 It is -C 1-4 Alkyl group. Even more appropriately, R 1 It is -C 1-3 Alkyl; and R 2 is-C 1-3 Alkyl group. Even more appropriately, R 1 It is methyl; and R 2 It is a methyl group.

[0123] In another suitable implementation, R 1 -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OCH3, and -OCF3; and R 2 It's hydrogen. More appropriately, R 1 It is -C 1-4 Alkyl; and R 2 It's hydrogen. Or even more accurately, R 1 It is -C 1-3 Alkyl; and R 2 It's hydrogen. Or even more accurately, R 1 It is methyl; and R 2 It is hydrogen.

[0124] In a suitable implementation scheme, R 1 It is hydrogen and R 2 It is hydrogen.

[0125] In another implementation, R 1 and R 2 They can connect together to form C along with the atoms they are connected to. 3-6 Cycloalkyl (i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or a 3- to 6-membered non-aromatic heterocyclic group containing one heteroatom selected from O and N (i.e., 3-, 4-, 5-, or 6-membered non-aromatic heterocyclic group), wherein the C 3-6 The cycloalkyl or 3- to 6-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens, -OH, -CH3, -OCH3, and -OCF3. For example, R 1 and R 2 They connect together to form C along with the atoms they are connected to. 3-5Cycloalkyl (i.e., cyclopropyl, cyclobutyl, or cyclopentyl) or a 3- to 5-membered non-aromatic heterocyclic group containing one heteroatom selected from O and N (i.e., a 3-, 4-, or 5-membered non-aromatic heterocyclic group), wherein the C 3-5 The cycloalkyl or 3- to 5-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens, -CH3, -OH, -OCH3, and -OCF. For example, R... 1 and R 2 They connect together to form C along with the atoms they are connected to. 3-5 cycloalkyl, wherein the C 3-5 The cycloalkyl group is optionally substituted with one or two substituents, each substituent being independently selected from halogens, -CH3, -OH, -OCH3, and -OCF3. For example, R... 1 and R 2 They connect together to form C along with the atoms they are connected to. 3-5 cycloalkyl, wherein the C 3-5 The cycloalkyl group is optionally substituted with one substituent, the substitution being selected from halogens, -CH3, -OH, -OCH3, and -OCF3. For example, R... 1 and R 2 They connect together to form C along with the atoms they are connected to. 3-5 Cycloalkyl.

[0126] In another implementation, R 1 and R 2 They connect together to form C along with the atoms they are connected to. 3-6 Cycloalkyl (i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), wherein the C 3-6 The cycloalkyl group is optionally substituted with one substituent, the substitution being selected from halogens, -CH3, -OH, -OCH3, and -OCF3. For example, R 1 and R 2 They connect together to form C along with the atoms they are connected to. 3-6 Cycloalkyl (i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0127] To avoid ambiguity, R is included in this context. 1 and R 2 In the interconnected implementation scheme, R 1 and R 3 Not connected.

[0128] R 3 It may be selected from hydrogen; -C may be optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents.3-6- Cycloalkyl, with each substituent independently selected from halogens, -OH, -CH3, -OCH3, and -OCF3. Suitably, R 3 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3. More preferably, R 3 Selected from hydrogen and -C atoms optionally substituted with 1, 2 or 3 F atoms. 1-4 Alkyl group. Even more appropriately, R 3 Selected from hydrogen and -C atoms optionally substituted with 1, 2 or 3 F atoms. 1-3 Alkyl group. Even more appropriately, R 3 Selected from hydrogen and methyl groups optionally substituted with 1, 2, or 3 F atoms. For example, R 3 It is hydrogen; or R 3 It is methyl; or R 3 It is -CF3.

[0129] In another implementation, R 1 and R 3 These can be linked together to form 3- to 6-membered non-aromatic heterocyclic groups (i.e., 3, 4, 5, or 6-membered non-aromatic heterocyclic groups) containing one N heteroatom, wherein the 3- to 6-membered non-aromatic heterocyclic groups are optionally substituted with one or two substituents, each substituent being independently selected from halogens, -CH3, -OH, -OCH3, and -OCF3, for example, halogens, -OH, -OCH3, and -OCF3. For example, R 1 and R 3 These groups are linked together to form a 4- to 6-membered non-aromatic heterocyclic group (i.e., a 4, 5, or 6-membered non-aromatic heterocyclic group) containing one N heteroatom, wherein the 4- to 6-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens, -CH3, -OH, -OCH3, and -OCF3, for example, halogens, -OH, -OCH3, and -OCF3. For example, R... 1 and R 3 These atoms are linked together to form a 5- or 6-membered non-aromatic heterocyclic group containing one N heteroatom, wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent independently selected from halogens, -CH3, -OH, -OCH3, and -OCF3, for example, halogens, -OH, -OCH3, and -OCF3. For example, R... 1 and R 3These atoms are linked together to form a 5- or 6-membered non-aromatic heterocyclic group containing one nitrogen atom, wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with one substituent selected from halogens, -CH3, -OH, -OCH3, and -OCF3, for example, halogens, -OH, -OCH3, and -OCF3. For example, R... 1 and R 3 They are linked together to form a 5- or 6-membered non-aromatic heterocyclic group containing one N heteroatom, together with the atoms to which they are linked.

[0130] In another implementation, R 1 and R 3 These atoms are linked together to form a 4- or 5-membered non-aromatic heterocyclic group containing one N heteroatom, wherein the 4- or 5-membered non-aromatic heterocyclic group is optionally substituted with one substituent selected from halogens, -CH3, -OH, -OCH3, and -OCF3, for example, halogens, -OH, -OCH3, and -OCF3. For example, R 1 and R 3 They are linked together to form a 4- or 5-membered non-aromatic heterocyclic group containing one N heteroatom, together with the atoms to which they are linked.

[0131] To avoid ambiguity, R is included in this context. 1 and R 3 In the interconnected implementation scheme, R 1 and R 2 Not connected.

[0132] In the compound of formula (I), X 2 Selected from CR 4 And N. Appropriately, X 2 It is CR 4 In such an embodiment, the compound of formula (I) is the compound of formula (Ic):

[0133]

[0134] When it exists, R 4 It can be selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from halogens, -OH, -OCH3, -OCF3, and -NR. a R b Appropriately, R 4 Selected from hydrogen; halogen; and -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, -OCH3, and -OCF3. More preferably, R 4Selected from hydrogen; halogen; and -C optionally substituted with one substituent selected from halogen, -OH, -OCH3, and -OCF3. 1-4 Alkyl group. Even more appropriately, R 4 Selected from hydrogen and -C 1-4 Alkyl group. In a particularly suitable embodiment, R 4 Selected from hydrogen and methyl, such as R 4 It is hydrogen.

[0135] Or, R 4 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3. More preferably, R 4 Selected from hydrogen and methyl groups optionally substituted with 1, 2, or 3 F atoms, such as R 4 It is hydrogen; or R 4 It is methyl; or R 4 It is -CF3.

[0136] When they exist, each R a and R b It can be independently selected from hydrogen and -C. 1-4 Alkyl groups. Suitablely, each R a and R b It can be independently selected from hydrogen and methyl. For example, R a It is hydrogen and R b It is hydrogen; or R a It is methyl and R b It is hydrogen; or R a It is methyl and R b It is a methyl group.

[0137] In a suitable embodiment of the invention, R 3 and R 4 Both are hydrogen.

[0138] In the compound of formula (I), R 5a and R 5d Independently selected from hydrogen; halogen; methyl group optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and methoxy group optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3. Suitably, R 5a and R 5d Independently selected from hydrogen; F; Cl; a methyl group optionally substituted with one substituent selected from halogen, -OH, -OCH3, and -OCF3; and a methoxy group optionally substituted with one substituent selected from halogen, -OH, -OCH3, and -OCF3. More preferably, R 5a and R5d Independently selected from hydrogen; F; Cl; methyl and methoxy. Even more appropriately, R 5a and R 5d Independently selected from hydrogen and methyl. In a very suitable embodiment, R 5a and R 5d Both are hydrogen.

[0139] In some suitable implementations, R 5a It is hydrogen and R 5d Selected from hydrogen; halogen; methyl group optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and methoxy group optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3. Suitably, R 5a It is hydrogen and R 5d The radical is selected from hydrogen; F; Cl; a methyl group optionally substituted with one substituent selected from halogen, -OH, -OCH3, and -OCF3; and a methoxy group optionally substituted with one substituent selected from halogen, -OH, -OCH3, and -OCF3. More preferably, R 5a It is hydrogen and R 5d Selected from hydrogen; F; Cl; methyl and methoxy. Even more appropriately, R 5a It is hydrogen and R 5d It is independently selected from hydrogen and methyl.

[0140] In some suitable implementations, R 5d It is hydrogen and R 5a Selected from hydrogen; halogen; methyl group optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and methoxy group optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3. More preferably, R 5d It is hydrogen and R 5a The radical is selected from hydrogen; F; Cl; a methyl group optionally substituted with one substituent selected from halogen, -OH, -OCH3, and -OCF3; and a methoxy group optionally substituted with one substituent selected from halogen, -OH, -OCH3, and -OCF3. Even more preferably, R 5d It is hydrogen and R 5a Selected from hydrogen; F; Cl; methyl and methoxy. Even more appropriately, R 5d It is hydrogen and R 5a It is independently selected from hydrogen and methyl.

[0141] In the compound of formula (I), R 5b and R 5cIt can be independently selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3;

[0142] Or R 5b and R 5c They can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from S, O, and N, wherein the 6-membered aryl group or the 5- or 6-membered aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogen, -OH, -OCH3, and -OCF3.

[0143] In some suitable implementations, R 5b and R 5c Independently selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, wherein each substituent is independently selected from halogen, -CH3, -OCH3, -OH, -OCH3, and -OCF3, for example, halogen, -CH3, -OH, -OCH3, and -OCF3. More preferably, R 5b and R 5c Independently selected from hydrogen; halogen; -C optionally substituted by one substituent selected from halogen, -OH, -OCH3 and -OCF3 1-4 Alkyl group; and -OC group optionally substituted with one substituent selected from halogen, -OH, -OCH3 and -OCF3. 1-4 Alkyl group; and C group optionally substituted with one substituent selected from halogen, -CH3, -OH, -OCH3 and -OCF3. 3-6 Cycloalkyl.

[0144] More appropriately, R 5b and R 5c Independently selected from hydrogen; halogen; and optionally substituted by one substituent selected from halogen, -OH, -OCH3, and -OCF3.1-4 Alkyl group. Even more appropriately, R 5b and R 5c Independently selected from hydrogen; F; Cl; and -C 1-4 Alkyl, for example, R 5b and R 5c Each is hydrogen on its own.

[0145] In a particularly suitable implementation, R 5a and R 5d It is hydrogen, and R 5b and R 5c Selected from hydrogen, halogens, and -C atoms optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from halogens, -OH, -OCH3, and -OCF3. For example, R 5a and R 5d It is hydrogen and R 5b and R 5c Selected from hydrogen, halogens, and -C groups optionally substituted with one of the substituents selected from halogens, -OH, -OCH3, and -OCF3. 1-4 alkyl.

[0146] In some suitable implementations, R 5b It is hydrogen and R 5c Selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogens, -CH3, -OH, -OCH3, and -OCF3. More preferably, R 5b It is hydrogen and R 5c Selected from hydrogen; halogen; -C optionally substituted with one substituent selected from halogen, -OH, -OCH3 and -OCF3 1-4 Alkyl group; and -OC group optionally substituted with one substituent selected from halogen, -OH, -OCH3 and -OCF3. 1-4 Alkyl group; C substituted with one substituent selected from halogen, -OH, -CH3, -OCH3 and -OCF3. 3-6 Cycloalkyl. More appropriately, R 5b It is hydrogen and R 5c Selected from hydrogen; halogen; and -C optionally substituted with one substituent selected from halogen, -OH, -OCH3, and -OCF3. 1-4 Alkyl group. Even more appropriately, R5b It is hydrogen and R 5c Selected from hydrogen; F; Cl; and -C 1-4 Alkyl groups (e.g., hydrogen; F; Cl; and methyl). In such embodiments, R is suitable. 5a and R 5d Both are hydrogen.

[0147] In a particularly suitable implementation, R 5c It is hydrogen and R 5c Selected from hydrogen; F; and Cl. In such an implementation, R is suitable. 5a and R 5d Both are hydrogen.

[0148] In a particularly suitable implementation, R 5c It is hydrogen and R 5b Selected from hydrogen; F; and Cl. In such an implementation, R is suitable. 5a and R 5d Both are hydrogen.

[0149] In some suitable implementations, R 5c It is hydrogen and R 5b Selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogens, -CH3, -OH, -OCH3, and -OCF3. More preferably, R 5c It is hydrogen and R 5b Selected from hydrogen; halogen; -C optionally substituted with one substituent selected from halogen, -OH, -OCH3 and -OCF3 1-4 Alkyl group; and -OC group optionally substituted with one substituent selected from halogen, -OH, -OCH3 and -OCF3. 1-4 Alkyl group; and C group optionally substituted with one substituent selected from halogen, -CH3, -OH, -OCH3 and -OCF3. 3-6 Cycloalkyl. More appropriately, R 5c It is hydrogen and R 5b Selected from hydrogen; halogen; and -C optionally substituted with one substituent selected from halogen, -OH, -OCH3, and -OCF3. 1-4 Alkyl group. Even more appropriately, R 5c It is hydrogen and R 5b Selected from hydrogen; F; Cl; and -C1-4 Alkyl groups (e.g., hydrogen; F; Cl; and methyl). In such embodiments, R is suitable. 5a and R 5d Both are hydrogen.

[0150] In a particularly suitable implementation, R 5b It is hydrogen and R 5c Selected from hydrogen and C 1-4 Alkyl groups (e.g., hydrogen and methyl). In such embodiments, R is suitable. 5a and R 5d Both are hydrogen. In a particularly suitable implementation, R 5a R 5b R 5c and R 5d Both are hydrogen.

[0151] In some other implementations, R 5b and R 5c These groups are linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from S, O, and N, wherein the 6-membered aryl group or the 5- or 6-membered aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogens, -OH, -OCH3, and -OCF3. For example, R 5b and R 5c These groups are linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from O and N, wherein the 6-membered aryl group or the 5- or 6-membered aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogens, -OH, -OCH3, and -OCF3. For example, R... 5b and R 5c These groups are linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two N heteroatoms, wherein the -6-membered aryl group or the 5- or 6-membered aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogens, -OH, -OCH3, and -OCF3. For example, R 5b and R 5c They are linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two N heteroatoms, together with the atoms to which they are linked. In such an embodiment, R 5a and R 5d For example, they can all be hydrogen.

[0152] In the compound of formula (I), R 6 It can be selected from hydrogen and methyl. Suitablely, R 6 It is hydrogen.

[0153] In a suitable embodiment of the invention, R 3 R 4 and R 6 Both are hydrogen.

[0154] In compounds of formula (I), p is 0, 1, or 2. For example, p can be 0 or 1. In some suitable embodiments, p is 0.

[0155] In a suitable embodiment of the invention, R 6 It is hydrogen; and p is 0. In another suitable embodiment of the invention, R... 3 R 4 and R 6 Both are hydrogen; and p is 0.

[0156] In compounds of formula (I), when present, each R 7 -C can be optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from halogens, -OH, -OCH3, and -OCF3. Suitably, when present, each R... 7 Independently, it is a -C group optionally substituted with one substituent selected from halogen, -OH, -OCH3, and -OCF3. 1-4 Alkyl groups. More preferably, when present, each R 7 Independently is -C 1-4 Alkyl groups. In another suitable embodiment, when present, each R... 7 It may be a methyl group that is optionally substituted with one of the substituents selected from halogen, -OH, -OCH3 and -OCF3.

[0157] In the compound of formula (I), R 8 It can be selected from hydrogen; halogen; -OH; -CN; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; -C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -CH3, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; -C groups optionally substituted with 1, 2, or 3 substituents. 1-4 alkenyl (e.g., -C) 2-4 Alkenyl), each substituent is independently selected from halogens, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens. Suitably, R8 Selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; -C group optionally substituted with 1, 2, or 3 substituents. 3-4 Cycloalkyl, each substituent independently selected from halogens, -CH3, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens (e.g., 1, 2, or 3 F atoms); -C optionally substituted with 1, 2, or 3 substituents. 1-4 alkenyl (e.g., -C) 2-4 Alkenyl), each substituent is independently selected from halogens, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, CN, and methoxy groups optionally substituted with one, two, or three halogens. More preferably, R 8 Selected from hydrogen; halogens (e.g., F or Cl); -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -CN, and methoxy group optionally substituted with 1, 2, or 3 halogens; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens. Even more preferably, R 8 Selected from hydrogen; halogens (e.g., F or Cl); -C optionally substituted with one substituent. 1-4 Alkyl group, wherein the substituent is selected from halogens, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with one substituent. 1-4 Alkyl group, wherein the substituent is selected from halogens, -OH, CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens. Even more preferably, R 8 Selected from hydrogen; halogens (e.g., F or Cl); -C optionally substituted with one substituent. 1-4 Alkyl groups, wherein the substituents are selected from halogens and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with one substituent. 1-4 Alkyl groups, wherein the substituents are selected from halogens and methoxy groups optionally substituted with one, two, or three halogens. Even more preferably, R 8 Selected from hydrogen; halogen; -C 1-4 Alkyl; and -OC 1-4 Alkyl group. For example, R 8 Selected from hydrogen; halogen; methyl; and methoxy.

[0158] Or, R8 Selected from hydrogen; halogens (e.g., F or Cl); methyl groups optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogens, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and methoxy groups optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogens, -OH, CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens. Suitably, R 8 Selected from hydrogen; halogens (e.g., F or Cl); methyl groups optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogens and methoxy groups optionally substituted with 1, 2, or 3 halogens; and methoxy groups optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogens and methoxy groups optionally substituted with 1, 2, or 3 halogens. More preferably, R 8 Selected from hydrogen; halogens (e.g., F or Cl); methyl groups optionally substituted with 1, 2, or 3 F atoms; and methoxy groups optionally substituted with 1, 2, or 3 F atoms. For example, R 8 Selected from hydrogen; halogen; methyl; -CF3; methoxy; and -OCF3. Suitablely, R 8 It's CF3. Appropriately, R 8 It is Cl.

[0159] In another implementation, R 8 Selected from hydrogen; halogen; -OH; -CN; -C optionally substituted with 1, 2 or 3 substituents. 1-3 Alkyl group, each substituent independently selected from halogens (e.g., F), -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens (e.g., 1, 2, or 3 F atoms); -C group optionally substituted with 1, 2, or 3 substituents. 3-4 Cycloalkyl, wherein each substituent is independently selected from halogens (e.g., F), -OH, -CH3, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens (e.g., 1, 2, or 3 F atoms); and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-3 The alkyl group, with each substituent independently selected from halogens (e.g., F), -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens (e.g., 1, 2, or 3 F atoms). In such embodiments, R is suitable. 9 It is hydrogen.

[0160] In the compound of formula (I), R 9 It can be selected from hydrogen and -C which may be optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, -OCH3, and -OCF3. Suitably, R 9 -C selected from hydrogen and optionally substituted with one substituent selected from halogen, -OH, -OCH3 and -OCF31-4 Alkyl group. More appropriately, R 9 Selected from hydrogen and -C 1-4 Alkyl group. More appropriately, R 9 Selected from hydrogen and methyl. In a particularly suitable embodiment, R 9 It is hydrogen.

[0161] Or, R 9 Selected from hydrogen and methyl groups optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogens, -OH, -OCH3, and -OCF3. Suitably, R 9 Selected from hydrogen and methyl groups optionally substituted with 1, 2, or 3 F atoms. For example, R 9 It is hydrogen; or R 9 It is methyl; or R 9 It is -CF3.

[0162] In a suitable embodiment of the invention, R 6 and R 9 All are hydrogen; and p is 0. In another suitable embodiment of the invention, R 3 R 4 R 6 and R 9 Both are hydrogen; and p is 0.

[0163] In the compound of formula (I), R 8 and R 9 They can connect together to form 6-membered aryl groups, C... 5-6 Cycloalkyl or a 5- or 6-membered aromatic heterocyclic group comprising one or two heteroatoms selected from N, O, and S (e.g., 1 heteroatom), wherein the 6-membered aryl group, C 5-6 The cycloalkyl or 5- to 6-membered aromatic heterocyclic group is optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens; -OH; -CN; -C optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent being independently selected from -halogen, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens.

[0164] In the compound of formula (I), R 8 and R 9 They connect together to form 6-membered aryl groups and C atoms together with the atoms they are attached to. 5-6Cycloalkyl or a 5- or 6-membered aromatic heterocyclic group comprising one or two heteroatoms selected from N, O, and S (e.g., 1 heteroatom), wherein the 6-membered aryl group, C 5-6 The cycloalkyl or 5- or 6-membered aromatic heterocyclic group is optionally substituted with 1, 2, or 3 substituents (e.g., 1 substituent), each substituent being independently selected from halogens; -OH; -CN; -C optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl groups, each substituent being independently selected from -halogen, -OH, -OCH3 and -OCF3.

[0165] In a suitable implementation scheme, R 8 and R 9 They connect together to form C along with the atoms they are connected to. 5-6 cycloalkyl, wherein the C 5-6 The cycloalkyl group is optionally substituted with 1, 2, or 3 substituents (e.g., 1 substituent), each substituent being independently selected from halogens; -OH; -CN; -C optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent being independently selected from -halogen, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens.

[0166] In a suitable implementation scheme, R 8 and R 9 They connect together to form C along with the atoms they are connected to. 5-6 cycloalkyl, wherein the C 5-6 The cycloalkyl group is optionally substituted with 1, 2, or 3 substituents (e.g., 1 substituent), said substituent being selected from halogens; -OH; -CN; -C optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl groups, each substituent being independently selected from -halogen, -OH, -OCH3 and -OCF3.

[0167] Even more appropriately, R 8 and R 9These atoms are linked together to form a C5 cycloalkyl group, wherein the C5 cycloalkyl group is optionally substituted with 1, 2, or 3 substituents (e.g., 1 substituent), each substituent being independently selected from halogens; -OH; -CN; and -C atoms optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent being independently selected from -halogen, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens.

[0168] Even more appropriately, R 8 and R 9 These atoms are linked together to form a C5 cycloalkyl group, wherein the C5 cycloalkyl group is optionally substituted with 1, 2, or 3 substituents (e.g., 1 substituent), the substituents being selected from halogens; -OH; -CN; and -C atoms optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl groups, each substituent being independently selected from -halogen, -OH, -OCH3 and -OCF3.

[0169] Or, R 8 and R 9 These atoms can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N, O, and S, wherein the 6-membered aryl group or the 5- or 6-membered aromatic heterocyclic group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens; -OH; -CN; -C optionally substituted with one, two, or three substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from -halogen, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens. For example, R 8 and R 9 These atoms can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N and O, wherein said 6-membered aryl group or 5- or 6-membered aromatic heterocyclic group is optionally substituted with one, two or three substituents, each substituent being independently selected from halogens; -OH; -CN; -C optionally substituted with one, two or three substituents. 1-4Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from -halogen, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens. For example, R... 8 and R 9 These atoms can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N and O, wherein said 6-membered aryl group or 5- to 6-membered aromatic heterocyclic group is optionally substituted with one, two, or three substituents, each substituent being independently selected from a halogen (e.g., F or Cl); the -C group optionally substituted with one, two, or three substituents... 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent being independently selected from -halogen, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens.

[0170] In another implementation, R 8 and R 9 These atoms can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N and O (e.g., one heteroatom), and said 6-membered aryl or 5- to 6-membered aromatic heterocyclic group is optionally substituted by one, two, or three substituents, each substituent being independently selected from a halogen (e.g., F or Cl); the -C group optionally substituted by one substituent... 1-4 Alkyl groups, wherein the substituents are selected from halogens and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with one substituent. 1-4 Alkyl groups, wherein the substituents are selected from halogens and methoxy groups optionally substituted with one, two, or three halogens. For example, R 8 and R 9 These atoms can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group comprising one or two heteroatoms selected from N and O (e.g., one heteroatom), and said 6-membered aryl or 5- to 6-membered aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogens (e.g., F or Cl); the -C group optionally substituted by one substituent 1-4 Alkyl groups, wherein the substituents are selected from halogens and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with one substituent. 1-4 Alkyl groups, wherein the substituents are selected from halogens and methoxy groups optionally substituted with one, two, or three halogens. For example, R 8 and R9 These can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N and O (e.g., one heteroatom), and said 6-membered aryl or 5- to 6-membered aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogens; -C 1-4 Alkyl; and -OC 1-4 Alkyl groups. For example, R 8 and R 9 These can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group comprising one or two heteroatoms selected from N and O (e.g., one heteroatom), and wherein said 6-membered aryl group or 5- to 6-membered aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from hydrogen; halogen; methyl; and methoxy. In another embodiment, R 8 and R 9 They can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N and O (e.g., 1 heteroatom).

