DNA polymerase theta inhibitors

Abstract

The present invention relates to compounds of Formula I and pharmaceutically salts thereof, wherein ring A, R1, R2, R3, integer a, integer b, X4, X5, X6 and X7 are each as defined herein. The compounds of the present invention inhibit Pol [theta]. Thus, the novel therapeutic compounds are useful in the treatment and / or prevention of diseases and conditions associated with Pol [theta] activity, such as, but not limited to, the treatment and / or prevention of cancer. The invention also relates to pharmaceutical compositions comprising the novel therapeutic compounds as defined herein, methods of synthesizing these compounds and their use for treating diseases and / or conditions associated with Pol [theta] activity.

Description

TECHNICAL FIELD

[0001] The present invention relates to novel therapeutic compounds. More specifically, the present invention relates to novel therapeutic compounds that inhibit Pol theta. Thus, the novel therapeutic compounds can be used for the treatment and / or prevention of diseases and conditions associated with Pol theta activity, such as, but not limited to, the treatment and / or prevention of cancer. The present invention also relates to pharmaceutical compositions comprising the novel therapeutic compounds as defined herein, methods