[0171] Alternatively, in one implementation, R 8 and R 9 These can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group comprising one or two heteroatoms selected from N and O (e.g., one heteroatom), wherein said 6-membered aryl or 5- to 6-membered aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent independently selected from halogens (e.g., F or Cl); a methyl group optionally substituted with one, two, or three substituents, each substituent independently selected from halogens, -OH, -CN, and a methoxy group optionally substituted with one, two, or three halogens, such as halogens, -OH, and methoxy groups optionally substituted with one, two, or three halogens; and a methoxy group optionally substituted with one, two, or three substituents, each substituent independently selected from halogens, -OH, CN, and a methoxy group optionally substituted with one, two, or three halogens, such as halogens, -OH, and methoxy groups optionally substituted with one, two, or three halogens. For example, R 8 and R 9These can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group comprising one or two heteroatoms selected from N and O (e.g., one heteroatom), wherein said 6-membered aryl or 5- to 6-membered aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent independently selected from a halogen (e.g., F or Cl); a methyl group optionally substituted with one, two, or three substituents, each substituent independently selected from a halogen; and a methoxy group optionally substituted with one, two, or three substituents, each substituent independently selected from a halogen; and a methoxy group optionally substituted with one, two, or three substituents, each substituent independently selected from a halogen; and a methoxy group optionally substituted with one, two, or three halogens. For example, R 8 and R 9 These can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group comprising one or two heteroatoms selected from N and O (e.g., one heteroatom), wherein said 6-membered aryl or 5- to 6-membered aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent independently selected from halogens (e.g., F or Cl); methyl groups optionally substituted with one, two, or three F atoms; and methoxy groups optionally substituted with one, two, or three F atoms. For example, R... 8 and R 9 They can be linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N and O (e.g., one heteroatom), and said 6-membered aryl group or 5- to 6-membered aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogen; methyl; -CF3; methoxy; and -OCF3.

[0172] Alternatively, in one implementation, R 8 and R 9 These atoms are linked together to form a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N, O, and S (e.g., one heteroatom), and the 5- or 6-membered aromatic heterocyclic group is optionally substituted by one, two, or three substituents, each substituent being independently selected from halogens; -OH; -CN; -C optionally substituted by one, two, or three substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent being independently selected from -halogen, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens.

[0173] Alternatively, in one implementation, R 8 and R 9These atoms are linked together to form a 5- or 6-membered aromatic heterocyclic group comprising one or two heteroatoms selected from N, O, and S (e.g., one heteroatom), wherein the 5- or 6-membered aromatic heterocyclic group is optionally substituted with one substituent selected from halogens; -OH; -CN; or -C optionally substituted with one, two, or three substituents. 1-3 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl groups, each substituent being independently selected from -halogen, -OH, -OCH3 and -OCF3.

[0174] In a suitable implementation scheme, R 8 and R 9 These atoms are linked together to form a 5-membered aromatic heterocyclic group containing one or two heteroatoms selected from N, O, and S (e.g., one heteroatom), and the 5-membered aromatic heterocyclic group is optionally substituted by one, two, or three substituents, each substituent being independently selected from halogens; -OH; -CN; -C optionally substituted by one, two, or three substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent being independently selected from -halogen, -OH and methoxy group optionally substituted with 1, 2 or 3 halogens;

[0175] In a suitable implementation scheme, R 8 and R 9 These atoms are linked together to form a 5-membered aromatic heterocyclic group containing one or two heteroatoms selected from N, O, and S (e.g., one heteroatom), and the 5-membered aromatic heterocyclic group is optionally substituted with one substituent selected from halogens; -OH; -CN; -C optionally substituted with one, two, or three substituents. 1-3 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-3 Alkyl groups, each substituent being independently selected from -halogen, -OH, -OCH3 and -OCF3.

[0176] In a suitable implementation scheme, R 8 and R 9 They link together to form, together with the atoms they are attached to, a 5-membered aromatic heterocyclic group selected from the following:

[0177]

[0178] In a suitable implementation, the 5-membered heterocyclic group is selected from:

[0179]

[0180] In a suitable implementation, the 5-membered heterocyclic group is:

[0181]

[0182] In a suitable implementation, the 5-membered heterocyclic group is:

[0183]

[0184] In a suitable implementation, the 5-membered heterocyclic group is:

[0185]

[0186] In a suitable implementation, the 5-membered heterocyclic group is:

[0187]

[0188] To avoid any ambiguity, in such an implementation plan, Indicates the connection point, for example, Equivalent to

[0189] In the compound of formula (I), Z can be a 5- to 13-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 13-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent), each substituent being independently selected from halogens; -C optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl group; -OC group optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; NR c R d ; and C substituted with one, two or three substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -OH, and -OC optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; or when two substituents are in adjacent ring positions, they can be linked together to form a C1 ring with the atoms to which they are linked.3-6 Cycloalkyl or a 4- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 4- to 6-membered non-aromatic heterocyclic group (i.e., 4, 5, or 6-membered non-aromatic heterocyclic group) is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C is optionally substituted with one, two, or three substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl;

[0190] R c and R d Independently selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and C4 groups optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3;

[0191] Or Z is -NR 10 R 11 .

[0192] In the compound of formula (I), Z can be a 5- to 13-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 13-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent), each substituent being independently selected from halogens; -C optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl group; -OC group optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl;

[0193] Or Z is -NR 10 R 11 .

[0194] Alternatively, Z can be a 5- to 13-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 13-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent), each substituent being independently selected from NR. c R d ; and C substituted with one, two or three substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -OH, and -OC optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; or when two substituents are in adjacent ring positions, they can be linked together to form a C1 ring with the atoms to which they are linked. 3-6 Cycloalkyl or a 4- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 4- to 6-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C is optionally substituted with one, two, or three substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl;

[0195] R c and R d Independently selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and C4 groups optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3;

[0196] Or Z is -NR 10 R 11 .

[0197] Alternatively, Z can be a 5- to 10-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 10-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent), each substituent being independently selected from halogens; -C optionally substituted with 1, 2, or 3 substituents. 1-6Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl;

[0198] Or Z is -NR 10 R 11 .

[0199] In embodiments where Z is a 5- to 13-membered nonaromatic heterocyclic group (i.e., 5, 6, 7, 8, 9, 10, 11, 12, or 13-membered nonaromatic heterocyclic group), suitably, the N heteroatom directly interacts with X contained in formula (I). 1 It is linked to a 6-membered aromatic heterocyclic group.

[0200] In embodiments where Z is a 5- to 13-membered non-aromatic heterocyclic group, Z can be azirropropyl, azirrobutyl, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, azirroheptyl, diazacycloheptyl (e.g., 1,4-diazacycloheptyl, 1,1-diazacycloheptyl or 1,5-diazacycloheptyl, suitably 1,4-diazacycloheptyl), diazabicycloheptyl (e.g., 3,6-diazabicyclo[3.2.0]heptyl), 1H-octahydropyrrolo[3,4-b]pyridyl, 2,5-diazabicyclo[2.2.0]heptyl). 2.1] Heptyl, cis-octahydropyrrolo[3,4-b]pyridyl, cis-octahydropyrrolo[3,4-c]pyridyl, 3,7-diazabicyclo[3.3.1]nonyl, 2,6-diazaspiro[3.3]heptyl, octahydropyrrolo[3,2-b]pyrryl, 1,7-diazaspiro[4.4]nonyl, 1,8-diazaspiro[4.5]decyl, decahydro-2,7-naphridyl, 2,8-diazaspiro[5.5]undecyl, 3,6-diazabicyclo[3.2.0]heptane, 2,8-diazaspiro[4.5]decyl, octahydropyrrolo[3,4-c]pyrryl, trans-octahydro-1H-pyrryl Pyrido[3,4-b]pyridyl, 2,6-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.5]decyl, 1,7-diazaspiro[3.5]nonyl, 1,6-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, (4aR,8aR)-decahydro-1,5-naphthidyl, 3,9-diazaspiro[5.5]undecyl, (3aS,6aS)-octahydropyrrolo[2,3-c]pyrryl, 2,9-diazaspiro[6.6]tridecyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7 -diazabicyclo[4.2.0]octyl, 9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonyl, cis-octahydropyrrolo[3,4-c]pyridyl, cis-decahydro-1,7-naphthidyl, 2,7-diazabicyclo[4.2.0]octyl, (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazinyl, 2,6-diazaspiro[3.4]octyl, 1,9-diazaspiro[6.6]tetrazyl, (4aS,8aS)-decahydro-1,5-naphthidyl, trans-decahydro-1,7-naphthidium, (1S,2S)-2,5-diazabicyclo[2.2.[1] Heptyl, trans-decahydro-1,7-naphthidyl, rac-(4aR,8aR)-octahydro-2H-pyrido[4,3-b]morpholinyl, decahydro-1,6-naphthidyl, octahydro-1H-pyrrolo[3,2-c]pyridyl, rac-(3aR,6aR)-octahydropyrrolo[2,3-c]pyrrolyl, or decahydropyrrolo[3,2-c]azapyrrolyl. Suitably, the N heteroatom of the heterocyclic group is directly related to X contained in formula (I). 1 It is linked to a 6-membered aromatic heterocyclic group.

[0201] In embodiments where Z is a 5- to 13-membered nonaromatic heterocyclic group, Z is suitably a 5- to 13-membered nonaromatic heterocyclic group (i.e., 5, 6, 7, 8, 9, 10, 11, 12, or 13-membered nonaromatic heterocyclic group) comprising 1, 2, or 3 heteroatoms selected from N and O, wherein at least one heteroatom is N, and wherein said 5- to 13-membered nonaromatic heterocyclic group is optionally substituted by 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). In this embodiment, suitably, the N heteroatom is directly coupled with X contained in formula (I). 1 The six-membered aromatic heterocyclic group is attached. For example, Z is a five- to ten-membered non-aromatic heterocyclic group. Suitably, Z is a five- to ten-membered non-aromatic heterocyclic group (i.e., a 5, 6, 7, 8, 9, or 10-membered non-aromatic heterocyclic group) containing one, two, or three heteroatoms selected from N and O, wherein at least one heteroatom is N, and wherein the five- to ten-membered non-aromatic heterocyclic group is optionally substituted by one, two, three, or four substituents (e.g., one, two, or three substituents; or one or two substituents; or one substituent). In this embodiment, suitably, the N heteroatom is directly attached to the X contained in formula (I). 1 It is linked to a 6-membered aromatic heterocyclic group.

[0202] Alternatively, Z is a 5- to 13-membered non-aromatic heterocyclic group. Suitably, Z is a 6- to 10-membered non-aromatic heterocyclic group (i.e., a 6, 7, 8, 9, or 10-membered non-aromatic heterocyclic group) comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 6- to 10-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). More suitably, Z is a 6- to 10-membered non-aromatic heterocyclic group comprising 2 or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 6- to 10-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). More preferably, Z is a 6- to 10-membered non-aromatic heterocyclic group comprising 2 or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 6- to 10-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). Even more preferably, Z is a 6- to 10-membered non-aromatic heterocyclic group comprising 2 or 3 heteroatoms selected from N and O, wherein at least one heteroatom is N, and wherein said 6- to 10-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). In this embodiment, suitably, the N heteroatom is directly coupled with X contained in formula (I). 1 It is linked to a 6-membered aromatic heterocyclic group.

[0203] Alternatively, Z is a 5- to 13-membered nonaromatic heterocyclic group. Suitably, Z is a 5- to 8-membered nonaromatic heterocyclic group (i.e., a 5, 6, 7, or 8-membered nonaromatic heterocyclic group) comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 8-membered nonaromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). More suitably, Z is a 5- to 8-membered nonaromatic heterocyclic group comprising 2 or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 8-membered nonaromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). More preferably, Z is a 5- to 8-membered non-aromatic heterocyclic group comprising 2 or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 8-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). Even more preferably, Z is a 5- to 8-membered non-aromatic heterocyclic group comprising 2 or 3 heteroatoms selected from N and O, wherein at least one heteroatom is N, and wherein said 5- to 8-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). In this embodiment, suitably, the N heteroatom is directly coupled with X contained in formula (I). 1 It is linked to a 6-membered aromatic heterocyclic group.

[0204] In a suitable embodiment, Z is a 5- to 13-membered nonaromatic heterocyclic group. Suitably, Z is a 6-membered nonaromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and said 6-membered nonaromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). More suitably, Z is a 6-membered nonaromatic heterocyclic group comprising 2 or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and said 6-membered nonaromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). More preferably, Z is a 6-membered non-aromatic heterocyclic group comprising 2 or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 6-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). Even more preferably, Z is a 6-membered non-aromatic heterocyclic group comprising 2 or 3 heteroatoms selected from N and O, wherein at least one heteroatom is N, and wherein said 6-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). In this embodiment, suitably, the N heteroatom is directly coupled with X contained in formula (I). 1 It is linked to a 6-membered aromatic heterocyclic group.

[0205] In embodiments where Z is optionally substituted (e.g., optionally substituted with 1, 2, 3, or 4 substituents; or optionally substituted with 1, 2, or 3 substituents; or optionally substituted with 1 or 2 substituents; or optionally substituted with 1 substituent), each substituent may be independently selected from halogens; -C optionally substituted with 1, 2, or 3 substituents 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl group. Suitably, each substituent is independently selected from halogens; -C is optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens.1-3 Alkyl group. More preferably, each substituent is independently selected from halogens; optionally substituted with one halogen, -OH, and -OC optionally substituted with one, two, or three halogens. 1-3 Alkyl substituents substituted -C 1-4 Alkyl group; and -OC group optionally substituted with one halogen selected from halogens, -OH, and optionally substituted with one, two, or three halogens. 1-3 Alkyl substituents -OC 1-4 Alkyl group. More preferably, each substituent is independently selected from halogens; optionally substituted with one halogen and optionally substituted with one, two or three halogens -OC. 1-3 Alkyl substituents substituted -C 1-4 Alkyl group; and -OC group optionally substituted with one halogen selected from halogens and optionally substituted with one, two, or three halogens. 1-3 Alkyl substituents -OC 1-4 Alkyl groups (e.g., each substituent is independently -OC, optionally substituted with one halogen and optionally substituted with one, two, or three halogens) 1-3 Alkyl substituents substituted -C 1-4 Alkyl group). Even more preferably, each substituent is independently selected from halogens; -OC is optionally substituted with one F atom and optionally with one, two or three F atoms. 1-3 Alkyl substituents substituted -C 1-4 Alkyl group; and -OC group optionally substituted with one atom selected from F and optionally substituted with one, two or three F atoms. 1-3 Alkyl substituents -OC 1-4 Alkyl groups (e.g., each substituent is independently -OC, optionally substituted by one F atom and optionally substituted by one, two, or three F atoms) 1-3 Alkyl substituents substituted -C 1-4 alkyl).

[0206] Alternatively, each substituent may be independently selected from halogens; -C may be optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl groups (e.g., each substituent is independently -C optionally substituted by 1, 2 or 3 substituents) 1-4 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl group). More preferably, each substituent is independently selected from halogens; -C is optionally substituted with 1, 2 or 3 substituents.1-4 Alkyl group, each substituent independently selected from halogens and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens and methoxy groups optionally substituted with 1, 2, or 3 halogens. Even more preferably, each substituent independently selected from halogens; -C optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from F and methoxy group optionally substituted with 1, 2 or 3 F atoms; and -OC group optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl groups, each substituent being independently selected from F and methoxy groups optionally substituted with 1, 2 or 3 F atoms.

[0207] In another suitable embodiment, each substituent of Z is independently selected from halogens; a methyl group optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from F and a methoxy group optionally substituted with 1, 2, or 3 F atoms; and a methoxy group optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from F and a methoxy group optionally substituted with 1, 2, or 3 F atoms (e.g., each substituent is independently a methyl group optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from F and a methoxy group optionally substituted with 1, 2, or 3 F atoms).

[0208] In a suitable embodiment, Z is a 5- to 13-membered non-aromatic heterocyclic group, suitably, Z is:

[0209]

[0210] (Or, appropriately, Z is)

[0211] );

[0212] (And even more appropriately, Z is) )in

[0213] Indicates the connection point.

[0214] m can be 0, 1, 2, or 3. Appropriately, m is 0, 1, or 2. More appropriately, m is 1 or 2.

[0215] r can be 0, 1, 2, or 3. Suitablely, r is 0, 1, or 2. In some embodiments, suitablely, r is 1 or 2. In some embodiments, suitablely, r is 0 or 1.

[0216] s can be 0, 1, 2, or 3. Suitablely, s is 0, 1, or 2. In some embodiments, suitablely, s is 1 or 2. In some embodiments, suitablely, s is 0 or 1. More suitablely, s is 0.

[0217] R 12 It can be selected from hydrogen and -C which may be optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 alkyl.

[0218] Appropriately, R 12 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl group. More appropriately, R 12 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl groups, each substituent independently selected from halogens and optionally methoxy groups substituted with one, two, or three halogens. More preferably, R 12 -C selected from hydrogen and optionally substituted with a methoxy group selected from halogens and optionally substituted with 1, 2, or 3 halogens (e.g., 1, 2, or 3 F atoms). 1-4 Alkyl group. More appropriately, R 12 Selected from -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl group. Even more appropriately, R 12 Selected from hydrogen and methyl. Even more appropriately, R 12 It's hydrogen. Or even more accurately, R 12 It is a methyl group.

[0219] In a suitable implementation scheme, Z is Appropriately, Z is Appropriately, Z is

[0220] When they exist, each R 13 Independently selected from halogens; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens.1-3 Alkyl; NR c R d ; and C substituted with one, two or three substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -OH, and -OC optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; or when two substituents are in adjacent ring positions, they can be linked together to form a C1 ring with the atoms to which they are linked. 3-6 Cycloalkyl or a 4- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 4- to 6-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C is optionally substituted with one, two, or three substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl;

[0221] R c and R d Independently selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and C4 groups optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3.

[0222] Suitable, the two substituents at adjacent ring positions are an R 12 And an R 13 Alternatively, both substituents at adjacent ring positions are R. 13 .

[0223] Alternatively, when m is 0 or 1, r is 2 or 3, and both R's are 0 or 1. 13 When in adjacent ring positions, the two R 13 They connect together to form C along with the atoms they are connected to. 3-6 Cycloalkyl or a 4- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 4- to 6-membered non-aromatic heterocyclic group (i.e., 4, 5, or 6-membered non-aromatic heterocyclic group) is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C is optionally substituted with one, two, or three substituents.1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl group. Suitablely, two R groups. 13 Groups link together to form C 3-6 Cycloalkyl groups, such as cyclopropyl groups, are preferably unsubstituted.

[0224] Or, when r is 1, 2, or 3 and an R 13 Groups in relation to NR 12 When in adjacent ring positions, the R 13 and R 12 These atoms are linked together to form a 5- or 6-membered nonaromatic heterocyclic group comprising one N heteroatom and optionally one heteroatom selected from O and N, wherein the 5- or 6-membered nonaromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C atoms are optionally substituted with one, two, or three substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; and

[0225] When they exist, each R 14 Independently selected from halogens; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl.

[0226] In a suitable implementation scheme, when present, each R 13 Independently is NR c R d C, or optionally substituted with 1, 2 or 3 substituents 3-6 Cycloalkyl, each substituent independently selected from halogens, -OH, and -OC optionally substituted with 1, 2, or 3 halogens.1-3 Alkyl groups. In a suitable embodiment, each R 13 Independently is NR c R d .

[0227] Even more appropriately, each R 13 Independently, it is a C that is optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -OH, and -OC optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups. Even more appropriately, each R 13 Independently, it is cyclopropyl, which is preferably unsubstituted.

[0228] In one implementation, R c It is hydrogen. In the second implementation, R c -C is optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3. In the third embodiment, R c C is a C that is optionally substituted with 1, 2 or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3.

[0229] Appropriately, R c It is unsubstituted -C 1-6 Alkyl groups, such as methyl, ethyl, and propyl, especially methyl and ethyl, particularly methyl.

[0230] Appropriately, R c It is unreplaced C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl and cyclopentyl, especially cyclopropyl.

[0231] In one implementation, R d It is hydrogen. In the second implementation, R d -C is optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3. In the third embodiment, R d C is a C that is optionally substituted with 1, 2 or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3.

[0232] Appropriately, R d It is unsubstituted -C 1-6 Alkyl groups, such as methyl, ethyl, and propyl, especially methyl and ethyl, particularly methyl.

[0233] Appropriately, R d It is unreplaced C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl and cyclopentyl, especially cyclopropyl.

[0234] In one implementation, R c It is hydrogen and R d It is methyl, which is preferably unsubstituted. In the second embodiment, R c and R d All are methyl groups, and preferably unsubstituted. In the third embodiment, R c and R d Both are hydrogen.

[0235] Or, when they exist, each R 13 It can be independently selected from halogens; -C can be optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; or, when m is 0 or 1, r is 2 or 3 and both R are alkyl; 13 When in adjacent ring positions, the two R 13 They connect together to form C along with the atoms they are connected to. 4-6 Cycloalkyl (i.e., cyclobutyl, cyclopentyl, or cyclohexyl) or a 4- to 6-membered non-aromatic heterocyclic group (i.e., 4, 5, or 6-membered non-aromatic heterocyclic group) containing one heteroatom selected from O and N, wherein the C 4-6 The cycloalkyl or 4- to 6-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C is optionally substituted with one, two, or three substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl;

[0236] Or, when r is 1, 2, or 3 and an R 13 Groups in relation to NR 12 When in adjacent ring positions, the R 13 and R 12These atoms are linked together to form a 5- or 6-membered nonaromatic heterocyclic group comprising one N heteroatom and optionally one heteroatom selected from O and N, wherein the 5- or 6-membered nonaromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C atoms are optionally substituted with one, two, or three substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl.

[0237] Appropriately, when they exist, each R 13 Independently selected from halogens; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups. Suitablely, when present, each R 13 -C is optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups. Even more appropriately, each R 13 It is methyl on its own.

[0238] When they exist, each R 14 It can be independently selected from halogens; -C can be optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl.

[0239] In some suitable implementations, each R13 (and / or by two Rs) 13 C formed by group 4-6 Substituents of cycloalkyl or 4- to 6-membered non-aromatic heterocyclic groups, or NR 12 and R 13 Each substituent of the 5- to 6-membered non-aromatic heterocyclic group formed by the group; or each R 14 The -C group is independently selected from halogens; it is optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups. More preferably, each R 13 (and / or by two Rs) 13 C formed by group 4-6 Substituents of cycloalkyl or 4- to 6-membered non-aromatic heterocyclic groups, or NR 12 and R 13 Each substituent of the 5- to 6-membered non-aromatic heterocyclic group formed by the group; or each R 14 Independently selected from halogens; optionally replaced by one halogen and optionally substituted by one, two or three halogens -OC 1-3 Alkyl substituents substituted -C 1-4 Alkyl group; and -OC group optionally substituted with one halogen selected from halogens and optionally substituted with one, two, or three halogens. 1-3 Alkyl substituents -OC 1-4 Alkyl groups (e.g., each substituent is independently -OC, optionally substituted with one halogen and optionally substituted with one, two, or three halogens) 1-3 Alkyl substituents substituted -C 1-4 Alkyl groups). Or even more appropriately, each R 13 (and / or by two Rs) 13 C formed by group 4-6 Substituents of cycloalkyl or 4- to 6-membered non-aromatic heterocyclic groups, or NR 12 and R 13 Each substituent of the 5- to 6-membered non-aromatic heterocyclic group formed by the group; or each R 14 Independently selected from halogens; optionally substituted by one F atom and optionally substituted by one, two or three F atoms -OC 1-3 Alkyl substituents substituted -C 1-4 Alkyl group; and -OC group optionally substituted with one atom selected from F and optionally substituted with one, two or three F atoms. 1-3Alkyl substituents -OC 1-4 Alkyl groups (e.g., each substituent is independently -OC, optionally substituted by one F atom and optionally substituted by one, two, or three F atoms) 1-3 Alkyl substituents substituted -C 1-4 alkyl).

[0240] Or, each R 13 (and / or by two Rs) 13 C formed by group 4-6 Substituents of cycloalkyl or 4- to 6-membered non-aromatic heterocyclic groups, or NR 12 and R 13 Each substituent of the 5- to 6-membered non-aromatic heterocyclic group formed by the group; or each R 14 The -C group is independently selected from halogens; it is optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl groups (e.g., each substituent is independently -C optionally substituted by 1, 2 or 3 substituents) 1-4 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl groups). More preferably, each R 13 (and / or by two Rs) 13 C formed by group 4-6 Substituents of cycloalkyl or 4- to 6-membered non-aromatic heterocyclic groups, or NR 12 and R 13 Each substituent of the 5- to 6-membered non-aromatic heterocyclic group formed by the group; or each R 14 The -C group is independently selected from halogens; it is optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from halogens and optionally methoxy groups substituted with one, two, or three halogens. Even more preferably, each R... 13 (and / or by two Rs) 13 C formed by group 4-6 Substituents of cycloalkyl or 4- to 6-membered non-aromatic heterocyclic groups, or NR 12 and R 13 Each substituent of the 5- to 6-membered non-aromatic heterocyclic group formed by the group; or each R14 The -C group is independently selected from halogens; it is optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from F and methoxy group optionally substituted with 1, 2 or 3 F atoms; and -OC group optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl groups, each substituent being independently selected from F and methoxy groups optionally substituted with 1, 2 or 3 F atoms.

[0241] In a suitable implementation scheme, Z is In this embodiment, the compound of formula (I) is the compound of formula (Id):

[0242]

[0243] In another suitable implementation, Z is (And more appropriately, Z is) )

[0244] in

[0245] Indicates the connection point;

[0246] m is 1 or 2; r is 0, 1 or 2; s is 0, 1 or 2;

[0247] R 12 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl (suitably, R) 12 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl; more preferably, R 12 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl group, each substituent independently selected from halogens and optionally methoxy groups substituted with 1, 2, or 3 halogens; more preferably, R 12 -C selected from hydrogen and optionally substituted with a methoxy group selected from halogens and optionally substituted with 1, 2, or 3 halogens (e.g., 1, 2, or 3 F atoms). 1-4 Alkyl); and

[0248] When they exist, each R 13 Independently selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-6Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; and

[0249] When they exist, each R 14 Independently selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl.

[0250] In a suitable implementation scheme, Z is

[0251] in Indicates the connection point.

[0252] m is 1 or 2; r is 0, 1 or 2.

[0253] When they exist, each R 13 Independently selected from halogens; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl group; -OC group optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; NR c R d and C, which is optionally substituted with 1, 2 or 3 substituents 3-6 Cycloalkyl (i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), each substituent independently selected from halogens, -OH, and -OC optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl.

[0254] Where Z can be -NR 10 R 11 In the implementation plan, R 10 It can be selected from hydrogen and -C 1-4 Alkyl group. Suitablely, R 10It is either hydrogen or methyl.

[0255] Where Z can be -NR 10 R 11 In the implementation plan, R 11 It can be a 5- to 10-membered non-aromatic heterocyclic group (i.e., a 5, 6, 7, 8, 9, or 10-membered non-aromatic heterocyclic group) containing 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and said 5- to 10-membered non-aromatic heterocyclic group is optionally substituted by 1, 2, 3, or 4 substituents (e.g., 1, 2, or 3 substituents; or 1 or 2 substituents; or 1 substituent). Suitably, R 11 It is a 5- or 6-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, or 3 substituents. More preferably, R 11 It is a 5- or 6-membered non-aromatic heterocyclic group containing 1, 2, or 3 heteroatoms selected from N and O, wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted by 1, 2, or 3 substituents.

[0256] Or, R 11 It is a 5- or 6-membered non-aromatic heterocyclic group comprising one or two heteroatoms selected from N, O, and S (e.g., one heteroatom), wherein at least one heteroatom is N, and wherein said 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with one, two, or three substituents. Suitably, R 11 It is a 5- or 6-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and O (e.g., 1 heteroatom), wherein at least one heteroatom is N, and wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with 1, 2 or 3 substituents.

[0257] In a suitable implementation scheme, R 11 It is a 5-membered non-aromatic heterocyclic group containing 1 or 2 N heteroatoms, wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted by 1, 2 or 3 substituents.

[0258] In a suitable implementation scheme, R 11 It is a 6-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and O, wherein at least one heteroatom is N, and wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted by 1, 2 or 3 substituents.

[0259] In some suitable implementations, R 11It is a 5- or 6-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- or 6-membered non-aromatic heterocyclic group is optionally substituted by 1 or 2 (e.g., 1) substituents. More preferably, R 11 It is a 5- or 6-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N and O, and wherein said 5- or 6-membered non-aromatic heterocyclic group is optionally substituted by 1 or 2 (e.g., 1) substituents. Alternatively, R 11 It is a 5- or 6-membered non-aromatic heterocyclic group comprising one or two heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- or 6-membered non-aromatic heterocyclic group is optionally substituted by one or two (e.g., one) substituents. Even more preferably, R 11 It is a 5- or 6-membered non-aromatic heterocyclic group containing one or two heteroatoms selected from N and O, wherein at least one heteroatom is N, and wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted by one or two (e.g., one) substituents.

[0260] In a suitable implementation scheme, R 11 It is a 5-membered non-aromatic heterocyclic group containing 1 or 2 N heteroatoms, wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted by 1 or 2 (e.g. 1) substituents.

[0261] In a suitable implementation scheme, R 11 It is a 6-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and O, wherein at least one heteroatom is N, and wherein the 5 or 6-membered non-aromatic heterocyclic group is optionally substituted by 1 or 2 (e.g. 1) substituents.

[0262] In which R 11 In optional substituted embodiments (e.g., optionally substituted with 1, 2, 3, or 4 substituents; or optionally substituted with 1, 2, or 3 substituents; or optionally substituted with 1 or 2 substituents; or optionally substituted with 1 substituent), each substituent may be independently selected from halogens; -OH; -C optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl group. Suitably, each substituent is independently selected from halogens; -OH; -C optionally substituted with 1, 2 or 3 substituents. 1-4Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl group. More preferably, each substituent is independently selected from halogens; -OH; optionally substituted with one halogen, -OH, and optionally substituted with one, two, or three halogens; -OC. 1-3 Alkyl substituents substituted -C 1-4 Alkyl group; and -OC group optionally substituted with one halogen selected from halogens, -OH, and optionally substituted with one, two, or three halogens. 1-3 Alkyl substituents -OC 1-4 Alkyl group. More preferably, each substituent is independently selected from halogens; optionally substituted with one halogen and optionally substituted with one, two or three halogens -OC. 1-3 Alkyl substituents substituted -C 1-4 Alkyl group; and -OC group optionally substituted with one halogen selected from halogens and optionally substituted with one, two, or three halogens. 1-3 Alkyl substituents -OC 1-4 Alkyl groups (e.g., each substituent is independently -OC, optionally substituted with one halogen and optionally substituted with one, two, or three halogens) 1-3 Alkyl substituents substituted -C 1-4 alkyl).

[0263] In a suitable embodiment, each substituent is independently selected from halogens; optionally substituted by one F atom and optionally substituted by one, two, or three F atoms, -OC 1-3 Alkyl substituents substituted -C 1-4 Alkyl group; and -OC group optionally substituted with one atom selected from F and optionally substituted with one, two or three F atoms. 1-3 Alkyl substituents -OC 1-4 Alkyl groups (e.g., each substituent is independently -OC, optionally substituted by one F atom and optionally substituted by one, two, or three F atoms) 1-3 Alkyl substituents substituted -C 1-4 alkyl).

[0264] Alternatively, each substituent may be independently selected from halogens; -C may be optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl groups (e.g., each substituent is independently -C optionally substituted by 1, 2 or 3 substituents) 1-4 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl group). More preferably, each substituent is independently selected from halogens; -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens and methoxy groups optionally substituted with 1, 2, or 3 halogens. Even more preferably, each substituent independently selected from halogens; -C optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from F and methoxy group optionally substituted with 1, 2 or 3 F atoms; and -OC group optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl groups, each substituent being independently selected from F and methoxy groups optionally substituted with 1, 2 or 3 F atoms.

[0265] In one implementation, Z is selected from:

[0266]

[0267]

[0268] in Indicates the connection point.

[0269] For example, Z is selected from:

[0270] in Indicates the connection point.

[0271] Alternatively, Z can be selected from:

[0272]

[0273]

[0274] in Indicates the connection point.

[0275] For example, Z is selected from:

[0276] in Indicates the connection point.

[0277] In a suitable implementation scheme, Z is selected from:

[0278]

[0279]

[0280] in Indicates the connection point. For example, Z is selected from:

[0281]

[0282] in Indicates the connection point. In a suitable implementation, Z is selected from:

[0283]

[0284] in Indicates the connection point.

[0285] In a particularly suitable implementation, Z is selected from:

[0286] in Indicates the connection point.

[0287] In a particularly suitable implementation, Z is:

[0288] in Indicates the connection point.

[0289] In a particularly suitable implementation, Z is:

[0290] in Indicates the connection point.

[0291] In a particularly suitable embodiment, the compound of formula (I) is a compound of formula (Ie), wherein the groups may be as defined above:

[0292]

[0293] In another particularly suitable embodiment, the compound of formula (I) is a compound of formula (If), wherein the groups may be as defined above:

[0294]

[0295] In another particularly suitable embodiment, the compound of formula (I) is a compound of formula (Ig), wherein the groups may be as defined above:

[0296]

[0297] In another particularly suitable embodiment, the compound of formula (I) is a compound of formula (Ih), wherein the groups may be as defined above:

[0298]

[0299] In another particularly suitable embodiment, the compound of formula (I) is a compound of formula (Ij), wherein the groups may be as defined above:

[0300]

[0301] In another particularly suitable embodiment, the compound of formula (I) is a compound of formula (Ik), wherein the groups may be as defined above:

[0302]

[0303] In a particularly suitable embodiment, the compound of formula (I) is a compound of formula (Im), wherein the groups may be as defined above:

[0304]

[0305] In a particularly suitable embodiment, the compound of formula (I) is a compound of formula (In), wherein the groups may be as defined above:

[0306]

[0307] In another particularly suitable embodiment, the compound of formula (I) is a compound of formula (Io), wherein the groups may be as defined above:

[0308]

[0309] In a particularly suitable embodiment, the compound of formula (I) is a compound of formula (Ip), wherein the groups may be as defined above:

[0310]

[0311] In a particularly suitable embodiment, the compound of formula (I) is the compound of formula (Iq):

[0312]

[0313] in:

[0314] R 3a It is H or C that is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OCH3 and -OCF3;

[0315] R 8a It is a halogen or a C that is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OCH3 and -OCF3;

[0316] ra is 0, 1, or 2;

[0317] m a It is 1 or 2;

[0318] R 12a It is H or C that is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and

[0319] When they exist, each R 13a Independently selected from C14 cells that are optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and C4 groups optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, each substituent independently selected from halogen, -CH3, -OCH3, and -OCF3; or when ra is 2 and both R are 2. 13a When the groups are in adjacent ring positions, the two R groups... 13a They are linked together to form C atoms, which are optionally substituted with one or two substituents, together with the atoms to which they are linked. 3-6 Cycloalkyl, each substituent independently selected from halogens; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl.

[0320] In one implementation, R 3a It is H. In the second implementation scheme, R 3a It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, are suitably unsubstituted, such as methyl, which is suitably unsubstituted.

[0321] In one implementation, R 8a It is a halogen, such as Cl, Br, or F, especially Cl. In the second embodiment, R 8a C is a C that is optionally substituted with 1, 2 or 3 substituents. 1-4Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; R 8a Especially CF3.

[0322] In one implementation, ra is 0. In a second implementation, ra is 1. In a third implementation, ra is 2.

[0323] In one implementation, m a It is 1. In the second implementation scheme, m a It is 2.

[0324] In one implementation, R 12a It is H. In the second implementation scheme, R 12a It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, are suitably unsubstituted, especially methyl or ethyl, which are suitably unsubstituted, especially methyl.

[0325] In one implementation scheme, each R 13a C is independent 1-4 Alkyl groups, such as methyl, ethyl, or propyl, are suitably unsubstituted, especially methyl or ethyl, and particularly methyl, which is suitably unsubstituted. In the second embodiment, each R 13a C is independent 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, or cyclopentyl, are suitably unsubstituted, especially cyclopropyl, which is suitably unsubstituted.

[0326] In one implementation, ra is 2 and two R 13a The two R groups are located at adjacent ring positions. 13a They connect together to form C along with the atoms they are connected to. 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, or cyclopentyl, are preferably unsubstituted, especially cyclopropyl.

[0327] In some suitable embodiments, the compound is selected from compounds 1 to 112 of the examples.

[0328] In a particularly suitable embodiment, the compound of formula (I) is selected from:

[0329] 1-{5-chloro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0330] 1-{5-chloro-2-[(2S)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0331] 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0332] 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyridin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0333] 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0334] 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0335] 1-(5-chloro-2-{3,6-diazabicyclo[3.2.0]hept-3-yl}pyrimidin-4-yl)-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0336] 1-(2-{3,6-diazabicyclo[3.2.0]hept-3-yl}-5-fluoropyrimidin-4-yl)-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0337] 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide;

[0338] 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide;

[0339] 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)zacyclobutane-3-carboxamide;

[0340] 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide;

[0341] 1-(2-{3,6-diazabicyclo[3.2.0]hept-3-yl}-5-fluoropyrimidin-4-yl)-N-({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide;

[0342] 1-{5-fluoro-2-[methyl(pyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0343] 1-[5-fluoro-2-(pyrrolidone-3-ylamino)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0344] 1-[5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0345] 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}-N-methylazacyclobutane-3-carboxamide;

[0346] 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide;

[0347] 1-[2-(1,4-diazacycloheptane-1-yl)-5-methoxypyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0348] 1-[2-(1,4-diazacycloheptane-1-yl)-5-methoxypyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)zacyclobutane-3-carboxamide;

[0349] 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-({6-fluoroimidozop[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide;

[0350] 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-({6-chloroimidazolo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide;

[0351] 1-[2-(1,4-diazacycloheptane-1-yl)-5-methoxypyrimidin-4-yl]-N-(1-{2-methylimidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide;

[0352] 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(1-{2-methylimidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide;

[0353] 1-[5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0354] 1-{5-fluoro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0355] 1-{5-chloro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0356] 1-{5-fluoro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0357] 1-{5-chloro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0358] 1-[5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide;

[0359] 1-[5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide;

[0360] 1-[5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0361] 1-[5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0362] N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methoxy-2-(piperazin-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide;

[0363] 1-{5-fluoro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0364] N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide;

[0365] 1-{5-chloro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0366] 1-{5-fluoro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0367] N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide;

[0368] 1-{5-fluoro-2-[methyl(pyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0369] 1-{5-chloro-2-[methyl(pyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0370] 1-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-methoxypyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0371] 1-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-chloropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0372] 1-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide

[0373] 1-{2-[(3S,5S)-3,5-dimethylpiperazin-1-yl]-5-methoxypyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0374] 1-{5-chloro-2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0375] 1-{2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0376] 1-{5-chloro-2-[(3S,5S)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0377] 1-{5-fluoro-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0378] 1-{5-chloro-2-[(2S)-2-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0379] 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide

[0380] 1-[5-fluoro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0381] 1-[5-chloro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide;

[0382] 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0383] 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0384] 1-[5-fluoro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0385] 1-[5-chloro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0386] 1-{5-fluoro-2-[methyl(1-methylpyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0387] 1-{5-chloro-2-[methyl(1-methylpyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0388] 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0389] 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{8-fluoroimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0390] N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methoxy-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide;

[0391] N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methoxy-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide;

[0392] 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide;

[0393] 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-3-methylazacyclobutane-3-carboxamide;

[0394] N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide;

[0395] 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0396] 1-{5-chloro-2-[(2R)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0397] 1-{5-chloro-2-[3-(fluoromethyl)-4-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0398] 1-[5-chloro-2-(4-ethylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0399] 1-{5-chloro-2-[4-(propyl-2-yl)piperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)azacyclobutane-3-carboxamide;

[0400] 1-{5-chloro-2-[4-(2-methoxyethyl)piperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0401] 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0402] 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0403] (3R)-1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide;

[0404] (3S)-1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide;

[0405] 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)piperidin-4-carboxamide;

[0406] 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0407] 1-{5-chloro-2-[(2S,3R)-2,3-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0408] 1-{5-chloro-2-[3-(methoxymethyl)-4-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0409] 1-(5-fluoro-2-{6-methyl-3,6-diazabicyclo[3.2.0]hept-3-yl}pyrimidin-4-yl)-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0410] 1-{2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0411] 1-{5-chloro-2-[(3S)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0412] 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0413] 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-methoxypyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0414] 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide;

[0415] 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-3-methylazacyclobutane-3-carboxamide;

[0416] N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide;

[0417] 1-{5-chloro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0418] 1-{5-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0419] N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide;

[0420] 1-{5-chloro-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0421] 1-{5-fluoro-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0422] N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide;

[0423] 1-{5-chloro-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0424] 1-{5-fluoro-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0425] 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0426] 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0427] (3R)-1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide;

[0428] (3S)-1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide;

[0429] 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)piperidin-4-carboxamide;

[0430] 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0431] 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyridin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0432] 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyridin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0433] 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyridin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0434] 1-{5-chloro-2-[(2S)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}-N-methylazacyclobutane-3-carboxamide;

[0435] 1-{5-chloro-2-[(2S)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0436] 1-{2-[(2S)-2,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0437] 1-{5-chloro-2-[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0438] 1-{5-chloro-2-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide;

[0439] 1-{5-fluoro-2-[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; and

[0440] 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide;

[0441] And any of their pharmaceutically acceptable esters, amides, carbamates and salts, including salts of these esters, amides and carbamates.

[0442] In a particularly suitable embodiment, the compound of formula (I) is selected from:

[0443] N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)quinazolin-4-yl)azacyclobutane-3-carboxamide;

[0444] N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)thienozo[2,3-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide;

[0445] N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidin-4-yl)azacyclobutane-3-carboxamide;

[0446] 1-(5-chloro-6-methyl-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0447] N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(6-methyl-2-(4-methyl-1,4-diazacycloheptane-1-yl)thienozo[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide;

[0448] N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(6-methyl-2-(4-methyl-1,4-diazacycloheptane-1-yl)thienozo[2,3-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide;

[0449] 1-(2-(1,4-diazacycloheptane-1-yl)thieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0450] 1-(5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0451] 1-(5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0452] 1-(5-chloro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0453] N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methyl-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)thieno[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide;

[0454] (R)-1-(5-chloro-2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0455] (S)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methyl-1-(2-(2-methylpiperazin-1-yl)thieno[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide;

[0456] (S)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(2-methylpiperazin-1-yl)thieno[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide;

[0457] 1-(5-chloro-2-(3,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0458] 1-(2-(4-aminopiperidin-1-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0459] 1-(5-chloro-2-(4,7-diazaspiro[2.5]oct-7-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0460] 1-(2-(4-aminoazacycloheptan-1-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0461] 1-(2-(2,5-diazabicyclo[2.2.1]hept-2-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0462] 1-(2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0463] 1-(5-chloro-2-(2,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0464] (S)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methyl-1-(2-(2-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidin-4-yl)azacyclobutane-3-carboxamide;

[0465] 1-(5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl)-N-ethyl-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0466] 1-(5-chloro-2-(3-ethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0467] (R)-1-(5-chloro-2-(2-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0468] (R)-1-(5-chloro-2-(2,4-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0469] (S)-1-(5-chloro-2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0470] (S)-1-(5-chloro-2-(3,4-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0471] (R)-1-(5-chloro-2-(2-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0472] 1-(5-chloro-2-(2,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0473] (S)-1-(5-chloro-2-(2-methylpiperazin-1-yl)pyrimidin-4-yl)-N-ethyl-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0474] 1-(2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0475] 1-(2-(2,5-diazabicyclo[4.1.0]hept-2-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0476] (S)-1-(5-chloro-2-(2-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0477] (S)-1-(5-chloro-2-(2-ethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0478] (S)-1-(5-chloro-2-(2-ethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0479] 1-(5-chloro-2-(2,2-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0480] 1-(5-chloro-2-(4,7-diazaspiro[2.5]oct-4-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide;

[0481] 1-(5-chloro-2-((2S,5S)-2,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0482] 1-(5-chloro-2-((2S,5S)-2,4,5-trimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0483] 1-(5-chloro-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; and

[0484] 1-(5-chloro-2-((2S,5R)-2,4,5-trimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide;

[0485] And any of their pharmaceutically acceptable esters, amides, carbamates and salts, including salts of these esters, amides and carbamates.

[0486] According to the invention, the compounds may form esters, amides, carbamates, or salts, including salts of esters, amides, and carbamates, based on the substituents present in the compounds. Suitably, if the compound is in the form of an ester, amide, carbamate, and / or salt, it is a pharmaceutically acceptable ester, amide, carbamate, and / or salt.

[0487] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. Salts of the compounds of the present invention suitable for pharmaceutical use are those in which the counterions are pharmaceutically acceptable. However, salts having non-pharmaceutically acceptable counterions are also within the scope of the present invention, for example, as intermediates in the preparation of the compounds of the present invention and their pharmaceutically acceptable salts. In one embodiment, the compounds of the present invention are not in the form of pharmaceutically acceptable salts.

[0488] Suitable salts of the present invention include salts formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the present invention include salts formed with inorganic acids, strong organic carboxylic acids, such as unsubstituted or halogenated alkyl carboxylic acids of 1-4 carbon atoms, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as unsubstituted or halogenated (C1-C4) alkyl or aryl sulfonic acids. Pharmaceutically acceptable acid addition salts include salts formed from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxyethanesulfonic acid, ascorbic acid, malic acid, phthalic acid, aspartic acid and glutamic acid, lysine and arginine. Other acids, whether or not pharmaceutically acceptable, may be used as intermediates to obtain the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0489] Pharmaceutically acceptable base salts include ammonium salts; alkali metal salts, such as potassium and sodium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts formed with organic bases, such as dicyclohexylamine, N-methyl-D-glucosamine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-alkylamines, such as ethylamine, tert-butylamine, diethylamine, diisopropylamine, triethylamine, tributylamine, or dimethylpropylamine, or mono-, di-, or tri-hydroxyalkylamines, such as mono-, di-, or tri-ethanolamine. Furthermore, corresponding internal salts can be formed.

[0490] The compounds of the present invention can have suitable groups that can be converted into esters, amides, or carbamates. Therefore, typical ester and amide groups formed from the acid groups in the compounds of the present invention include COOR. G -CONR G 2. -SO2OR G or -SO2N(R) G )2, derived from the OH or -NHR in the compounds of this invention G - Typical ester, amide, and carbamate groups formed include -OC(O)R G -NR G C(O)R G -NR G CO2R G -OSO2R G and -NR G SO2R G , where R G Selected from C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C3-8 cycloalkyl and C 3-8 cycloalkyl C 1-8 Alkyl, Halogenated C 1-8 Alkyl, dihalogenated C 1-8 Alkyl, trihalogenated C 1-8 Alkyl, phenyl and phenyl C 1-4 Alkyl; more preferably, R G Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl and C 3-8 cycloalkyl C 1-6 alkyl.

[0491] Those skilled in the art of organic chemistry will understand that many organic compounds can form complexes with solvents in which they react, precipitate, or crystallize. These complexes are called “solvents.” For example, a complex with water is called a “hydrate.” Solvents such as hydrates are present when a drug substance is incorporated into its crystal lattice in stoichiometric or nonstoichiometric amounts with a solvent such as water. The presence of hydrates in drug substances is routinely screened, as hydrates can be encountered at any stage of the drug manufacturing process or during the storage of the drug substance or dosage form. S. Byrn et al., Pharmaceutical Research, 1995, 12(7): 954-954 and Water-Insoluble Drug Formulation, 2nd ed., R. Liu, CRC Press, p. 553 describe solvates, which are incorporated herein by reference. Therefore, those skilled in the art will understand that the compounds of the present invention can therefore exist in the form of solvates. Solvents of the compounds of the present invention suitable for pharmaceutical use are those in which the associated solvent is pharmaceutically acceptable. For example, hydrates are an example of pharmaceutically acceptable solvates. However, solvates having non-pharmaceutically acceptable associating solvents can be used as intermediates in the preparation of the compounds of the present invention. In one embodiment, the compounds of the present invention are not in the form of solvates.

[0492] Suitable pharmaceutically acceptable derivatives of the compounds of this invention are salts.

[0493] Uses of the compounds of this invention

[0494] As mentioned above, inhibiting human NMT has been suggested as a target for the treatment or prevention of various diseases or conditions.

[0495] Since the compounds of the present invention are NMT inhibitors, they can be used to treat diseases or conditions associated with NMT activity, or can be used to treat diseases or conditions by targeting NMT activity (e.g., in hyperproliferative diseases such as cancer and viral infections such as microRNA infections). Therefore, the present invention provides compounds of the present invention for use as medicaments, or pharmaceutical compositions comprising compounds of the present invention and pharmaceutically acceptable carriers. The present invention also provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention and pharmaceutically acceptable carriers for treating or preventing diseases or conditions in which inhibition of N-myristoyltransferase provides a therapeutic or preventive effect. Compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention and pharmaceutically acceptable carriers are also provided for treating diseases or conditions in which inhibition of N-myristoyltransferase provides a therapeutic effect. Compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention and pharmaceutically acceptable carriers are also provided for preventing diseases or conditions in which inhibition of N-myristoyltransferase provides a preventive effect.

[0496] The present invention also provides methods for treating or preventing diseases or conditions in an individual, wherein inhibition of N-myristoyltransferase provides a therapeutic or preventive effect in the individual (e.g., a mammal, such as a human), said methods comprising administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The present invention also provides methods for treating diseases or conditions in an individual, wherein inhibition of N-myristoyltransferase provides a therapeutic effect in the individual (e.g., a mammal, such as a human), said methods comprising administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The present invention also provides methods for preventing diseases or conditions in an individual, wherein inhibition of N-myristoyltransferase provides a preventive effect in the individual (e.g., a mammal, such as a human), said methods comprising administering to the individual a preventively effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.

[0497] The present invention also provides the use of the compounds of the present invention in the preparation of a medicament for treating or preventing diseases or conditions in which inhibition of N-myristoyltransferase is provided for therapeutic or preventive effects. The present invention also provides the use of the compounds of the present invention in the preparation of a medicament for treating diseases or conditions in which inhibition of N-myristoyltransferase is provided for therapeutic effects. The present invention also provides the use of the compounds of the present invention in the preparation of a medicament for preventing diseases or conditions in which inhibition of N-myristoyltransferase is provided for preventive effects.

[0498] Diseases and conditions for which inhibition of N-myristoyltransferase provides therapeutic or preventative effects include: proliferative disorders, viral infections, neurological disorders, ischemic attacks, osteoporosis, diabetes, autoimmune diseases, and inflammatory diseases. Therefore, the compounds of this invention can be used to treat or prevent these conditions / diseases.

[0499] Diseases or conditions for which inhibition of N-myristyltransferase provides therapeutic or preventative effects also include microbial infections; such as fungal infections and protozoan infections, such as malaria, leishmaniasis, human African trypanosomiasis (sleeping sickness), and American trypanosomiasis (chagas disease).

[0500] The compounds of the present invention are also expected to have specific utility in targeting diseases in specific patient populations, namely, diseases that are expected to be particularly affected by inhibition of N-myristoyltransferases, such as human N-myristoyltransferase. Such diseases include hyperproliferative disorders, particularly cancers, such as hematologic malignancies (e.g., lymphomas, especially B-cell lymphomas (e.g., high-grade mantle lymphoma, follicular lymphoma, plasmablastic lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma), myeloma (e.g., multiple myeloma) or leukemias (e.g., chronic lymphocytic leukemia, AML, and acute B-cell lymphocytic leukemia)) or solid tumors (e.g., brain, lung, breast (e.g., triple-negative breast cancer or invasive breast cancer), prostate, ovary, colorectal (e.g., colon), gallbladder, kidney, or liver cancer or neuroblastoma).

[0501] Compounds that are particularly good inhibitors of human NMT may be suitably used to treat and / or prevent hyperproliferative diseases (such as cancer) and viral infections (such as human immunodeficiency virus (HIV), human rhinovirus (RV, formally abbreviated as HRV)), as well as other conditions for which inhibition of human NMT has been suggested as a treatment.

[0502] In a suitable embodiment, the compounds of the present invention are used to treat diseases or conditions selected from hyperproliferative disorders and viral infections.

[0503] Hyperproliferative disorders

[0504] In a particularly suitable embodiment, the compounds of the present invention are used for the prevention or treatment of hyperproliferative diseases, wherein the hyperproliferative disease is cancer. In a particularly suitable embodiment, the compounds of the present invention are used for the prevention of hyperproliferative diseases, wherein the hyperproliferative disease is cancer. In a particularly suitable embodiment, the compounds of the present invention are used for the treatment of hyperproliferative diseases, wherein the hyperproliferative disease is cancer. Cancer may be selected from colorectal cancer, gallbladder cancer, brain tumors, lymphomas (e.g., B-cell lymphomas (e.g., diffuse large B-cell lymphoma)), leukemias (e.g., acute myeloid leukemia (AML)), and neuroblastomas.

[0505] The cancer may additionally or alternatively be a solid tumor selected from 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, the cancer may be ovarian serous cystadenocarcinoma, esophageal cancer, squamous cell carcinoma of the lung, lung adenocarcinoma, bladder urethral epithelial carcinoma, uterine carcinosarcoma, gastric adenocarcinoma, invasive breast cancer, or hepatocellular carcinoma. In some embodiments, the cancer is breast cancer, such as triple-negative breast cancer or invasive breast cancer. In some embodiments, the cancer is brain cancer, breast cancer, prostate cancer, colon cancer, gallbladder cancer, or kidney cancer. In some embodiments, the cancer is breast cancer, colon cancer, or gallbladder cancer.

[0506] Cancer may also be, alternatively, a hematologic malignancy selected from lymphomas (e.g., B-cell lymphomas, particularly those selected from high-grade mantle lymphoma, follicular lymphoma, plasmablastic lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma), myelomas (e.g., multiple myeloma), and leukemias (e.g., leukemias selected from chronic lymphocytic leukemia, AML, and acute B-cell lymphocytic leukemia).

[0507] Alternatively or concurrently, the cancer may also be a neuronal cancer (i.e., a cancer of the nervous system), specifically, a cancer selected from neuroblastoma, retinoblastoma, glioblastoma, small cell lung cancer, and astrocytoma. In one specific embodiment, the cancer is a blastoma, particularly a neuroblastoma, retinoblastoma, or glioblastoma. In some embodiments, the cancer is a neuroblastoma.

[0508] In one embodiment, the cancer may be selected from diffuse large B-cell lymphoma, Burkitt lymphoma, multiple myeloma, neuroblastoma, AML, and acute B-lymphoblastic leukemia. In another embodiment, the cancer may be selected from diffuse large B-cell lymphoma, Burkitt lymphoma, neuroblastoma, AML, acute B-lymphoblastic leukemia, and breast cancer. In another embodiment, the cancer may be selected from diffuse large B-cell lymphoma, neuroblastoma, acute B-lymphoblastic leukemia, and triple-negative breast cancer. In yet another embodiment, the cancer may be selected from colorectal cancer, gallbladder cancer, brain tumors, lymphomas (e.g., diffuse large B-cell lymphoma), leukemias (e.g., acute myeloid leukemia), and blastomas (e.g., neuroblastoma, retinoblastoma, or glioblastoma, and suitably neuroblastoma). In another embodiment, the cancer may be selected from diffuse large B-cell lymphoma, Burkitt lymphoma, multiple myeloma, neuroblastoma, AML, acute B-lymphoblastic leukemia, and triple-negative breast cancer. In another embodiment, the cancer may be selected from multiple myeloma, neuroblastoma, AML, acute B-lymphoblastic leukemia, and triple-negative breast cancer. In another embodiment, the cancer may be selected from multiple myeloma, neuroblastoma, and triple-negative breast cancer.

[0509] Oncogenes c-MYC and MYCN are common diagnostic markers for particularly aggressive malignancies, and recent studies have shown that overexpression and / or mutation of c-MYC and MYCN are strongly associated with some of the worst clinical outcomes (Jung et al., Tumor and Stem Cell Biology, 2016, 65(16), 7065-7070; Habermann et al., Blood, 2016, 128(22), 155; Xu et al., Genes Cancer, 2010, 1(6), 629-640). Therefore, there remains a need for improved therapies that can target cancers with one or more structural alterations in the MYC oncogene.

[0510] The compounds of the present invention are also particularly suitable for treating the following cancers: i) addiction to the MYC oncogene; and / or ii) having one or more structural alterations in the MYC oncogene locus.

[0511] Therefore, the compounds of the present invention can be used to treat cancers of MYC addiction. Suitably, the compounds can be used to prevent cancers of MYC addiction. Suitably, the compounds of the present invention can be used to prevent or treat cancers of MYC addiction. Suitably, cancers of MYC addiction are cancers of addiction to c-MYC and / or MYCN. In some embodiments, cancers of MYC addiction are cancers of addiction to c-MYC, and suitably, cancers of MYC addiction are cancers of addiction to c-MYC transcription. In other embodiments, cancers of MYC addiction are cancers of addiction to MYCN, and suitably, cancers of MYC addiction are cancers of addiction to MYCN transcription.

[0512] In one specific embodiment, the present invention provides compounds of the present invention for the prevention or treatment, for example, of cancers involving c-MYC or MYCN addiction, wherein the c-MYC or MYCN oncogene is overexpressed. Suitably, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, solvates, or hydrates thereof for the prevention or treatment, for example, of cancers involving c-MYC or MYCN addiction, wherein the c-MYC or MYCN oncogene is overexpressed such that the levels of c-MYC or MYCN RNA transcripts and / or proteins are at least 25% higher than the levels of c-MYC or MYCN RNA transcripts and / or proteins found in normal, healthy cells.

[0513] More preferably, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, solvates or hydrates thereof for the prevention or treatment, for example, of cancers of c-MYC or MYCN addiction, wherein c-MYC or MYCN is overexpressed such that the levels of c-MYC or N-MYC RNA transcripts and / or proteins are at least 50% higher than the levels of c-MYC or N-MYC RNA transcripts and / or proteins found in normal, healthy cells.

[0514] The present invention also provides compounds of the present invention for the prevention or treatment, for example, of cancers with MYC dysregulation. Cancers with MYC dysregulation may include, for example, cancers containing mutations and / or structural alterations to the MYC oncogene, said mutations and / or structural alterations conferring, for example, overexpression or stabilization of protein and / or mRNA levels of MYC. A non-restrictive list of possible mutations includes: i) point mutations in the MYC coding region (Bahram et al., Blood, 2000, 95, 2104-2110); ii) mutations in the distal enhancer (Sur et al., Science, 2012, 338, 1360-1363 and Zhang et al., Nat. Genet., 2016, 48-176-182); and iii) mutations in the activation signal transduction pathway that increase MYC expression (Herranz et al., Nat. Med., 2014, 20, 1130-1137, Muncan et al., Mol. Cell Biol., 2006, 26, 8418-8426 and Weng et al., Genes Dev., 2006, 20, 2096-2109).

[0515] In one embodiment, MYC-dysregulated cancer is MYC oncogene overexpression cancer. Suitably, MYC-dysregulated cancer is c-MYC or MYCN oncogene overexpression cancer. More preferably, said MYC oncogene dysregulated cancer is c-MYC or MYCN oncogene overexpression cancer, wherein c-MYC or MYCN is overexpressed such that the level of c-MYC or MYCN RNA transcripts and / or proteins is at least 25% higher than the level of c-MYC or MYCN RNA transcripts and / or proteins found in normal, healthy cells. Most preferably, said MYC-dysregulated cancer is c-MYC or MYCN oncogene overexpression cancer, wherein said c-MYC or MYCN is overexpressed such that the level of c-MYC or MYCN RNA transcripts and / or proteins is at least 50% higher than the level of c-MYC or MYCN RNA transcripts and / or proteins found in normal, healthy cells.

[0516] The present invention also provides compounds of the present invention for the prevention or treatment, such as the treatment of cancer, wherein said cancer comprises one or more structural alterations to the MYC locus. Non-limiting examples of “structural alteration” include, for example, mutations, copy number increases, and / or chromosomal rearrangements. In one embodiment, compounds of the present invention are provided for the prevention or treatment, such as the treatment of cancer, wherein said cancer comprises one or more mutations to the MYC locus. Suitably, the present invention provides compounds of the present invention for the prevention or treatment, such as the treatment of cancer, wherein said cancer comprises one or more mutations to the MYC locus conferring overexpression of MYC. More suitably, the present invention provides compounds of the present invention for the prevention or treatment, such as the treatment of cancer, wherein said cancer comprises one or more mutations to the MYC locus conferring overexpression of c-MYC or MYCN. In one specific embodiment, the present invention provides compounds of the present invention for the prevention or treatment, such as the treatment of cancer, wherein said cancer comprises one or more mutations to c-MYC. In another specific embodiment, the present invention provides compounds of the present invention for the prevention or treatment, such as the treatment of cancer, wherein said cancer comprises one or more mutations to MYCN.

[0517] In one specific embodiment, the present invention provides compounds for the prevention or treatment, such as the treatment of cancer, wherein the cancer comprises one or more mutations at the MYC locus that confer MYC stabilization.

[0518] In one specific implementation, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations of the MYC locus is selected from hematologic malignancies or solid tumors.

[0519] In another embodiment, the MYC-addictive cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is a hematologic malignancy. Suitably, the MYC-addictive cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is a hematologic malignancy selected from lymphoma, myeloma, or leukemia.

[0520] In another embodiment, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is lymphoma. Suitably, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is a lymphoma selected from high-grade mantle lymphoma, follicular lymphoma, plasmablastic lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma. More suitably, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is a lymphoma selected from diffuse large B-cell lymphoma or Burkitt lymphoma. Most suitably, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is diffuse large B-cell lymphoma.

[0521] In another embodiment, the MYC-addictive cancer, the MYC-dysregulated cancer, or the cancer containing one or more structural alterations to the MYC locus is myeloma. Suitably, the MYC-addictive cancer, the MYC-dysregulated cancer, or the cancer containing one or more structural alterations to the MYC locus is multiple myeloma.

[0522] In another embodiment, the MYC-addictive cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is leukemia. Suitably, the MYC-addictive cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is a leukemia selected from chronic lymphocytic leukemia, acute myeloid leukemia, and acute B-lymphocytic leukemia. Most suitably, the MYC-addictive cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is acute B-lymphocytic leukemia.

[0523] In another embodiment, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is a blastoma. Suitably, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is a blastoma selected from neuroblastoma, retinoblastoma, and glioblastoma. More suitably, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is a blastoma selected from retinoblastoma and glioblastoma. In a specific embodiment, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is a neuroblastoma.

[0524] In another embodiment, the MYC-addictive cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is a neuronal-originating cancer (i.e., a nervous system cancer). In one specific embodiment, the MYC-addictive cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is selected from neuroblastoma, retinoblastoma, glioblastoma, small cell lung cancer, and astrocytoma.

[0525] In another embodiment, the MYC-addictive cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is a solid tumor. In some embodiments, the solid tumor is carcinoma. Suitably, the MYC-addictive cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is a solid tumor selected from organs such as the brain, lung, breast, prostate, ovary, colon, gallbladder, kidney, and liver. More suitably, the MYC-addictive cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is a solid tumor selected from organs such as the brain, breast, prostate, colon, gallbladder, and kidney. Still more suitably, the MYC-addictive cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is a solid tumor selected from organs such as the breast, colon, and gallbladder.

[0526] In some embodiments, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations of the MYC locus is a solid tumor selected from ovarian serous cystadenocarcinoma, esophageal cancer, lung squamous cell carcinoma, lung adenocarcinoma, bladder urethral epithelial carcinoma, uterine carcinosarcoma, gastric adenocarcinoma, invasive breast cancer, and hepatocellular carcinoma.

[0527] In some embodiments, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is breast cancer. Suitably, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is triple-negative breast cancer or invasive breast cancer. In a specific embodiment, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is basal-like breast cancer.

[0528] In other embodiments, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations of the MYC locus is gallbladder cancer.

[0529] In other embodiments, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations of the MYC locus is colorectal cancer.

[0530] In other embodiments, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations of the MYC locus is a brain cancer (e.g., astrocytoma).

[0531] In some embodiments, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is selected from diffuse large B-cell lymphoma, Burkitt lymphoma, multiple myeloma, blastoma (e.g., neuroblastoma, retinoblastoma, or glioblastoma), acute myeloid leukemia, acute B-lymphocytic leukemia, and solid tumors selected from organs such as the breast, colon, and gallbladder. Suitably, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations at the MYC locus is selected from diffuse large B-cell lymphoma, Burkitt lymphoma, neuroblastoma, retinoblastoma, glioblastoma, acute myeloid leukemia, acute B-lymphocytic leukemia, and breast cancer. More appropriately, the cancers of MYC addiction, MYC dysregulation, or cancers containing one or more structural alterations of the MYC locus are selected from diffuse large B-cell lymphoma, neuroblastoma, acute B-lymphoblastic leukemia, and triple-negative breast cancer.

[0532] In one specific implementation, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations of the MYC locus is colorectal cancer, gallbladder cancer, brain tumor, lymphoma (e.g., diffuse large B-cell lymphoma), leukemia (e.g., acute myeloid leukemia), or blastoma (e.g., neuroblastoma, retinoblastoma, or glioblastoma).

[0533] In some embodiments, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is diffuse large B-cell lymphoma, Burkitt lymphoma, multiple myeloma, blastoma (e.g., neuroblastoma, retinoblastoma, or glioblastoma), acute myeloid leukemia, acute B-lymphocytic leukemia, or triple-negative breast cancer. Suitably, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is multiple myeloma, neuroblastoma, retinoblastoma, glioblastoma, acute myeloid leukemia, acute B-lymphocytic leukemia, or triple-negative breast cancer. More suitably, the MYC-addicted cancer, MYC-dysregulated cancer, or cancer containing one or more structural alterations to the MYC locus is multiple myeloma, neuroblastoma, retinoblastoma, glioblastoma, or triple-negative breast cancer. Even more appropriately, cancers of MYC addiction, MYC dysregulation, or cancers involving one or more structural alterations of the MYC locus are neuroblastomas or triple-negative breast cancers (such as basal-like breast cancer).

[0534] In one specific embodiment, the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, solvates, or hydrates thereof, for the prevention or treatment, for example, of blastoma, wherein the blastoma comprises one or more mutations in MYCN. Suitably, the blastoma is selected from neuroblastoma, retinoblastoma, and glioblastoma. Most preferably, the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, solvates, or hydrates thereof, for the prevention or treatment, for example, of neuroblastoma, wherein the neuroblastoma comprises one or more mutations in MYCN.

[0535] In another specific embodiment, the present invention provides compounds for the prevention or treatment, for example, of cancers causing c-MYC addiction, wherein the c-MYC-addictive cancer is breast cancer. Suitably, the present invention provides compounds for the prevention or treatment, for example, of cancers causing c-MYC addiction, wherein the c-MYC-addictive cancer is triple-negative breast cancer (e.g., basal cell-like breast cancer) or invasive breast cancer.

[0536] The present invention also provides a method for preventing or treating, for example, cancer of MYC addiction in an individual requiring such treatment, the method comprising administering a therapeutically effective amount of the compound of the present invention. Suitably, the cancer of MYC addiction is any of the aforementioned cancers of MYC addiction.

[0537] A method for preventing or treating, for example, cancer of MYC dysregulation in an individual requiring such treatment is further provided, the method comprising administering a therapeutically effective amount of the compound of the present invention. Suitably, the cancer of MYC dysregulation is any of the aforementioned cancers of MYC dysregulation.

[0538] A further method is provided for preventing or treating, for example, cancer in an individual requiring such treatment, said cancer comprising one or more structural alterations at the MYC locus, said method comprising administering a therapeutically effective amount of the compound of the present invention. Suitably, the cancer comprising one or more structural alterations at the MYC locus is any of the cancers described above.

[0539] According to another aspect of the present invention, a method is provided for determining whether an individual suffering from cancer will benefit from treatment with the compounds of the present invention, the method comprising the following steps:

[0540] i) Collect cancer cell samples from the individuals mentioned above;

[0541] ii) Analyze the cancer cells from step i) to examine for the presence of one or more structural alterations (e.g., chromosomal rearrangement, copy number increase, and / or mutation) at the MYC locus;

[0542] iii) Determine whether one or more structural alterations (e.g., chromosomal rearrangements, copy number increases, and / or mutations) are present in the MYC locus of cancer cell samples compared to controls; and

[0543] iv) Determine whether the individual will benefit from the application of the compounds of the present invention to treat the cancer, wherein if the cancer cell sample contains one or more structural alterations (e.g., chromosomal rearrangement, copy number increase, and / or mutation) at the MYC locus, the individual will benefit from the application of the compounds of the present invention, and if the cancer cell sample does not contain one or more structural alterations (e.g., chromosomal rearrangement, copy number increase, and / or mutation) at the MYC locus, the individual will not benefit from the application of the compounds of the present invention.

[0544] In one embodiment, the one or more structural alterations are chromosomal rearrangements. Therefore, suitably, step ii) of the above method includes analyzing the cancer cells of step i) to examine for the presence of one or more chromosomal rearrangements at the MYC locus. Those skilled in the art can readily determine suitable techniques for examining the presence of one or more chromosomal rearrangements at the MYC locus. A non-limiting example of a suitable technique for examining the presence of one or more chromosomal rearrangements at the MYC locus is fluorescence in situ hybridization (FISH).

[0545] In another embodiment, the one or more structural alterations are mutations. Therefore, suitably, step ii) of the above method includes analyzing the cancer cells of step i) to check for the presence of one or more mutations at the MYC locus. Those skilled in the art will be able to readily determine suitable techniques for checking for the presence of one or more mutations at the MYC locus. A non-limiting example of a suitable technique for checking for the presence of one or more mutations at the MYC locus is gene sequencing.

[0546] Appropriately, the control in step iii) is the structural arrangement of the MYC locus found in normal, healthy cells; in particular, the control in step iii) is the chromosomal arrangement and / or genetic sequence found in the MYC locus in normal, healthy cells.

[0547] It should be understood that cancer cell samples obtained from said individual can be obtained by any suitable method known in the art. For example, cancer cell samples collected from said individual may be those collected from a biopsy, or they may be circulating tumor cell (CTC) samples collected from the individual.

[0548] According to another aspect of the present invention, a method is provided for determining whether an individual suffering from cancer will benefit from treatment with an NMT inhibitor, the method comprising the following steps:

[0549] i) Measure the expression level of MYC in cancer cell samples obtained from said individual;

[0550] ii) Compare the MYC expression levels from step i) with the control;

[0551] iii) Determine whether MYC expression in the cancer cell sample is increased compared to the control; and iv) Determine whether the individual will benefit from the administration of the compound of the present invention to treat the cancer, wherein if MYC expression in the cancer cell sample is higher than that in the control, the individual will benefit from the administration of the compound of the present invention, and if MYC expression in the cancer cell sample is not higher than that in the control, the individual will not benefit from the administration of the compound of the present invention.

[0552] It should be understood that the expression level of MYC in cancer cell samples can be determined by any suitable method known in the art. For example, the expression level of MYC can be determined by measuring the MYC protein level. The MYC protein level can be measured using any suitable technique known in the art, such as SDS-PAGE, followed by Western blotting using a suitable antibody against the target protein. Alternatively, the expression level of MYC can be determined by measuring the mRNA level. The mRNA level can be measured using any suitable technique known in the art, such as Northern blotting or quantitative RT-PCR (qRT-PCR).

[0553] Suitablely, the control for step ii) above is the MYC expression level found in normal, healthy cells, such as normal, healthy cells of the same type as the cells under study. It should be understood that the MYC expression level found in normal, healthy cells can also be determined using any of the techniques described in paragraph

[0091] above.

[0554] According to another aspect of the invention, a method for preventing or treating, for example, cancer in an individual who has been identified by the method as benefiting from the application of the compound of the invention is provided, wherein the method comprises applying a therapeutically effective amount of the compound of the invention.

[0555] Viral infections and related diseases

[0556] In another suitable embodiment, the compounds of the present invention are used for the prevention or treatment, for example, of viral infections, particularly enterovirus infections, retrovirus infections, or poxvirus infections. For example, enterovirus infections can be microRNA infections (e.g., rhinovirus, poliovirus, foot-and-mouth disease virus, Coxsackievirus, hepatitis A virus, or enterovirus 71 infection); retrovirus infections can be lentivirus infections (e.g., HIV infection); and poxvirus infections can be orthopoxvirus, parapoxvirus, attapoxvirus, or molluscum poxvirus infection. Therefore, viral infections can be selected from rhinovirus infections (e.g., RV, also known as the common cold), slow virus infections (e.g., HIV infection), poliovirus infection, foot-and-mouth disease virus infection, Coxsackievirus infection, hepatitis A virus infection, enterovirus 71 infection, smallpox virus (smallpox) infection, vaccinia virus infection, cowpox virus infection, monkeypox virus infection, buffalopox virus infection, camelpox virus infection, mousepox virus infection, rabbitpox virus infection, raccoonpox virus infection, sealpox virus infection, skunkpox virus infection, African gerbilpox virus infection, volepox virus infection, sheeppox virus infection, pseudococcosis virus infection, bovine papular stomatitis virus infection; tanapoxetine virus infection, macaque tumor virus infection, and molluscum contagiosum virus (MCV) infection. It can be suitably selected from rhinovirus infections (e.g., RV, also known as the common cold), slow virus infections (e.g., HIV infection), poliovirus infection, foot-and-mouth disease virus infection, Coxsackievirus infection, hepatitis A virus infection, enterovirus 71 infection, smallpox virus (smallpox) infection, vaccinia virus infection, cowpox virus infection, monkeypox virus infection, sheeppox virus infection, pseudococcosis infection, bovine papular stomatitis virus infection; tanapoxetine virus infection, maculopapular tumor virus infection, and molluscum contagiosum virus (MCV) infection. In a particularly suitable embodiment, the compounds of the present invention are used for prevention or treatment, for example, treatment of viral infections, wherein the viral infection is a microRNA virus infection, and more particularly rhinovirus infection (e.g., RV, also known as the common cold).

[0557] The aforementioned viral infections cause many types of illnesses. For example: rhinovirus infections cause the common cold; various parvovirus infections (especially Coxsackievirus and Enterovirus 71) cause hand-foot-and-mouth disease and poliomyelitis-like syndrome; Coxsackievirus can also cause flaccid paralysis, herpetic pharyngitis, acute hemorrhagic conjunctivitis, nonspecific febrile illnesses, rashes, upper respiratory tract infections, pericardial effusion, insulin-dependent diabetes mellitus (IDDM), Sjögren's syndrome, myocarditis (cardiac inflammation), pericarditis (inflammation of the sacs around the heart), meningitis (inflammation of the endocardium of the brain and spinal cord), and pancreatitis (inflammation of the pancreas); Enterovirus 71 can also cause severe illness in children. Severe neurological diseases; foot-and-mouth disease virus (FMDV); hepatitis A virus (HAV); HIV infection can cause acquired immunodeficiency syndrome (AIDS); smallpox virus (Smallpox) infection causes smallpox; cowpox virus infection causes cowpox; monkeypox virus infection causes monkeypox; sheeppox virus infection causes sheeppox; pseudococcosis virus infection causes pseudococcosis; bovine papular stomatitis virus infection causes bovine papular stomatitis; tanapoxetine virus infection can cause acute febrile illness and local skin lesions; maculopapular tumor virus infection can cause the formation of skin histiocytoma; molluscum contagiosum virus (MCV) infection causes molluscum contagiosum. The compounds of this invention can be used for the prevention or treatment, for example, of the diseases caused by the above-mentioned viral infections, as well as other diseases and symptoms caused by enterovirus infection, retrovirus infection, or poxvirus infection.

[0558] Microbial infection

[0559] In another embodiment, the compounds of the present invention are used for the prevention or treatment, for example, of diseases or conditions caused by microbial infections; such as fungal infections like Aspergillus infection, and protozoan infections such as malaria, leishmaniasis, human African trypanosomiasis (sleeping sickness), and American trypanosomiasis (Chagas disease). In some embodiments, the compounds of the present invention are used for the prevention or treatment, for example, of diseases or conditions selected from Aspergillus infection, malaria, leishmaniasis, human African trypanosomiasis (sleeping sickness), and American trypanosomiasis (Chagas disease), particularly malaria, leishmaniasis, human African trypanosomiasis (sleeping sickness), and American trypanosomiasis (Chagas disease).

[0560] In one embodiment, the compounds of the present invention are used to prevent or treat, for example, diseases or conditions caused by protozoan infections of species of the genera Plasmodium, Leishmania, or Trypanosoma (e.g., Plasmodium falciparum, Plasmodium vivax, Leishmania donovani, Leishmania macrophylla, Trypanosoma brucei, Trypanosoma krusei).

[0561] Compounds that are particularly effective inhibitors of NMT enzymes in specific non-human species (e.g., Plasmodium falciparum, Plasmodium vivax, Leishmania donovani, Leishmania macrophylla, Trypanosoma brevicornu, Trypanosoma krusei); and / or compounds of the present invention that exhibit greater selectivity for NMT enzymes in specific species (e.g., Plasmodium falciparum, Plasmodium vivax, Leishmania donovani, Leishmania macrophylla, Trypanosoma brevicornu, Trypanosoma krusei) than human NMT (human NMT1 and / or human NMT2) may be particularly useful for the prevention or treatment, e.g., for the treatment of diseases or conditions associated with those species. For example, they may be particularly useful for the prevention or treatment, e.g., for the treatment of diseases or conditions selected from malaria, leishmaniasis, and sleeping sickness.

[0562] For example, using selective NMT inhibitors can result in fewer side effects compared to using compounds with lower selectivity. In one embodiment, the NMT inhibitor has higher selectivity for non-human NMTs (e.g., Plasmodium falciparum, Plasmodium vivax, Leishmania donovani, Trypanosoma brucei, and / or Trypanosoma krusei) than for human NMTs (e.g., human NMT1 and / or human NMT2). ​​If human NMT IC 50 Value and Non-human NMT IC 50 If the ratio of values ​​is greater than 5, appropriately greater than 10, more appropriately greater than 100, and most appropriately greater than 1000, then the NMT inhibitor is considered selective.

[0563] Other diseases

[0564] In another embodiment, the compounds of the present invention are used for the prevention or treatment, for example, of diseases or conditions selected from neurological diseases / conditions, ischemia, osteoporosis, and diabetes. In another embodiment, the compounds of the present invention are used for the prevention or treatment, for example, of diseases or conditions selected from autoimmune diseases and inflammatory diseases.

[0565] diagnosis

[0566] In one embodiment, the compounds of the present invention comprise isotopic atoms, suitably radioactive isotopic atoms. As defined herein, an isotopic atom is an atom of an element that is not the most common naturally occurring isotope. These compounds can be used as diagnostic reagents for diagnosing diseases or conditions in which inhibition of NMT provides a therapeutic or preventative effect. Therefore, the present invention also provides the use of the compounds of the present invention comprising isotopic atoms, suitably radioactive isotopic atoms, as diagnostic reagents for diagnosing diseases or conditions in which inhibition of NMT provides a therapeutic or preventative effect.

[0567] Dosage and formulation

[0568] Of course, the amount of active ingredient required to achieve a therapeutic effect will vary depending on the specific compound, route of administration, and the individual being treated, including the individual's type, species, age, weight, sex, and medical condition, as well as the individual's kidney and liver function, the specific condition or disease being treated, and its severity. A generally skilled physician, veterinarian, or clinician can easily determine and prescribe the effective amount of medication needed to prevent, counteract, or halt the progression of a disease.

[0569] When used for a specified effect, the oral dose of the present invention will be between about 0.01 mg / kg body weight / day (mg / kg / day) and about 500 mg / kg / day, suitably between 0.01 mg / kg body weight / day (mg / kg / day) and 100 mg / kg / day, and most suitable for adults is between 0.05 and 50 mg / kg / day, for example 0.05, 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 mg / kg / day. For oral administration, the composition is suitable to be provided in tablet form or other forms provided in discrete units, containing 0.01, 0.05, 0.1, 0.25, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, and 500 mg of active ingredient for symptom-adjusted dosing in 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 250 mg of active ingredient, for example about 1 mg to about 150 mg of active ingredient. When administered intravenously, the most suitable dose range during a constant-rate infusion is about 0.1 to about 10 mg / kg / min. Advantageously, the compounds of the invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three, or four times daily. Furthermore, the compounds of the present invention can be administered in intranasal form via a suitable intranasal carrier, or via a transdermal route using those forms of transdermal skin patches well known to those skilled in the art. For administration via a transdermal delivery system, the dosage is, of course, continuous rather than intermittent throughout the dosing regimen.

[0570] Although the active ingredient can be administered alone, it is suitable to be present in a pharmaceutical formulation or composition. Therefore, the present invention provides pharmaceutical formulations or compositions comprising the compounds of the present invention and pharmaceutically acceptable diluents, excipients, or carriers (collectively referred to herein as “carrier” materials). The pharmaceutical compositions of the present invention may be in the form of pharmaceutical formulations as described below.

[0571] The pharmaceutical formulations of the present invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [rapid concentration or infusion] and intra-articular), intranasal (also known as nasal administration), inhalation (including fine particulate powder or mist, which can be produced by various types of metered-dose pressurized aerosols, nebulizers or blowers), inhalation, rectal, intraperitoneal and topical (including skin, mouth, sublingual and intraocular) administration, the most suitable route of administration depending on, for example, the recipient's condition and impairment.

[0572] In some embodiments, the compounds of the present invention are administered via intranasal, inhalation (including fine particulate dust or mist, which can be produced by various types of metered-dose pressurized aerosols, nebulizers, or blowpipes), or inhalation. Such embodiments are particularly suitable for, for example, treating microRNA infections, such as human rhinovirus infections. This method of administration allows for the delivery of low doses of the compounds of the present invention, which can result in a reduction of side effects. For example, daily doses of the compounds of the present invention in the range of 10 to 0.01 μg, suitably 1 to 0.01 μg, and more suitably down to 0.1 μg (100 ng) can be used.

[0573] Formulations can be conveniently present in unit dosage forms and can be prepared by any method known in the pharmaceutical field. All methods involve the step of binding the active ingredient with a carrier constituting one or more auxiliary ingredients. Typically, formulations are prepared by uniformly and tightly binding the active ingredient with a liquid carrier or a finely fragmented solid carrier, or both, and then, if desired, shaping the product into the desired formulation.

[0574] The formulations of the present invention suitable for oral administration can exist in discrete units, such as capsules, pouches, pills, or tablets, each containing a predetermined amount of the active ingredient; in powder or granule form; as a solution or suspension in an aqueous or non-aqueous liquid, such as an elixir, tincture, suspension, or syrup; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient can also exist in large pills, saccharides, or pastes.

[0575] Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can be formulated to provide a slow or controlled release of the active ingredient therein. The compounds of the present invention can be administered, for example, in a form suitable for immediate or extended release. Immediate or extended release can be achieved by using a suitable pharmaceutical composition comprising the compounds of the present invention, or particularly in the case of extended release, by using a device such as a subcutaneous implant or an osmotic pump. The compounds of the present invention can also be administered liposomeically.

[0576] Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for volume impartation, alginate or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents, such as those known in the art; and immediate-release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and / or lactose and / or other excipients, binders, expanders, 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, waxes, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. The compounds of the present invention can also be delivered orally via sublingual and / oral administration. Molded tablets, compressed tablets, or lyophilized tablets are exemplary forms that can be used. Exemplary compositions include those formulated with readily soluble diluents such as mannitol, lactose, sucrose, and / or cyclodextrin. These formulations may also include high molecular weight excipients such as cellulose (Avicel) or polyethylene glycol (PEG). Such formulations may also contain excipients that promote mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez), and controlled-release agents such as polyacrylic acid copolymers (e.g., Carbopol 934). For ease of manufacture and use, lubricants, flow aids, flavoring agents, colorants, and stabilizers may also be added. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. For oral administration in liquid form, the oral pharmaceutical component may be combined with any orally available, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerin, water, etc.

[0577] The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (cephalin), or phosphatidylcholine (lecithin).

[0578] Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. Formulations may be available in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, just before use. Immediate-use injectable 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 that may contain, for example, suitable non-toxic, parenteral-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 cremaphores.

[0579] Exemplary compositions for intranasal, aerosol, or inhaled administration include saline solutions that may contain, for example, benzyl alcohol or other suitable preservatives, bioavailability enhancers, and / or other solubilizers or dispersants, such as those known in the art.

[0580] Rectal administration formulations can be in the form of suppositories containing commonly used carriers such as cocoa butter, synthetic glycerides, or polyethylene glycol. Such carriers are typically solid at room temperature but liquefy and / or dissolve in the rectal lumen to release the drug.

[0581] Formulations for oral or sublingual administration include tablets containing the active ingredient in a flavoring matrix such as sucrose and gum arabic or tragacanth gum, and soft tablets containing the active ingredient in a matrix such as gelatin and glycerin or sucrose and gum arabic. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0582] Suitable unit-dose formulations are those containing the active ingredient at the effective dose or an appropriate portion thereof as described above.

[0583] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of the present invention may contain other agents conventional in the art and relevant to the type of formulation discussed, such as flavoring agents for those suitable for oral administration.

[0584] While the compounds of the present invention can be used as the sole active ingredient in a medicament, they can also be used in combination with one or more other therapeutic agents. Therefore, the present invention also provides compounds of the present invention in combination with other therapeutic agents. These other therapeutic agents can be administered simultaneously, sequentially, or separately. The present invention also provides a kit comprising: (a) a first pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier; and (b) a second pharmaceutical composition comprising a further therapeutic agent and a pharmaceutically acceptable carrier.

[0585] These additional therapeutic agents may be other NMT inhibitors, such as other compounds of the present invention (i.e., other compounds of formula (I) (or (Ia) to (Ip))), or pharmaceutically acceptable esters, amides, or carbamates or salts thereof, including salts of such esters, amides, or carbamates.

[0586] The compounds of the present invention can be used in combination with one or more other therapeutic agents for treating or preventing diseases or conditions in which inhibition of N-myristoyltransferase provides a therapeutic or preventive effect (e.g., agents for treating or preventing hyperproliferative disorders, viral infections, microbial infections, neurological diseases, ischemia, osteoporosis, diabetes, autoimmune diseases, and inflammatory diseases, particularly hyperproliferative disorders (e.g., cancer) and viral infections (e.g., RV or HIV infection)). The individual components of such combinations can be administered separately at different times during treatment, or simultaneously in separate or single-component combinations. Therefore, the present invention should be understood to include all such simultaneous or alternating treatment regimens, and the term "administration" should be interpreted accordingly. It should be understood that the scope of combinations of the compounds of the present invention with other therapeutic agents for treating or preventing diseases or conditions in which inhibition of N-myristoyltransferase provides a therapeutic or preventive effect generally includes any combination with any pharmaceutical composition for treating or preventing diseases or conditions in which inhibition of N-myristoyltransferase provides a therapeutic or preventive effect.

[0587] When used in conjunction with the compounds of the present invention, other therapeutic agents may be used, for example, in the amount indicated for the therapeutic agent in the Physicians' Desk Reference (PDR), or in other amounts determined by those skilled in the art.

[0588] When the compounds of the present invention are used simultaneously or sequentially in combination with one or more other therapeutic agents, the following combination ratios and dosage ranges are suitable: when combined with other therapeutic agents, the compounds of the present invention may be used, for example, in a weight ratio of about 10:1 to about 1:10 with other therapeutic agents.

[0589] In one embodiment, when the compounds of the present invention are used to treat or prevent cancer, the compounds of the present invention may be used in combination with one or more other therapeutic agents simultaneously or sequentially for the treatment of cancer.

[0590] In one embodiment, when the compounds of the present invention are used to treat or prevent RV (also known as the common cold), the compounds of the present invention may be used simultaneously or sequentially in combination with one or more other therapeutic agents for the treatment of RV and / or asthma and / or chronic obstructive pulmonary disease (COPD).

[0591] In one embodiment, for example when the compounds of the present invention are used to treat or prevent microbial infections, particularly protozoan infections, the compounds of the present invention are administered in combination with effective amounts of other antiprotozoan agents, such as (i) antimalarial agents; and / or (ii) antileishmaniasis agents; and / or (iii) agents against human African trypanosomiasis or American trypanosomiasis. One or more of these additional antiprotozoan agents may be used in combination with the compounds of the present invention.

[0592] The present invention also provides a kit comprising: (a) a first pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier; and (b) a second pharmaceutical composition comprising an additional therapeutic agent, suitably an additional N-myristyltransferase inhibitor and a pharmaceutically acceptable carrier.

[0593] Synthesis of the compounds of the present invention

[0594] Those skilled in the art can devise numerous synthetic routes for the compounds of this invention, and the exemplary synthetic routes described below do not limit the invention. Many methods for synthesizing heterocycles exist in the literature, for example: Joule, JA; Mills, K., Heterocyclic Chemistry, 2010, 5th edition, Pub. Wiley. Many possible synthetic routes are illustrated below. Where appropriate, any initially generated compound of this invention can be converted into another compound of this invention by known methods.

[0595] General synthesis scheme

[0596] The following synthetic routes describe in detail the synthetic routes for the compounds of the present invention and intermediates for synthesizing such compounds. In the following routes, reactive groups may be protected with protecting groups and deprotected according to established techniques known to those skilled in the art.

[0597] The compounds can be prepared by the general methods described below. In the following description, unless otherwise specified, all groups such as the group R... 1 R 2 R 3 R5a R 5b R 5c R 5d R 6 R 7 R 8 R 9 R 12 R 13 X 1 X 2 m, p, r, n1, n2 and Z have the meanings defined above for compounds of formula (I).

[0598] Option 1

[0599]

[0600] R 12 It is C 1-6 Alkyl compounds of formula (I) can be prepared by reductive amination. In this case, R is... 12 Another compound of formula (I) of H (as shown above) reacts with aldehydes such as formaldehyde in the presence of a reducing agent such as NaCNBH3.

[0601] Option 2

[0602]

[0603] R 12 Compounds of formula (I) with H can be prepared by reacting a compound of formula (II) (where Q is a nitrogen protecting group such as tert-butoxycarbonyl (BOC)) with an acid such as trifluoroacetic acid.

[0604] Option 3

[0605]

[0606] Compound (II) can be obtained by reacting compound (V) (where D is a halogen such as chlorine) with compound (IV) (where Q is a nitrogen protecting group such as tert-butoxycarbonyl (BOC)) in the presence of an alcohol such as n-BuOH under microwave irradiation.

[0607] Furthermore, compounds of formulas (V) and (IV) can also be reacted under transition metal catalysis using palladium catalysts such as bis(dibenzylideneacetone)palladium(0) (Pd2(dba)3), ligands such as SPhos (2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl) and bases such as cesium carbonate.

[0608] Option 4

[0609]

[0610] Compound (V) can be prepared by reacting compound (VI) with compound (VII) in the presence of a base such as triethylamine and a coupling agent such as propylphosphonic anhydride.

[0611] Option 5

[0612]

[0613] Compound (VII) can be prepared by reacting compound (VIII) with compound (IX) (where D and E are each independently a halogen such as chlorine).

[0614] Option 6

[0615]

[0616] R 12 Compounds of formula (I) of H can also be obtained by combining compounds of formula (X) with compounds of formula (XI) (where T is C). 1-6 Alkyl groups, such as methyl, and Q being a nitrogen-protecting group, such as tert-butoxycarbonyl (BOC), are reacted in the presence of a base, such as triethylamine, to yield the product. R... 12 It is C 1-6 Alkyl compounds of formula (I) can be obtained by the reductive amination method described herein.

[0617] Option 7

[0618]

[0619] Compound (XI) can be produced by combining compound (XII) (where T is C) 1-6 Alkyl groups (such as methyl groups) are reacted under oxidizing conditions with an oxidizing agent such as m-chloroperoxybenzoic acid (m-CPBA). Compounds of formula (XII) can be obtained by reacting a compound of formula (XIII) (where D is a halogen such as chlorine and T is C) with an oxidizing agent such as m-chloroperoxybenzoic acid (m-CPBA). 1-6 Alkyl groups, such as methyl groups, are reacted with a compound of formula (IV) (where Q is a nitrogen-protecting group, such as tert-butoxycarbonyl (BOC)) in the presence of an alcohol, such as n-BuOH, under microwave irradiation to obtain the compound. Wherein D is a halogen, such as chlorine, and T is C. 1-6 Alkyl compounds of formula (XIII), such as methyl, can be obtained by reacting a compound of formula (XIV), in which D and E are each independently a halogen such as chlorine, with a thiolated agent such as sodium thiomethoxide.

[0620] Option 8

[0621]

[0622] Compound (X) can be obtained by reacting compound (XV) (where Q is a nitrogen protecting group such as tert-butoxycarbonyl (BOC)) with an acid such as trifluoroacetic acid. Compound (XV) can be obtained by reacting compound (XVI) with compound (XVII) in the presence of a base such as triethylamine and a coupling agent such as propylphosphonic anhydride.

[0623] Z is The compounds can be prepared using methods similar to those described above, for example:

[0624] Option 9

[0625]

[0626] Compound (II') can be prepared by reacting compound (V') and compound (IV') under the conditions described herein, such as those described in Scheme 3. The functional group within Z can be transformed to obtain compound (I) using conditions and methods known to those skilled in the art or as described below.

[0627] Option 10

[0628]

[0629] Compound (I) can be obtained by reacting compound (X) with compound (XI') under the conditions described herein, such as those described in Scheme 6.

[0630] Option 11

[0631]

[0632] Compound (XI') can be produced by combining compound (XII') (where T is C) 1-6 Alkyl groups (such as methyl groups) are reacted under oxidizing conditions with an oxidizing agent such as m-chloroperoxybenzoic acid (m-CPBA). Compounds of formula (XII') can be obtained by reacting a compound of formula (XIII) (where D is a halogen such as chlorine and T is C) with an oxidizing agent such as m-chloroperoxybenzoic acid (m-CPBA). 1-6 The compound is obtained by reacting an alkyl group (such as methyl) with a compound of formula (IV') in the presence of an alcohol such as n-BuOH under microwave irradiation. The compound of formula (XIII) can be obtained by the methods described herein, such as those described in Scheme 7.

[0633] The method of the present invention

[0634] Another aspect of the invention provides a method for preparing a compound of formula (I) or an ester, amide, carbamate or salt thereof, such as a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a salt of such ester, amide or carbamate (such as a pharmaceutically acceptable salt thereof), and a method for preparing an intermediate or salt thereof in the synthesis of a compound of formula (I).

[0635] The method of the present invention is as described above and includes any individual step of a multi-step scheme.

[0636] Intermediate of the present invention

[0637] The present invention also provides novel intermediates for use in the synthesis of compounds of formula (I), such as compounds of formulas (II) to (XVI). Specifically interesting intermediates are those of the following general formulas, wherein the variable groups and preferred options are as defined above with respect to compounds of formula (I) or as defined above.

[0638] Therefore, in one embodiment, compounds selected from the following are provided:

[0639] Compound of formula (II)

[0640]

[0641] Where R 1 R 2 R 3 R 5a R 5b R 5c R 5d R 6 R 7 R 8 R 9 X 1 X 2 m, p, r, n1, n2 and R 13 As defined with respect to compound (I), and Q as defined above;

[0642] Compound of formula (V)

[0643]

[0644] Where D is a halogen such as chlorine and R 1 R 2 R 3 R 5a R 5b R 5c R 5d R 6 R 7 R 8 R9 X 1 X 2 p, n1, and n2 are as defined with respect to compounds of formula (I);

[0645] Compound of formula (VII)

[0646]

[0647] Where D is a halogen such as chlorine and R 6 R 7 R 8 R 9 p, X 1 n1 and n2 are as defined with respect to compounds of formula (I);

[0648] Compound of formula (X)

[0649]

[0650] Where R 1 R 2 R 3 R 5a R 5b R 5c R 5d R 6 R 7 p, X 2 n1 and n2 are as defined with respect to compounds of formula (I);

[0651] Compound of formula (XI)

[0652]

[0653] Where Q is a nitrogen protecting group such as tert-butoxycarbonyl (BOC), and T is a carbonyl group. 1-6 Alkyl groups such as methyl, R 8 R 9 R 13 X 1 r and m are as defined with respect to compounds of formula (I); and

[0654] Compound of formula (XII)

[0655]

[0656] Where Q is a nitrogen protecting group such as tert-butoxycarbonyl (BOC), and T is a carbonyl group. 1-6 Alkyl groups such as methyl, and R 8 R 9 R 13 X 1 r and m are as defined with respect to the compound of formula (I).

[0657] The present invention also provides salts of the intermediate, such as pharmaceutically acceptable salts. Example

[0658] The following compounds illustrate the compounds of the present invention or, where appropriate, the compounds used in the present invention.

[0659] Hplc

[0660] Purity of certain embodiments was determined by analytical HPLC using Eclipse Extend or XDB 5μm C18 (150×4.6mm), Xbridge 5μm C18 (100×4.6mm), Zorbax Extend 5μm C18 (150×4.6mm), or Shimadzu L-column 2ODS 5μm C18 (150×4.6mm) columns, with gradient elution using an aqueous solution of acetonitrile containing 10mM ammonium acetate for 15 min (HPLC B), 17 min (B1), or 21 min (B2). Purity of some embodiments was determined by analytical HPLC using a Poroshell 120 2.7 μm EC18 (100 × 4.6 mm), Luna Omega Polar 3 μm C18 (100 × 4.6 mm), Xbridge 5 μm C18 (150 × 4.6 mm), or Sunfire 5 μm C18 (100 × 4.6 mm) column, with gradient elution of acetonitrile-water solution containing 0.05% trifluoroacetic acid for 12 min (HPLC A), 14 min (A1), or 17 min (A2). Purity of some other embodiments was determined by analytical HPLC using a Gemini NX 3 μm C18 (100 × 4.6 mm) column, with gradient elution of acetonitrile-water solution containing 0.05% formic acid for 12 min (A3). The HPLC methods used for each embodiment are shown below.

[0661] NMR

[0662] Unless otherwise stated, 1 H and 13 C10 NMR spectra were recorded at room temperature on Bruker AV instruments at 400 MHz and 101 MHz, respectively, with reference to residual solvent signals. Data are represented as follows: chemical shift, integral, multiplicity (br = broad peak, app = apparent, s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplytet) and coupling constant in ppm.

[0663] Preparative HPLC

[0664] Preparative HPLC was performed on a Waters automated purification system. Column name: YMC Triart Actus C18 (250x20mm, 5μm), operated at ambient temperature and a flow rate of 16 mL / min. Mobile phase: A = 20 mM ammonium bicarbonate aqueous solution, B = acetonitrile; gradient distribution: initial mobile phase composition 80% A and 20% B, then changed to 70% A and 30% B within 3 minutes, then to 20% A and 80% B within 20 minutes, then to 5% A and 95% B within 21 minutes, held at this composition for up to 23 minutes for column washing, then returned to the initial composition within 24 minutes and held for up to 26 minutes.

[0665] Preparative TLC

[0666] Preparative TLC using 60g of TLC silica gel F 254 The glass plate is 20 x 20 cm (Merck).

[0667] microwave

[0668] All microwave reactions were carried out in a CEM Discover (model 908010) microwave reactor.

[0669] General Method

[0670] Boc deprotection

[0671] The DCM solution of the Boc-protected amine under stirring was treated with TFA (trifluoroacetic acid). The reaction mixture was stirred at room temperature for 4 h. All volatiles were removed under reduced pressure, and the product was purified by LC-MS or preparative TLC.

[0672] Reductive amination

[0673] The MeOH solution of the secondary amine under stirring was treated with an aqueous formaldehyde solution (5 molar equivalents), and the mixture was stirred at room temperature (RT) for 1 h. Sodium cyanoborohydride (NaCNBH3) (3 molar equivalents) was added at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was terminated with sodium bicarbonate solution and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative TLC or LC-MS.

[0674] Diamine substitution (Method A)

[0675] A solution of 2-chloropyrimidine and diamine (3 molar equivalents) in n-butanol was treated with triethylamine (6 molar equivalents) and then heated to 160 °C for 160 min under microwave irradiation. The reaction mixture was evaporated under reduced pressure and the crude product was purified by LC-MS or preparative TLC.

[0676] Diamine replacement (Method B)

[0677] A DME solution of 2-chloropyridine or 2-chloropyrimidine, diamine (3 molar equivalents), and cesium carbonate (5 molar equivalents) was purified under argon for 10 minutes. Then, a catalytic amount of Pd₂(dba)₃ (0.05 equiv) and 2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl (SPhOs) or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xantphos) (1.2 equiv) were added. After further purification under argon for 5 minutes, the mixture was heated to 120 °C overnight. The reaction mixture was extracted with EtOAc and washed with water and brine, dried over sodium sulfate, and evaporated under vacuum. The crude product was then purified by column chromatography, LC-MS, or preparative TLC.

[0678] Intermediate 1

[0679]

[0680] 1-(2,5-Dichloropyrimidin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide

[0681] Step 1

[0682] To a stirred solution of 2,4,5-trichloropyrimidine (6.0 g, 32.8 mmol) in EtOH (20 mL) and water (50 mL), aziridine-3-carboxylic acid (3.31 g, 32.8 mmol) was added, and the mixture was heated to reflux for 5 h. The reaction mixture was cooled to room temperature, filtered, and the solid was collected. The solid was azeotropically reacted with toluene to give a white solid of 1-(2,5-dichloropyrimidin-4-yl)aziridine-3-carboxylic acid (3.5 g, 43%). 1 H NMR(DMSO-d6)12.8(s,1H),8.15(s,1H),4.0-4.8(br.m 4H),3.50(m,1H). LCMS m / z248.

[0683] Step 2

[0684] Add Et3N (7.87 mL, 56 mmol) to a THF (40 mL) solution of 1-(2,5-dichloropyrimidin-4-yl)azacyclobutane-3-carboxylic acid (3.5 g, 14.1 mmol) and 2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-amine (2.47 g, 14.1 mmol). Add propylphosphonic anhydride ( (50%, 12.4 mL, 42 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was terminated with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under reduced pressure to give the desired product 1-(2,5-dichloropyrimidin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide (4.0 g, 70%). 1 H NMR(DMSO-d6)8.45(d,1H),8.40(s,1H),8.11(s,1H),7.56(d,1H),7.45(s,1H) ,7.16-7.25(m,2H),6.91(t,1H),3.8-4.6(br.m,4H),3.48(m,1H),1.75(s,6H). LCMS m / z 405.

[0685] Intermediate 2

[0686] 1-(2-chloro-5-fluoropyridin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide

[0687] Step 11 - (2-chloro-5-fluoropyridin-4-yl)azacyclobutane-3-carboxylic acid methyl ester

[0688] A solution of 2-chloro-5-fluoro-4-iodopyridine (300 mg, 1.16 mmol), methyl aziridine-3-carboxylate trifluoroacetic acid (TFA) salt (267 mg, 1.16 mmol), and cesium carbonate (1.1 g, 3.5 mmol) in dioxane (5 mL) was purged with argon for 10 min, followed by the addition of Pd₂(OAc)₂ (10.4 mg, 0.047 mmol) and XanthphO₂ (40.5 mg, 0.07 mmol). After purging with argon for another 5 min, the mixture was heated to 110 °C and maintained for 16 h. The reaction mixture was extracted with EtOAc and washed with water and brine, dried over sodium sulfate, and evaporated under vacuum. The crude product was then purified by Combiflush chromatography, eluting with 3% MeOH in DCM solution to give methyl 1-(2-chloro-5-fluoropyridin-4-yl)azacyclobutane-3-carboxylate (150 mg, 53%). LCMSMH + 245.

[0689] Step 2

[0690] 1-(2-chloro-5-fluoropyridin-4-yl)azacyclobutane-3-carboxylic acid

[0691] A solution of methyl 1-(2-chloro-5-fluoropyridin-4-yl)azacyclobutane-3-carboxylic acid (300 mg, 1.22 mmol) in THF-methanol (10:1, 8.8 mL) was treated with a solution of lithium hydroxide (128 mg, 3.1 mmol) in water (1.5 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0 °C, acidified with saturated citric acid solution, and extracted with 5% MeOH in DCM solution. The organic layer was dried over sodium sulfate and concentrated to give 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methylazacyclobutane-3-carboxylic acid (200 mg, 70%). 1 H NMR(DMSO-d6)7.97(d,1H),7.39(br.s,1H),6.57(d,1H),4.30(m,2H),4.17(m,2H),3.58(m,1H).

[0692] Step 3

[0693] 1-(2-chloro-5-fluoropyridin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide

[0694] Add Et3N (0.725 mL, 5.2 mmol) to a THF (80 mL) solution of 1-(2-chloro-5-fluoropyridin-4-yl)azacyclobutane-3-carboxylic acid (300 mg, 1.3 mmol) and 2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-amine (228 mg, 1.3 mmol). (50%, 1.1 mL, 3.9 mmol) and stirred at room temperature for 1 day. The reaction mixture was terminated with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, purified by column chromatography, and eluted with 2% MeOH in DCM solution to give 1-(2-chloro-5-fluoropyridin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide (150 mg, 30%). 1 H NMR(DMSO-d6)8.44(d,1H),8.39(s,1H),7.92(d,1H),7.56(d,1H),7.45(s,1H),7.39(s,1H), 7.21(dd,1H),6.91(t,1H),6.48(d,1H),4.20(m,2H),3.96(m,2H),3.53(m,1H),1.73(s,6H). LCMS m / z 388.

[0695] Intermediate 3-31

[0696] 1. All 2-chloropyrimidine intermediates were prepared from suitable 2,4-dichloropyrimidine, amino acids, and {imidazo[1,2-a]pyridin-3-yl}methylamine using the same two-step method as described above with respect to intermediate 1.

[0697] Table 1

[0698]

[0699]

[0700]

[0701] Intermediate 20 is prepared using the conditions described in intermediate 1 and step 2.

[0702] 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methylazacyclobutane-3-carboxylic acid is prepared by the following route.

[0703] Step 1

[0704] methyl 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methylazacyclobutane-3-carboxylate

[0705] A solution of methyl 3-methylazacyclobutane carboxylate (491 mg, 3.0 mmol) in isopropanol (IPA, 7 mL) under stirring was treated with triethylamine (1.25 mL, 9 mmol) and 2,4-dichloro-5-fluoropyrimidine (500 mg, 3 mmol). The reaction mixture was refluxed overnight, then concentrated under reduced pressure and partitioned between ethyl acetate and an aqueous solution of NaHCO3. The organic layer was concentrated under reduced pressure and purified by column chromatography, eluting with 30% EtOAC-hexane to give a colorless, resinous methyl 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methylazacyclobutane-3-carboxylate (300 mg, 39%). 1 H NMR(DMSO-d6)8.13(d,1H),4,45(m,2H),4.07(m,2H),3.70(s,3H),1.53(s,3H).

[0706] Step 2

[0707] 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methylazacyclobutane-3-carboxylic acid

[0708] A solution of 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methylazacyclobutane-3-carboxylic acid (300 mg, 1.16 mmol) in THF-water (4:1, 15 mL) was cooled at 0 °C and treated with methanol (0.02 mL) and lithium hydroxide (121 mg, 2.9 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was cooled at 0 °C, acidified with saturated citric acid solution, and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated to give a colorless solid of 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methylazacyclobutane-3-carboxylic acid (280 mg, 98%). 1 H NMR(DMSO-d6)12.94(s,1H),8.11(d,1H),4,41(m,2H),4.04(m,2H),3.70(s,3H),1.51(s,3H).

[0709] Intermediate 24

[0710] Step 1

[0711] (3R)-3-[(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester

[0712] (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (300 mg, 1.67 mmol) and 2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-amine (293 mg, 1.67 mmol) were dissolved in THF (6 mL) and treated with triethylamine (0.93 mL, 6.69 mmol), then... (50% solution, 1.46 mL, 5.0 mmol) treatment. The mixture was stirred overnight at room temperature, then the reaction was terminated with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give (3R)-3-[(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 19%). 1 H NMR(DMSO-d6)8.44(d,1H),8.30(s,1H),7.55(d,1H),7.42(s,1H),7.19(dd,1H),6 .88(t,1H),5.76(s,1H),2.90-3.40(m,6H),1.93(m,1H),1.70(s,6H),1.36(s,9H).

[0713] Step 2

[0714] ((3R)-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)pyrrolidine-3-carboxamide TFA salt

[0715] (3R)-3-[(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.54 mmol) was dissolved in DCM (5 mL) and treated with TFA (0.4 mL). The mixture was stirred at room temperature for 4 h and evaporated under reduced pressure. The crude product ((3R)-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)pyrrolidine-3-carboxamide TFA salt, 207 mg) was used without purification.

[0716] Step 3

[0717] (3R)-1-(2,5-dichloropyrimidin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)pyrrolidine-3-carboxamide

[0718] The crude product from step 2 was dissolved in isopropanol (6 mL), treated with 2,4,5-trichloropyrimidine (150 mg, 0.8 mmol), and then treated with triethylamine (0.23 mL, 1.64 mmol). The reaction mixture was heated to 100 °C for 16 h, concentrated, extracted with ethyl acetate, and washed with brine. The crude product was purified by silica gel column chromatography (5% EtOAc-hexane) to give the desired product (3R)-1-(2,5-dichloropyrimidine-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)pyrrolidine-3-carboxamide (125 mg, 36%). 1 H NMR(DMSO-d6)8.48(d,1H),8.42(s,1H),8.13(s,1H),7.56(d,1H),7.44(s,1H),7.21(dd,1H),6 .90(t,1H),3.87(m,1H),3.65-3.75(m,3H),3.06(m,1H),2.09(m,1H),1.86(m,1H),1.72(s,6H).

[0719] Intermediate 23 was prepared from (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid using the same route as intermediate 24.

[0720] Intermediate 27 (1-(2-chloro-5-fluoropyrimidin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide) was prepared from intermediate 7.

[0721]

[0722] A solution of (1-(2-chloro-5-fluoropyrimidin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)-azacyclobutane-3-carboxamide) (intermediate 7,350 mg, 0.9 mmol) in THF / DME (1:1, 6 mL) was cooled to 0 °C and treated with sodium hydride (60%, 55 mg, 1.35 mmol). The mixture was kept at 0 °C for 30 min, then treated with methyl iodide (0.067 mL, 1.08 mmol) and stirred for 1 h. The reaction mixture was terminated with water and extracted with ethyl acetate. The organic extract was washed with brine, dried with sodium sulfate and concentrated under reduced pressure to obtain (1-(2-chloro-5-fluoropyrimidin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)-N-methylazacyclobutane-3-carboxamide) (240 mg, 66%). 1 H NMR(DMSO-d6)8.27(d,1H),8.10(d,1H),7.55(d,1H),7.46(s,1H),7.19(dd ,1H),6.87(t,1H),4.2-4.4(m,4H),3.90(m,1H),2.75(s,3H),1.80(s,6H).

[0723] Intermediate 28 was prepared from intermediate 1 using the same route as intermediate 27.

[0724] Intermediate 29 was prepared from 2,5-dichloro-4-iodopyridine using the same route as intermediate 2.

[0725]

[0726] Component preparation

[0727] All components are obtained from commercial sources or using methods described in the literature, except for the component compounds listed below:

[0728] 2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-amine

[0729] Step 1

[0730] A mixture of 2-aminopyridine (11 g, 117 mmol) in DMF dimethyl acetal (23.3 mL, 175 mmol) was stirred at 100 °C for 16 h. The reaction mixture was evaporated and the crude compound was dissolved in EtOH (60 mL), and treated with chloroacetone (10.6 mL, 132 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was terminated with saturated NaHCO3 solution, extracted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica, 1% MeOH-DCM) to give 1-{imidazo[1,2-a]pyridin-3-yl}ethyl-1-one (9.0 g, 48%). 1 H NMR(CDCl3)9.63(d,1H),8.33(s,1H),7.74(d,1H),7.48(dd,1H),7.07(t,1H),2.60(s,3H).

[0731] Step 2

[0732] At -20°C, MeMgBr (30 mL, 90 mmol in 3 M ether solution) was added to a THF (250 mL) solution of 1-{imidazo[1,2-a]pyridin-3-yl}ethyl-1-one (7.0 g, 43.7 mmol) under stirring, and the reaction was stirred at room temperature for 3 h. The reaction mixture was terminated with NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 2.5% MeOH-DCM) to give 2-{imidazo[1,2-a]pyridin-3-yl}prop-2-ol (6.0 g, 78%). 1 H NMR(DMSO-d6)8.73(d,1H),7.54(d,1H),7.39(s,1H),7.21(dd,1H),6.89(t,1H),5.37(s,1H),1.61(s,6H). LCMS m / z 177.

[0733] Step 3

[0734] Sodium azide (11.07 g, 170 mmol) was added to a TFA (90 mL) solution of 2-{imidazo[1,2-a]pyridin-3-yl}prop-2-ol (6.0 g, 34 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was alkalized with K2CO3 solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 3-(2-azidoprop-2-yl)imidazo[1,2-a]pyridine (5.3 g, 77%). 1H NMR(CDCl3)8.46(d,1H),7.63(d,1H),7.52(s,1H),7.22(dd,1H),6.85(t,1H),1.78(s,6H). LCMS m / z 191.

[0735] Step 4

[0736] A solution of 5.5 g (27.3 mmol) of 3-(2-azidopropyl-2-yl)imidazo[1,2-a]pyridine in MeOH (110 mL) was degassed with argon for 15 minutes, then Pd-C (200 mg) was added, and the reaction mixture was stirred under an H2 balloon for 30 minutes. The reaction mixture was then passed through a Celite tube. TM The filtrate was filtered and concentrated under reduced pressure to obtain 2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-amine (4.75 g, 99%). 1 H NMR(CDCl3)8.96(d,1H),7.56(d,1H),7.41(s,1H),7.12(dd,1H),6.74(t,1H),1.64(s,6H),1.50(br,s,2H). LCMS m / z 176.

[0737] 2-{6-methylimidazo[1,2-a]pyridin-3-yl}propyl-2-amine and 2-{8-fluoroimidazo[1,2-a]pyridin-3-yl}propyl-2-amine were prepared from (5-methylpyridin-2-yl)amine and (3-fluoropyridin-2-yl)amine by the same four-step method used to prepare 2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-amine.

[0738] Preparation of Examples 1-112

[0739] Example 1

[0740]

[0741] 1-{5-chloro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)azacyclobutane-3-carboxamide

[0742] Step 1

[0743] A solution of 1-(2,5-dichloropyrimidin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide (intermediate 1, 60 mg, 0.148 mmol) and ((R)-1-N-Boc-2-methylpiperazine (148 mg, 0.74 mmol) in n-BuOH (0.8 mL) under microwave irradiation was heated at 120 °C for 30 min. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was then purified by preparative TLC (3%). A solution of MeOH in EtOAc yielded a white solid (2R)-4-(5-chloro-4-{3-[(2-{imidazo-1,2-a]pyridin-3-yl}propyl-2-yl)carbamoyl]azacyclobutane-1-yl}pyrimidin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (42 mg, 50%). LCMS MH + 569.

[0744] Step 2

[0745] The DCM (1 mL) solution of (2R)-4-(5-chloro-4-{3-[(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)carbamoyl]azacyclobutane-1-yl}pyrimidin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (42 mg, 0.074 mmol) under stirring was treated with TFA (0.057 mL, 0.74 mmol). The reaction mixture was stirred at room temperature for 4 h. The crude product was dissolved in MeOH and loaded onto... SCX column. The column was washed with MeOH. The compound was then eluted with NH3-MeOH and the collected fraction was concentrated under reduced pressure to give a creamy white solid (2R)-4-(-{5-chloro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide (33 mg, 95.35%). 1 H NMR(400MHz,DMSO-d6)δ8.44(d,1H),8.37(s,1H),7.79(s,1H),7.56(d,1H),7.44(s,1H),7.18(t,1H),6.88(t,1H),4.32-4.22(m,4H), 4.05-4.01(m,2H),3.47-3.40(m,1H),2.91(d,1H),2.74-2.66(m,1H),2.62-2.54(m,2H),2.40-2.32(m,1H),1.72(s,6H),0.99(d,3H). HPLC RT(B2)7.23min; LCMS MH + 469.

[0746] Example 2

[0747]

[0748] 1-{5-chloro-2-[(2S)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide

[0749] A solution of 1-(2,5-dichloropyrimidin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide (intermediate 1, 50 mg, 0.12 mmol) and [(3S)-1,3-dimethylpiperazine diTFA salt (211 mg, 0.61 mmol)] in n-butanol (0.7 mL) was treated with triethylamine (0.17 mL, 1.23 mmol) and then heated to 160 °C for 160 minutes under microwave irradiation. The reaction mixture was evaporated under reduced pressure and the crude product was purified by preparative TLC. The crude product was eluted with 9% MeOH in DCM solution to give a pale yellow solid 1-{5-chloro-2-[(2S)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide (27 mg, 45%). 1 HNMR(400MHz,DMSO-d6)δ8.41(d,1H),8.33(s,1H),7.77(s,1H),7.53(d,1H),7 .41(s,1H),7.16(dd,1H),6.85(t,1H),4.58(m,1H),4.15-4.20(m,3H),4.05(m 2H),3.41(t,1H),2.93(t,1H),2.73(m,1H),2.60(m,1H),2.14(s,3H),1.95(m,1H),1.74(m,1H),1.69(s,6H),1.09(d,3H). HPLC RT(B1)7.16min; LCMS MH + 483. HRMS measured value: 483.2384, calculated value: 483.288 (C 24 H 32 ClN8O).

[0750] Example 2A

[0751] 1-{5-chloro-2-[(2R)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide

[0752] Example 2A can be prepared from a suitable chloropyrimidine intermediate and a Boc-protected diamine using the method described in Example 2.

[0753] Example 3

[0754]

[0755] 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide

[0756] To a stirred MeOH solution (6 mL) of 1-{5-chloro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)azacyclobutane-3-carboxamide diTFA salt (Example 1, 800 mg, 1.15 mmol), HCHO solution (172 μL, 5.7 mmol of 37% H2O solution) was added, and the mixture was stirred at room temperature for 1 h. Then, NaCNBH3 (214 mg, 3.5 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 16 h.

[0757] The reaction mixture was terminated with sodium bicarbonate solution and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative TLC (6% MeOH in DCM solution) to give a white solid 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)azacyclobutane-3-carboxamide (320 mg, 58%). 1 H NMR(DMSO-d6)8.44(d,1H),8.36(s,1H),7.79(s,1H),7.56(d,1H),7.44(s,1H),7.19(dd,1H),4.15-4.25(m,4H),4.00-4.05 (p,2H),3.46(7,1H),2.92(t,1H),2.73(t,1H),2.50-2.55(m,1H),2.17(s,3H),1.90-2.00(m,2H),1.73(s,6H),0.99(d,3H). HPLC RT(A1)4.89min; LCMS MH + 483. HRMS measured value: 483.2387, calculated value: 483.288 (C 24 H 32 ClN8O).

[0758] Example 4

[0759]

[0760] 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyridin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide

[0761] A solution of 1-(2-chloro-5-fluoropyridin-4-yl)-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide (intermediate 2, 90 mg, 0.23 mmol), 1-methylpiperazine (69 mg, 0.69 mmol), and cesium carbonate (377 mg, 1.16 mmol) in dimethoxyethane (DME, 3 mL) was purified with argon for 10 min. Then, Pd₂(dba)₃ (42.6 mg, 0.046 mmol) and SPhOs (49.5 mg, 0.12 mmol) were added. After further purification with argon for 5 min, the mixture was heated to 120 °C for 16 h. The reaction mixture was extracted with EtOAc, washed with water and brine, dried over sodium sulfate, and evaporated under vacuum. The crude product was then purified by Combiflush chromatography and eluted with 3% MeOH in DCM solution to obtain a white solid 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyridin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide (30 mg, 29%).

[0762] 1 H NMR(400MHz,DMSO-d6)δ8.40(d,1H),8.32(s,1H),7.65(d,1H),7.53(d,1H),7.41(s,1H),7.17(dd,1H), 6.86(t,1H),5.65(d,1H),4.04(t,2H),3.48(t,1H),3.28(s,4H),2.31(m,4H),2.16(s,3H),1.70(s,6H). HPLC RT(A2)5.58min; LCMS MH + 452.

[0763] Examples 5-51 and 112 were prepared from a suitable chloropyrimidine intermediate and a Boc-protected diamine by the same method as described in Example 1.

[0764] surface

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778] Examples 52-80 were prepared from a suitable chloropyrimidine intermediate and a diamine using the same method as in Example 2.

[0779] Table 3

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788] Examples 81-102 were prepared from a suitable secondary amine intermediate and formaldehyde using the same method as in Example 3. Examples 103 and 104 were prepared by the method of Example 4 (Buchwald amine substitution on chloropyridine), followed by Boc deprotection (Example 1), and then by the reductive amination method of Example 3.

[0789] Table 4

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799] Examples 105-111 were prepared from a suitable chloropyridine or chloropyrimidine intermediate and a diamine using the same method as in Example 4.

[0800] Table 5

[0801]

[0802]

[0803]

[0804] HPLC methods of Examples 113 to 158:

[0805] Eclipse Extend or XDB 5μm C18 (150x 4.6mm), Xbridge 5μm C18 (100x 4.6mm), Zorbax Extend 5μm C18 (150x 4.6mm), or Shimadzu L Column 2ODS 5μm C18 (150x 4.6mm) columns were used for gradient elution with an aqueous solution of acetonitrile (ACN) containing 10mM ammonium acetate for 15 min (HPLC B), 17 min (B1), 21 min (B2), and 18 min (B3). Purity of some embodiments was determined by analytical HPLC using a Poroshell 120 2.7 μm EC18 (100 × 4.6 mm), Luna Omega Polar 3 μm C18 (100 × 4.6 mm), Xbridge 5 μm C18 (150 × 4.6 mm), or Sunfire 5 μm C18 (100 × 4.6 mm) column, with gradient elution using an aqueous solution of acetonitrile (ACN) containing 0.05% trifluoroacetic acid for 12 min (HPLC A), 14 min (A1), or 17 min (A2) and 16 min (A4). Purity of some other embodiments was determined by analytical HPLC using a Gemini NX 3 μm C18 (100 × 4.6 mm) column, with gradient elution using an aqueous solution of acetonitrile containing 0.05% formic acid for 12 min (A3), 14 min (A5), and 16 min (A6).

[0806] Example 113: Synthesis of N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)thieno[2,3-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide

[0807] Step 1

[0808]

[0809] Et3N (0.864 ml, 6.198 mmol) was added to a 5 ml solution of N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (TFA salt, 300 mg, 0.62 mmol) (the product of step 2 in Example 118) in 2-propanol at 0 °C. Then, 2,4-dichlorothiophene[2,3-d]pyrimidine (190.6 mg, 0.93 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by combiflash (12 g silica gel column) and eluted with 3% MeOH in DCM solution to give 1-(2-chlorothieno[2,3-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (200 mg, 75.58%). 1 H NMR(400MHz,DMSO-d6)δ8.48-8.45(m,2H),7.59-7.54(m,2H),7.45(s,1H),7.34(d,1H),7.22-7.18(m,1H),6.95-6.91(m,1 H),4.65-4.60(m,1H),4.45-4.29(m,2H),4.05-4.00(m,1H),3.60-3.57(m,1H),1.75(s,6H); LCMS(HCOOH:ACN):M+H=427,R t = 1.41 minutes, running time 3 minutes.

[0810] Step 2

[0811]

[0812] A solution of 1-(2-chlorothieno[2,3-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (100 mg, 0.235 mmol) and 1-methyl-1,4-diazacycloheptane (0.146 mL, 1.174 mmol) in n-BuOH (0.75 mL) was microwaved at 115 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC (6% MeOH-DCM) to give a white solid N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)thieno[2,3-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide (Example 113) (50 mg, 42.21%).

[0813] 1 H NMR(400MHz,MeOD)δ8.44(d,1H),7.55(d,1H),7.49(s,1H),7.30-7.26(m,1H ),7.03(d,1H),6.95-6.92(m,1H),6.83(d,1H),4.42-4.37(m,2H),4.23-4.20 (m,2H),3.87-3.85(m,2H),3.79-3.76(m,2H),3.62-3.60(m,1H),2.74-2.72 (m,2H),2.62-2.59(m,2H),2.37(s,3H),1.99-1.96(m,2H),1.84(s,6H); HPLC RT (Method A6) 3.80 min; LCMS (NH4OAc:ACN): M+H=505, Rt=2.59 min, run time 5 min.

[0814] Example 114: Synthesis of N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidin-4-yl)azacyclobutane-3-carboxamide - Step 1

[0815]

[0816] Et3N (0.864 ml, 6.198 mmol) was added to a 5 ml solution of N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (TFA salt, 300 mg, 0.62 mmol) (the product of step 2 in Example 118) in 2-propanol at 0 °C. Then, 2,4-dichloro-6,7-dihydro-5H-cyclopentadien[d]pyrimidine (175.723 mg, 0.93 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by combiflash (12 g silica gel column) and eluted with 3% MeOH in DCM solution to give 1-(2-chloro-6,7-dihydro-5H-cyclopentadien[d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (170 mg, 66.75%). 1 H NMR(400MHz,DMSO-d6)δ8.44(d,1H),8.37(s,1H),7.56(d,1H),7.45(s,1H),7.21(t,1H),6.91(t,1H),4.26-4.20(m,2H),4. 07-4.01(m,2H),3.50-3.45(m,1H),2.79(t,2H),2.65(t,2H),1.98-1.92(m,2H),1.73(s,6H); LCMS(HCOOH:ACN):M+H=411,R t = 1.34 minutes, running time 3 minutes.

[0817] Step 2

[0818]

[0819] A solution of 1-(2-chloro-6,7-dihydro-5H-cyclopentadien[d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (11) (100 mg, 0.244 mmol) and 1-methyl-1,4-diazacycloheptane (0.15 mL, 1.22 mmol) in n-BuOH (0.75 mL) was microwaved at 115 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC (6% MeOH-DCM) to give a white solid N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidin-4-yl)azacyclobutane-3-carboxamide (Example 114) (45 mg, 37.76%). 1 H NMR(400MHz,MeOD)δ8.42(d,1H),7.55(d,1H),7.49(s,1H),7.28(t,1H),6.9 3(t,1H),4.23-4.06(m,2H),4.05-4.03(m,2H),3.84-3.80(m,2H),3.74-3.71 (m,2H),3.52-3.49(m,1H),2.92-2.88(m,2H),2.81-2.78(m,2H),2.74-2.70 (m,2H),2.63-2.61(m,2H),2.51(s,3H),2.00-1.94(m,4H),1.82(s,6H); HPLC RT (Method B3) 7.39 min; LCMS (NH4OAc:ACN): M+H=489, Rt=2.06 min, run time 5 min.

[0820] Example 115: Synthesis of 1-(5-chloro-6-methyl-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide - Step 1

[0821]

[0822] Et3N (0.864 ml, 6.198 mmol) was added to a 5 ml solution of N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (TFA salt, 300 mg, 0.62 mmol) (the product of step 2 in Example 118) in 2-propanol at 0 °C. Then, 2,4,5-trichloro-6-methylpyrimidine (183.161 mg, 0.93 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by combiflash (12 g silica gel column) and eluted with 3% MeOH in DCM solution to give 1-(2,5-dichloro-6-methylpyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (200 mg, 76.95%). 1 H NMR(400MHz,DMSO-d6)δ8.44(d,1H),8.38(s,1H),7.56(d,1H),7.45(s,1H),7.20(t,1H),6.90(t, 1H),4.50-4.10(m,4H),3.48-3.42(m,1H),2.28(s,3H),1.73(s,6H); LCMS(HCOOH:ACN):M+H=419,R t = 1.67 minutes, running time 3 minutes.

[0823] Step 2

[0824]

[0825] A solution of 1-(2,5-dichloro-6-methylpyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (100 mg, 0.239 mmol) and 1-methyl-1,4-diazacycloheptane (7) (0.15 mL, 1.196 mmol) in n-BuOH (0.75 mL) was microwaved at 115 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC (6% MeOH-DCM) to give a white solid 1-(5-chloro-6-methyl-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (Example 115) (60 mg, 50.46%). 1H NMR(400MHz,MeOD)δ8.42(d,1H),7.55(d,1H),7.48(s,1H),7.27(t,1H),6.92(t,1H),4.29(t,2H),4.14(t,2H),3.76-3.73(m,2H),3 HPLC RT (Method B3) 7.41min;

[0826] LCMS(NH4OAc:ACN): M+H=497, Rt=2.95 minutes, running time 5 minutes.

[0827] Example 116: Synthesis of 1-(2-chloro-6-methylthieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide

[0828] Step 1

[0829]

[0830] Et3N (0.864 ml, 6.198 mmol) was added to a 5 ml solution of N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (TFA salt, 300 mg, 0.62 mmol) (the product of step 2 in Example 118) in 2-propanol at 0 °C. Then, 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (203.616 mg, 0.93 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by combiflash (12 g silica gel column) and eluted with 3% MeOH in DCM solution to give 1-(2-chloro-6-methylthieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (200 mg, 73.18%). 1HNMR(400MHz,DMSO-d6)δ8.49-8.47(m,2H),7.56(d,1H),7.45(s,1H),7.21(t,1H),7.08(s,1H), 6.93(t,1H),4.42-4.38(m,2H),4.17-4.13(m,2H),3.59-3.57(m,1H),2.59(s,3H),1.74(s,6H).

[0831] LCMS(HCOOH:ACN): M+H=441,R t = 1.42 minutes, running time 3 minutes.

[0832] Step 2

[0833]

[0834] A solution of 1-(2-chloro-6-methylthieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (100 mg, 0.227 mmol) and 1-methyl-1,4-diazacycloheptane (0.141 mL, 1.136 mmol) in n-BuOH (0.75 mL) was microwaved at 115 °C for 1 h. The reaction mixture was then... The mixture should be cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC (6% MeOH-DCM) to give a white solid N-(2-(imidazo[1,2-a]pyridin-3-yl)propyl-2-yl)-1-(6-methyl-2-(4-methyl-1,4-diazacycloheptane-1-yl)thieno[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide (Example 116) (50 mg, 42.42%). 1 H NMR(400MHz,DMSO-d6)δ8.46(d,1H),8.39(s,1H),7.55(d,1H),7.44(s,1 H),7.19(t,1H),6.89(t,1H),6.78(s,1H),4.25-4.20(m,2H),4.04-4.01( m,2H),3.76-3.72(m,2H),3.67-3.64(m,2H),3.56-3.52(m,1H),2.50-2. 48(m,4H),2.41(s,3H),2.23(s,3H),1.84-1.80(m,2H),1.73(s,6H); HPLC RT (Method A4) 5.04 min; LCMS (NH4OAc:ACN): M+H=519, Rt=2.62 min, run time 5 min.

[0835] Example 117: Synthesis of N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(6-methyl-2-(4-methyl-1,4-diazacycloheptane-1-yl)thieno[2,3-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide

[0836] Step 1

[0837]

[0838] Et3N (0.864 ml, 6.198 mmol) was added to a 5 ml solution of N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (TFA salt, 300 mg, 0.62 mmol) (the product of step 2 in Example 118) in 2-propanol at 0 °C. Then, 2,4-dichloro-6-methylthieno[2,3-d]pyrimidine (203.616 mg, 0.93 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by combiflash (12 g silica gel column) and eluted with 3% MeOH in DCM solution to give 1-(2-chloro-6-methylthieno[2,3-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (180 mg, 65.86%). 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 8.48–8.44 (m, 2H), 7.56 (d, 1H), 7.45 (s, 1H), 7.20 (t, 1H), 7.07 (s, 1H), 6.93 (t, 1H), 4.59–4.52 (m, 1H), 4.4–4.26 (m, 2H), 4.02–3.98 (m, 1H), 3.58–3.56 (m, 1H), 1.75 (s, 6H). (The three H atoms of the methyl group are buried in the 2.5 ppm peak of DMSO); LCMS (HCOOH:ACN): M+H=441, R t = 1.41 minutes, running time 3 minutes.

[0839] Step 2

[0840]

[0841] A solution of 1-(2-chloro-6-methylthieno[2,3-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (100 mg, 0.227 mmol) and 1-methyl-1,4-diazacycloheptane (0.141 mL, 1.136 mmol) in n-BuOH (0.75 mL) was microwaved at 115 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC (6% MeOH-DCM) to obtain a white solid N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(6-methyl-2-(4-methyl-1,4-diazacycloheptane-1-yl)thieno[2,3-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide (Example 117) (40 mg, 33.93%). 1 H NMR(400MHz,DMSO-d6)δ8.46(d,1H),8.39(s,1H),7.55(d,1H),7.44(s,1H), 7.18(t,1H),6.90(t,1H),6.74(s,1H),4.27(brs,2H),4.05(brs,2H),3.75- 3.72(m,2H),3.66-3.63(m,2H),3.55-3.51(m,1H),2.54-2.50(m,2H),2.44- 2.40(m,2H),2.36(s,3H),2.23(s,3H),1.83-1.79(m,2H),1.73(s,6H); HPLC RT (Method A6) 3.92 min; LCMS (NH4OAc:ACN): M+H=519, Rt=2.71 min, run time 5 min.

[0842] Example 118: Synthesis of N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)quinazolin-4-yl)azacyclobutane-3-carboxamide

[0843] Step 1

[0844]

[0845] Et3N (3.47 mL, 24.876 mmol) was added to a THF (30 mL) solution of 2-(imidazo[1,2-a]pyridin-3-yl)prop-2-amine (0.87 g, 4.975 mmol) and 1-(tert-butoxycarbonyl)azacyclobutane-3-carboxylic acid (1 g, 4.975 mmol). Then Et3N was added... (50%, 8.9 mL, 14.925 mmol) and stirred at room temperature for 16 h. The reaction mixture was terminated with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, purified by column chromatography, and eluted with 6% MeOH in DCM solution to give a off-white solid of tert-butyl 3-((2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)carbamoyl)azacyclobutane-1-carboxylate (1.4 g, 78.51%). LCMS (HCOOH:ACN): M+H=359, R t = 1.33 minutes, running time 3 minutes.

[0846] Step 2

[0847]

[0848] Trifluoroacetic acid (4.16 ml, 54.404 mmol) was added to a DCM (30 ml) solution of tert-butyl 3-((2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)carbamoyl)azacyclobutane-1-carboxylate (1.95 g, 5.44 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (2.6 g, 98.74%) as a TFA salt. 1 H NMR(400MHz,DMSO-d6)δ8.86(d,1H),8.82(brs,1H),8.73(s,1H),8.59(brs,1H),8.20(s,1H),8.03(d,1H),7.96(t,1 H),7.50(t,1H),3.99-3.94(m,2H),3.81-3.73(m,2H),3.64-3.58(m,1H),1.74(s,6H); LCMS(HCOOH:ACN):M+H=259,R t = 0.2 minutes, running time 3 minutes.

[0849] Step 3

[0850]

[0851] Et3N (0.864 mL, 6.198 mmol) was added to a 5 mL solution of N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (TFA salt, 300 mg, 0.62 mmol) in 2-propanol at 0 °C. Then 2,4-dichloroquinazoline (185 mg, 0.93 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by preparative TLC, eluting with 3% MeOH in DCM solution to give 1-(2-chloroquinazoline-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (100 mg, 38.33%). 1 H NMR(400MHz,DMSO-d6)δ8.50-8.48(m,2H),7.89(d,1H),7.78(t,1H),7.62-7.55(m,2H),7.4 8-7.45(m,2H),7.21(t,1H),6.93(t,1H),4.90-4.10(m,4H),3.63-3.60(m,1H),1.76(s,6H).

[0852] LCMS(HCOOH:ACN): M+H=421,R t = 1.45 minutes, running time 3 minutes.

[0853] Step 4

[0854]

[0855] A solution of 1-(2-chloroquinazoline-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (75 mg, 0.179 mmol) and 1-methyl-1,4-diazacycloheptane (0.111 mL, 0.893 mmol) in n-BuOH (0.75 mL) under stirring was microwave-treated at 115 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC (6% MeOH-DCM) to give a white solid N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)quinazoline-4-yl)azacyclobutane-3-carboxamide (Example 118) (30 mg, 33.7%). 1H NMR(400MHz DMSO-d6)δ8.47(d,1H),8.41(s,1H),7.61(d,1H),7.55(d,1H),7.47(d,1H), 7.44(s,1H),7.25(d,1H),7.21-7.17(m,1H),6.97(t,1H),6.90(t,1H),4.50- 4.46(m,2H),4.24-4.20(m,2H),3.82-3.79(m,2H),3.75-3.72(m,2H),3.60- 3.55(m,1H),2.62-2.60(m,2H),2.28(s,3H),1.87-1.86(m,2H),1.74(s,6H). (2H is buried in the 2.5ppm peak of DMSO); HPLC RT (Method A4) 4.86 min; LCMS (ACN:HCOOH): M+H=499, Rt=1.63 min, run time 5 min.

[0856] Example 119: Synthesis of 1-(5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide

[0857] Step 1

[0858]

[0859] A stirred solution of 1-(2,5-dichloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)propyl-2-yl)-N-methylazacyclobutane-3-carboxamide (intermediate 28) (100 mg, 0.235 mmol) and piperazine-1-carboxylic acid tert-butyl ester (245 mg, 1.315 mmol) in n-BuOH (1 mL) was microwave-irradiated at 130 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC (4% MeOH-DCM) to give 4-(5-chloro-4-(3-((2-(imidazo[1,2-a]pyridin-3-yl)propyl-2-yl)(methyl)carbamoyl)azacyclobutane-1-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (90 mg, 60.11%). 1H NMR(400MHz,DMSO-d6)δ8.23(d,1H),7.83(s,1H),7.54(d,1H),7.45(s,1H),7.18(t,1H),6.85(t,1H),4.45-4.28(m,2 H),4.27-4.10(m,2H),3.83-3.77(m,1H),3.60-3.58(m,4H),3.35-3.31(m,4H),2.80(s,3H),1.78(s,6H),1.41(s,9H).

[0860] Step 2

[0861]

[0862] A solution of tert-butyl piperazine-1-carboxylate (110 mg, 0.194 mmol) in DCM (2 mL) was treated with TFA (0.221 mL, 1.936 mmol). The reaction mixture was stirred at room temperature for 4 h. The crude product was dissolved in MeOH and loaded onto a plate. SCX column. The column was washed with MeOH. The compound was then eluted with NH3-MeOH and the collected fraction was concentrated under reduced pressure to give a creamy white viscous solid 1-(5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide (Example 119) (46 mg, 50.67%). 1 ¹H NMR (400MHz, MeOD) δ 8.23 ​​(d, 1H), 7.71 (s, 1H), 7.55 (d, 1H), 7.48 (s, 1H), 7.27 (t, 1H), 6.92 (t, 1H), 4.40 (brs, 2H), 4.27 (brs, 2H), 3.85–3.82 (m, 1H), 3.66–3.64 (m, 4H), 2.94 (s, 3H), 2.83–2.81 (m, 4H), 1.88 (s, 6H); HPLC RT (Method B3) 7.54 min; LCMS (NH₄OAc:ACN): M+H = 469, Rt = 2.13 min, run time 5 min.

[0863] Example 120: Synthesis of 1-(5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide

[0864] Step 1

[0865]

[0866] A solution of 1-(2,5-dichloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide (intermediate 28) (125 mg, 0.299 mmol) and tert-butyl 1,4-diazacycloheptane-1-carboxylate (178 mg, 1.495 mmol) in n-BuOH (2 mL) was microwaved at 130 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC (4% MeOH-DCM) to give tert-butyl 4-(5-chloro-4-(3-((2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)(methyl)carbamoyl)azacyclobutane-1-yl)pyrimidin-2-yl)-1,4-diazacycloheptane-1-carboxylate (80 mg, 45.89%). 1 H NMR(400MHz,DMSO-d6)δ8.22(brs,1H),7.80(s,1H),7.55(d,1H),7.45(s,1H),7.18(t,1H),6.85(t,1H),4.40-4.25(m,2H),4.24-4.10(m,2H),3. 81-3.79(m,1H),3.70-3.68(m,2H),3.60-3.57(m,2H),3.48-3.35(m,2H) ,3.25-3.20(m,2H),2.80(brs,3H),1.78-1.59(m,8H),1.33-1.26(m,9H).

[0867] Step 2

[0868]

[0869] A solution of tert-butyl 4-(5-chloro-4-(3-((2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)(methyl)carbamoyl)azacyclobutan-1-yl)pyrimidin-2-yl)-1,4-diazacycloheptane-1-carboxylate (85 mg, 0.146 mmol) in DCM (2 mL) was treated with TFA (0.166 mL, 1.457 mmol). The reaction mixture was stirred at room temperature for 4 h. The crude product was dissolved in MeOH and loaded onto... SCX column. The column was washed with MeOH. The compound was then eluted with NH3-MeOH and the collected fraction was concentrated under reduced pressure to give a creamy white viscous solid 1-(5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide (Example 120) (30 mg, 42.62%).

[0870] 1 ¹H NMR (400MHz, MeOD) δ 8.23 ​​(d, 1H), 7.69 (s, 1H), 7.56 (d, 1H), 7.49 (s, 1H), 7.27 (t, 1H), 6.92 (t, 1H), 4.39 (brs, 2H), 4.26–4.20 (m, 2H), 3.84–3.80 (m, 1H), 3.73–3.69 (m, 4H), 2.97–2.93 (m, 5H), 2.82–2.79 (m, 2H), 1.88 (m, 8H); HPLC RT (Method B3) 7.59 min; LCMS (NH₄OAc:ACN): M+H = 483, Rt = 2.17 min, run time 5 min.

[0871] Example 121: Synthesis of 1-(5-chloro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide

[0872]

[0873] A solution of 1-(2,5-dichloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide (intermediate 28) (60 mg, 0.144 mmol) and 1-methyl-1,4-diazacycloheptane (82 mg, 0.718 mmol) in n-BuOH (1 mL) was microwaved at 130 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC (4% MeOH-DCM) to give 1-(5-chloro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide (Example 121) (32 mg, 44.88%). 1H NMR(400MHz,MeOD)δ8.23(d,1H),7.69(s,1H),7.55(d,1H),7.49(s,1H),7.27(t,1H),6.93(t,1H),4.39(brs,2H),4.26-4.25(m,2H),3. HPLC RT (Method A4) 4.70 min; LCMS (NH4OAc:ACN): M+H=497, Rt=2.65 min, run time 5 min.

[0874] Synthesis of Example 122: N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methyl-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)thieno[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide

[0875] Step 1

[0876]

[0877] NaH (60%, 74 mg, 1.852 mmol) was added to a DMF (5 ml) solution of 1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (500 mg, 1.235 mmol) (the product of step 1 in Example 123) under stirring at 0 °C, and the mixture was stirred for 30 minutes. Then, iodomethane (210 mg, 1.481 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then terminated with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by combiflash column chromatography (12 g silica gel column) and eluted with DCM solution of MeOH to give 1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide (400 mg, 73.31%). 1¹H NMR (400MHz, DMSO-d⁶) δ 8.30–8.27 (m, 2H), 7.55 (d, 1H), 7.46 (s, 1H), 7.36 (d, 1H), 7.18 (t, 1H), 6.86 (t, 1H), 4.51–4.10 (m, 4H), 3.96–3.94 (m, 1H), 2.79 (s, 3H), 1.80 (s, 6H); LCMS (HCOOH:ACN): M+H = 441, Rt = 1.42 minutes, run time 3 minutes.

[0878] Step 2

[0879]

[0880] The mixture of 1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide (100 mg, 0.227 mmol) and 1-methyl-1,4-diazacycloheptane (0.128 mL, 1.136 mmol) in an n-BuOH solution (1 mL) was microwaved at 130 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC (4% MeOH-DCM) to give N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methyl-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)thieno[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide (Example 122) (52 mg, 44.15%). 1 H NMR(400MHz,DMSO-d6)δ8.25(d,1H),7.93(d,1H),7.54(d,1H),7.45(s,1H) ,7.17(t,1H),7.06(d,1H),6.84(t,1H),4.34(brs,2H),4.17(brs,2H),3.9 1(brs,1H),3.80-3.76(m,2H),3.72-3.68(m,2H),2.83(s,3H),2.58-2.56( m,2H),2.45-2.43(m,2H),2.24(s,3H),1.86-1.82(m,2H),1.79(s,6H); HPLC RT (Method B3) 7.59 min; LCMS (NH4OAc:ACN): M+H=519, Rt=2.57 min, run time 5 min.

[0881] Example 123: Synthesis of 1-(2-(1,4-diazacycloheptane-1-yl)thieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide

[0882] Step 1

[0883]

[0884] Et3N (3 ml, 21.505 mmol) was added to a 10 ml solution of N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (TFA salt, 800 mg, 2.151 mmol) (the product of step 2 in Example 118) in 2-propanol at 0 °C. Then, 2,4-dichlorothieno[3,2-d]pyrimidine (658 mg, 3.226 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by combiflash (12 g silica gel column) and eluted with 3% MeOH in DCM solution to give 1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (400 mg, 43.57%). 1 H NMR(400MHz,DMSO-d6)δ8.54(d,1H),8.51(s,1H),8.26(d,1H),7.62(d,1H),7.55(s,1H),7.35(d,1H),7. 30(t,1H),7.00(t,1H),4.55-4.05(m,4H),3.62-3.58(m,1H),1.75(s,6H); LCMS(HCOOH:ACN):M+H=427,R t = 1.37 minutes, running time 3 minutes.

[0885] Step 2

[0886]

[0887] A solution of 1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (100 mg, 0.235 mmol) and tert-butyl 1,4-diazacycloheptane-1-carboxylate (0.231 mL, 1.174 mmol) in n-BuOH (1 mL) was microwaved at 130 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC (4% MeOH-DCM) to give tert-butyl 4-(4-(3-((2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)carbamoyl)azacyclobutane-1-yl)thieno[3,2-d]pyrimidin-2-yl)-1,4-diazacycloheptane-1-carboxylate (60 mg, 43.27%). LCMS (HCOOH:ACN): M+H=591, R t = 1.43 minutes, running time 3 minutes.

[0888] Step 3

[0889]

[0890] A solution of tert-butyl 4-(4-(3-((2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)carbamoyl)azacyclobutane-1-yl)thieno[3,2-d]pyrimidin-2-yl)-1,4-diazacycloheptane-1-carboxylate (90 mg, 0.152 mmol) in DCM (1 mL) was treated with TFA (0.117 mL, 1.525 mmol). The reaction mixture was stirred at room temperature for 4 h. The crude product was dissolved in MeOH and loaded onto... SCX column. The column was washed with MeOH. The compound was then eluted with NH3-MeOH and the collected fraction was concentrated under reduced pressure to give a creamy white solid 1-(2-(1,4-diazacycloheptane-1-yl)thieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide (Example 123) (20 mg, 26.74%). 1H NMR(400MHz,MeOD)δ8.45(d,1H),7.76(d,1H),7.55(d,1H),7.49(s,1H),7.28(t,1H),7.07(d,1H),6.94(t,1H),4.39(t HPLC RT (Method A4) 4.68min; LCMS (CF3COOH:ACN): M+H=491, R t = 4.06 min, running time 10 minutes.

[0891] Example 124: Synthesis of (R)-1-(5-chloro-2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide

[0892] Step 1

[0893]

[0894] A solution of 1-(2,5-dichloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide (150 mg, 0.358 mmol) (intermediate 28) and (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (357.995 mg, 1.79 mmol) in n-BuOH (2 mL) was microwaved at 130 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC, eluting with 4% MeOH in DCM solution to give a white solid (R)-4-(5-chloro-4-(3-((2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)(methyl)carbamoyl)azacyclobutan-1-yl)pyrimidin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (60 mg, 28.74%). LCMS (HCOOH:ACN): M+H=583, Rt=1.57 min, run time 3 min.

[0895] Step 2

[0896]

[0897] Trifluoroacetic acid (0.118 ml, 1.546 mmol) was added to a solution of (R)-4-(5-chloro-4-(3-((2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)(methyl)carbamoyl)azacyclobutan-1-yl)pyrimidin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.155 mmol) in DCM (2 ml) and stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in MeOH and loaded onto a plate. SCX column. The column was washed with MeOH. The compound was then eluted with NH3-MeOH and the collected fraction was concentrated under reduced pressure to give a white solid (R)-1-(5-chloro-2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide (Example 124) (35 mg, 46.88%). 1 ¹H NMR (400MHz, DMSO-d6) δ 8.20 (bs, 1H), 7.77 (s, 1H), 7.52 (d, 1H), 7.42 (s, 1H), 7.16 (t, 1H), 6.82 (t, 1H), 4.38–4.08 (m, 6H), 3.79–3.71 (m, 1H), 2.88–2.52 (m, 7H), 2.36–2.32 (m, 1H), 1.76 (s, 6H), 0.95 (d, 3H); HPLC RT (Method A6) 3.90 min; LCMS (HCOOH:ACN): M+H=483, Rt=1.61 min, run time 12 min.

[0898] Example 125: Synthesis of (S)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methyl-1-(2-(2-methylpiperazin-1-yl)thieno[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide

[0899] Step 1

[0900]

[0901] Cs₂CO₃ (553.977 mg, 1.705 mmol) was added to a DME (2 ml) solution of 1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide (the product of step 1 in Example 122) (150 mg, 0.341 mmol) and (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (340.909 mg, 1.705 mmol). The reaction mixture was degassed with argon for 10 min, and then Pd₂(dba)₃ (62.436 mg, 0.068 mmol) and S-Phos (62.436 mg, 0.17 mmol) were added and degassed again for about 5 min. The reaction mixture was then microwaved at 120 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative TLC, eluting with 4% MeOH in DCM solution to give a white solid (S)-4-(4-(3-((2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)(methyl)carbamoyl)azacyclobutane-1-yl)thieno[3,2-d]pyrimidin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (80 mg, 38.8%). LCMS (NH4OAc:ACN): M+H=605, Rt=3.44 min, run time 5 min.

[0902] Step 2

[0903]

[0904] ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: n1 is 1 or 2; n2 is 1 or 2; X 1 Selected from CR x and N; When it exists, R x Selected from hydrogen, halogens, and -C atoms optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, -OCH3 and -OCF3; R 1 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogens, -CH3, -OCH3, and -OCF3; R 2 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogens, -CH3, -OCH3, and -OCF3; Or R 1 and R 2 They connect together to form C along with the atoms they are connected to. 3-6 Cycloalkyl or a 3- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 3 to 6-membered non-aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogen, -OH, -CH3, -OCH3 and -OCF3; R 3 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -OH, -CH3, -OCH3 and -OCF3; Or R 1 and R 3 These atoms are linked together to form a 3- to 6-membered nonaromatic heterocyclic group containing one N heteroatom, wherein the 3- to 6-membered nonaromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens, -CH3, -OH, -OCH3, and -OCF3; X 2 Selected from CR 4 and N; When it exists, R 4 Selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl groups, each substituent independently selected from halogens, -OH, -OCH3, -OCF3, and -NR. a R b ; R 5a and R 5d The methyl group is independently selected from hydrogen; halogen; methyl group optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3; and methoxy group optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3; R 5b and R 5c Independently selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3; Or R 5b and R 5c They are linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from S, O and N, wherein the 6-membered aryl group or the 5- or 6-membered aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3. R 6 Selected from hydrogen and methyl; When they exist, each R 7 -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, -OCH3 and -OCF3; R 8 Selected from hydrogen; halogen; -OH; -CN; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; -C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -CH3, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; -C groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkenyl group, each substituent independently selected from halogen, -OH, -CN, and methoxy group optionally substituted with 1, 2, or 3 halogens; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, CN and methoxy group optionally substituted with 1, 2 or 3 halogens; R 9 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; or R 8 and R 9 They connect together to form 6-membered aryl groups and C atoms together with the atoms they are attached to. 5-6 Cycloalkyl or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N, O, and S, wherein the 6-membered aryl group, C 5-6 The cycloalkyl or 5- to 6-membered aromatic heterocyclic group is optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens; -OH; -CN; -C optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent being independently selected from -halogen, -OH and methoxy group optionally substituted with 1, 2 or 3 halogens; p is 0, 1, or 2; Z is a 5- to 13-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein the 5- to 13-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents, each substituent being independently selected from halogens; -C optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl group; -OC group optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; NR c R d ; and C substituted with one, two or three substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -OH, and -OC optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; or when two substituents are in adjacent ring positions, they can be linked together to form a C1 ring with the atoms to which they are linked. 3-6 Cycloalkyl or a 4- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 4- to 6-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C group is optionally substituted with one, two, or three substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl; R c and R d Independently selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and C4 groups optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3, and -OCF3; or Z is -NR. 10 R 11 ,in R 10 Selected from hydrogen and -C 1-4 Alkyl; and R 11 It is a 5- to 10-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 10-membered non-aromatic heterocyclic group is optionally substituted by 1, 2, 3, or 4 substituents, said substituents being independently selected from halogens; -OH; -C optionally substituted by 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; and When they exist, each R a and R b Independently selected from hydrogen and -C 1-4 alkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof: in: n1 is 1 or 2; n2 is 1 or 2; X 1 Selected from CR x and N; When it exists, R x Selected from hydrogen, halogens, and -C atoms optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, -OCH3 and -OCF3; R 1 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogens, -CH3, -OCH3, and -OCF3; R 2 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogens, -CH3, -OCH3, and -OCF3; Or R 1 and R 2 They connect together to form C along with the atoms they are connected to. 3-6 Cycloalkyl or a 3- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 3 to 6-membered non-aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogen, -OH, -CH3, -OCH3 and -OCF3; R 3 Selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and -C optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -OH, -CH3, -OCH3 and -OCF3; Or R 1 and R 3 They are linked together to form a 3 to 6 membered nonaromatic heterocyclic group containing one N heteroatom, wherein the 3 to 6 membered nonaromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3; X 2 Selected from CR 4 and N; When it exists, R 4 Selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3 and -OCF3; and -NR a R b ; R 5a and R 5d The methyl group is independently selected from hydrogen; halogen; methyl group optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3; and methoxy group optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3; R 5b and R 5c Independently selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; and C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3; Or R 5b and R 5c They are linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from S, O and N, wherein the 6-membered aryl group or the 5- or 6-membered aromatic heterocyclic group is optionally substituted by one or two substituents, each substituent being independently selected from halogen, -OH, -OCH3 and -OCF3. R 6 Selected from hydrogen and methyl; When they exist, each R 7 -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, -OCH3 and -OCF3; R 8 Selected from hydrogen; halogen; -OH; -CN; -C optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; -C group optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -CH3, -OH, -CN, and methoxy groups optionally substituted with 1, 2, or 3 halogens; -C groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkenyl group, each substituent independently selected from halogen, -OH, -CN, and methoxy group optionally substituted with 1, 2, or 3 halogens; and -OC group optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OH, CN and methoxy group optionally substituted with 1, 2 or 3 halogens; R 9 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-4 Alkyl group, each substituent independently selected from halogen, -OH, -OCH3, and -OCF3; or R 8 and R 9 These groups are linked together to form a 6-membered aryl group or a 5- or 6-membered aromatic heterocyclic group containing one or two heteroatoms selected from N, O, and S, wherein the 6-membered aryl group or the 5- or 6-membered aromatic heterocyclic group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens; -OH; -CN; -C optionally substituted with one, two, or three substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OH, and methoxy groups optionally substituted with 1, 2, or 3 halogens; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-4 Alkyl group, each substituent being independently selected from -halogen, -OH and methoxy group optionally substituted with 1, 2 or 3 halogens; p is 0, 1, or 2; Z is a 5- to 13-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein the 5- to 10-membered non-aromatic heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents, each substituent being independently selected from halogens; -C optionally substituted with 1, 2, or 3 substituents 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; or Z is -NR 10 R 11 ,in R 10 Selected from hydrogen and -C 1-4 Alkyl; and R 11 It is a 5- to 10-membered non-aromatic heterocyclic group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N, and wherein said 5- to 10-membered non-aromatic heterocyclic group is optionally substituted by 1, 2, 3, or 4 substituents, said substituents being independently selected from halogens; -OH; -C optionally substituted by 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; and When they exist, each R a and R b Independently selected from hydrogen and -C 1-4 alkyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is an optionally substituted 5- to 8-membered non-aromatic heterocyclic group.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is: in Indicates the connection point; m is 0, 1, 2, or 3; r is 0, 1, 2, or 3; s is 0, 1, or 2; R 12 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-6 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 Alkyl; and When they exist, each R 13 Independently selected from halogens; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; NR c R d ; and C substituted with one, two or three substituents. 3-6 Cycloalkyl, each substituent independently selected from halogens, -OH, and -OC optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; or when two substituents are in adjacent ring positions, they are linked together to form a C1 ring with the atoms to which they are attached. 3-6 Cycloalkyl or a 4- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 4- to 6-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C group is optionally substituted with one, two, or three substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl; R c and R d Independently selected from hydrogen; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and C4 groups optionally substituted with 1, 2, or 3 substituents. 3-6 Cycloalkyl, with each substituent independently selected from halogen, -CH3, -OH, -OCH3 and -OCF3; Alternatively, when m is 0 or 1, r is 2 or 3, and both R's are 0 or 1. 13 When in adjacent ring positions, the two R 13 They connect together to form C along with the atoms they are connected to. 3-6 Cycloalkyl or a 4- to 6-membered nonaromatic heterocyclic group comprising one heteroatom selected from O and N, wherein the C 3-6 The cycloalkyl or 4- to 6-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C group is optionally substituted with one, two, or three substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl; Or, when r is 1, 2, or 3 and an R 13 Groups in relation to NR 12 When in adjacent ring positions, the R 13 and R 12 These atoms are linked together to form a 5- or 6-membered non-aromatic heterocyclic group comprising one N heteroatom and optionally one heteroatom selected from O and N, wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with one or two substituents, each substituent being independently selected from halogens; the -C atoms are optionally substituted with one, two, or three substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; and When they exist, each R 14 Independently selected from halogens; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2; r is 0, 1, or 2; s is 0, 1, or 2; R 12 Selected from hydrogen and -C which are optionally substituted with 1, 2 or 3 substituents 1-6 Alkyl groups, each substituent independently selected from halogens and optionally substituted with 1, 2, or 3 halogens, are -OC groups. 1-3 alkyl; When they exist, each R 13 Independently selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl; and When they exist, each R 14 Independently selected from hydrogen; halogen; -C optionally substituted with 1, 2 or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 Alkyl groups; and -OC groups optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl group, each substituent independently selected from halogens, -OH, and -OC, optionally substituted with 1, 2, or 3 halogens. 1-3 alkyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is selected from: in Indicates the connection point.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent independently selected from halogens, -OCH3, and -OCF3; and R 2 -C is optionally substituted with 1, 2 or 3 substituents. 1-4 Alkyl group, each substituent is independently selected from halogen, -OCH3 and -OCF3; And appropriately, where R 1 It is methyl and R 2 It is a methyl group.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from hydrogen, halogen, methyl, CF3, methoxy and OCF3.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n1 is 1 and n2 is 1.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 2 It is CR 4 R 4 Selected from hydrogen and methyl groups optionally substituted with 1, 2, or 3 F atoms, and X 1 It is N.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5a R 5b R 5c R 5d R 3 R 6 and R 9 Both are hydrogen; and p is 0.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 1-{5-chloro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyridin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-(5-chloro-2-{3,6-diazabicyclo[3.2.0]hept-3-yl}pyrimidin-4-yl)-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-(2-{3,6-diazabicyclo[3.2.0]hept-3-yl}-5-fluoropyrimidin-4-yl)-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)zacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide; 1-(2-{3,6-diazabicyclo[3.2.0]hept-3-yl}-5-fluoropyrimidin-4-yl)-N-({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[methyl(pyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(pyrrolidone-3-ylamino)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}-N-methylazacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-methoxypyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-methoxypyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)zacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-({6-fluoroimidozop[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-({6-chloroimidazolo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-methoxypyrimidin-4-yl]-N-(1-{2-methylimidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(1-{2-methylimidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methoxy-2-(piperazin-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[methyl(pyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[methyl(pyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-methoxypyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-chloropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide 1-{2-[(3S,5S)-3,5-dimethylpiperazin-1-yl]-5-methoxypyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3S,5S)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S)-2-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide 1-[5-fluoro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[methyl(1-methylpyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[methyl(1-methylpyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{8-fluoroimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methoxy-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methoxy-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-3-methylazacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2R)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[3-(fluoromethyl)-4-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-ethylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[4-(propyl-2-yl)piperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[4-(2-methoxyethyl)piperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)-N-methylazacyclobutane-3-carboxamide; (3R)-1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; (3S)-1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)piperidin-4-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S,3R)-2,3-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[3-(methoxymethyl)-4-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-(5-fluoro-2-{6-methyl-3,6-diazabicyclo[3.2.0]hept-3-yl}pyrimidin-4-yl)-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-{2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3S)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-methoxypyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-3-methylazacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; (3R)-1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; (3S)-1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)piperidin-4-carboxamide; 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyridin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyridin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyridin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}-N-methylazacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-{2-[(2S)-2,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)quinazolin-4-yl)azacyclobutane-3-carboxamide; N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)thienozo[2,3-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide; N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidin-4-yl)azacyclobutane-3-carboxamide; 1-(5-chloro-6-methyl-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(6-methyl-2-(4-methyl-1,4-diazacycloheptane-1-yl)thienozo[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide; N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(6-methyl-2-(4-methyl-1,4-diazacycloheptane-1-yl)thienozo[2,3-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide; 1-(2-(1,4-diazacycloheptane-1-yl)thieno[3,2-d]pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; 1-(5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-(5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-(5-chloro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methyl-1-(2-(4-methyl-1,4-diazacycloheptane-1-yl)thieno[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide; (R)-1-(5-chloro-2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; (S)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methyl-1-(2-(2-methylpiperazin-1-yl)thieno[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide; (S)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-1-(2-(2-methylpiperazin-1-yl)thieno[3,2-d]pyrimidin-4-yl)azacyclobutane-3-carboxamide; 1-(5-chloro-2-(3,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-(2-(4-aminopiperidin-1-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-(5-chloro-2-(4,7-diazaspiro[2.5]oct-7-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-(2-(4-aminoazacycloheptan-1-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-(2-(2,5-diazabicyclo[2.2.1]hept-2-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-(2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-(5-chloro-2-(2,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; (S)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methyl-1-(2-(2-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidin-4-yl)azacyclobutane-3-carboxamide; 1-(5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl)-N-ethyl-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; 1-(5-chloro-2-(3-ethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; (R)-1-(5-chloro-2-(2-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; (R)-1-(5-chloro-2-(2,4-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; (S)-1-(5-chloro-2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; (S)-1-(5-chloro-2-(3,4-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; (R)-1-(5-chloro-2-(2-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; 1-(5-chloro-2-(2,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; (S)-1-(5-chloro-2-(2-methylpiperazin-1-yl)pyrimidin-4-yl)-N-ethyl-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; 1-(2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; 1-(2-(2,5-diazabicyclo[4.1.0]hept-2-yl)-5-chloropyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; (S)-1-(5-chloro-2-(2-methylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; (S)-1-(5-chloro-2-(2-ethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; (S)-1-(5-chloro-2-(2-ethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide: 1-(5-chloro-2-(2,2-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-(5-chloro-2-(4,7-diazaspiro[2.5]oct-4-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-(5-chloro-2-((2S,5S)-2,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; 1-(5-chloro-2-((2S,5S)-2,4,5-trimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; 1-(5-chloro-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; and 1-(5-chloro-2-((2S,5R)-2,4,5-trimethylpiperazin-1-yl)pyrimidin-4-yl)-N-(2-(imidazo[1,2-a]pyridin-3-yl)prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2R)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyridin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-(5-chloro-2-{3,6-diazabicyclo[3.2.0]hept-3-yl}pyrimidin-4-yl)-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-(2-{3,6-diazabicyclo[3.2.0]hept-3-yl}-5-fluoropyrimidin-4-yl)-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)zacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-fluoropyrimidin-4-yl]-N-({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide; 1-(2-{3,6-diazabicyclo[3.2.0]hept-3-yl}-5-fluoropyrimidin-4-yl)-N-({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[methyl(pyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(pyrrolidone-3-ylamino)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}-N-methylazacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-methoxypyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-methoxypyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)zacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-({6-fluoroimidozop[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-({6-chloroimidazolo[1,2-a]pyridin-3-yl}methyl)azacyclobutane-3-carboxamide; 1-[2-(1,4-diazacycloheptane-1-yl)-5-methoxypyrimidin-4-yl]-N-(1-{2-methylimidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(1-{2-methylimidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methoxy-2-(piperazin-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[methyl(pyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[methyl(pyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-methoxypyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-chloropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3S,5S)-3,5-dimethylpiperazin-1-yl]-5-methoxypyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3S,5S)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3S,5S)-3,5-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3S,5S)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2R)-2-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(1-{imidazo[1,2-a]pyridin-3-yl}ethyl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[methyl(1-methylpyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[methyl(1-methylpyrrolidin-3-yl)amino]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{8-fluoroimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methoxy-2-(4-methyl-1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methoxy-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-3-methylazacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-[5-methyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[3-(fluoromethyl)-4-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-ethylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[4-(propyl-2-yl)piperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[4-(2-methoxyethyl)piperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)-N-methylazacyclobutane-3-carboxamide; (3R)-1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; (3S)-1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)piperidin-4-carboxamide; 1-[5-fluoro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S,3R)-2,3-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[3-(methoxymethyl)-4-methylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-(5-fluoro-2-{6-methyl-3,6-diazabicyclo[3.2.0]hept-3-yl}pyrimidin-4-yl)-N-{imidazo[1,2-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; 1-{2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3S)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-methoxypyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; 1-{2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-3-methylazacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-1-{5-methoxy-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{6-methylimidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; (3R)-1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; (3S)-1-{5-chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)pyrrolidine-3-carboxamide; 1-{5-chloro-2-[(3S)-3,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}propyl-2-yl)piperidin-4-carboxamide; 1-{2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-{5-chloro-2-[(3S)-3,4-dimethylpiperazin-1-yl]pyridin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-fluoropyridin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-[5-chloro-2-(4-methylpiperazin-1-yl)pyridin-4-yl]-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-{imidazo[1,2-a]pyridin-3-ylmethyl}-N-methylazacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S)-2,4-dimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-{2-[(2S)-2,4-dimethylpiperazin-1-yl]-5-fluoropyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)-N-methylazacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-chloro-2-[(2S,5S)-2,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; 1-{5-fluoro-2-[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl}-N-(2-{imidazo[1,2-a]pyridin-3-yl}prop-2-yl)azacyclobutane-3-carboxamide; and 1-[5-chloro-2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-N-{[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl}azacyclobutane-3-carboxamide; Or any of its pharmaceutically acceptable salts.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically suitable carrier; and optionally further comprising an additional therapeutic agent.

14. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, used as a medicine.

15. Use of the compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 13 in the preparation of a medicament for the treatment or prevention of cancer.

16. The use according to claim 15, wherein the cancer is selected from: (i) hematologic malignancies selected from lymphoma, leukemia and myeloma, and (ii) solid tumors selected from brain cancer, lung cancer, breast cancer, prostate cancer, ovarian cancer, colorectal cancer, gallbladder cancer, kidney cancer or liver cancer and blastoma.

17. Selected from the following compounds: Compound of formula (II) Where Q is a nitrogen protecting group, and R 1 R 2 R 3 R 5a R 5b R 5c R 5d R 6 R 7 R 8 R 9 X 1 X 2 m, p, r, n1, n2 and R 13 As defined with respect to compounds of formula (I); Compound of formula (V) Where D is a halogen, and R 1 R 2 R 3 R 5a R 5b R 5c R 5d R 6 R 7 R 8 R 9 X 1 X 2 p, n1, and n2 are as defined with respect to compounds of formula (I); and Compound of formula (X) Where X 2 It is CH and R 1 R 2 R 3 R 5a R 5b R 5c R 5d R 6 R 7 p, n1, and n2 are as defined with respect to compounds of formula (I); or n1 and n2 are both 1 and R 1 R 2 R 3 R 5a R 5b R 5c R 5d R 6 R 7 p and X 2 As defined with respect to compounds of formula (I); or A salt of any compound.

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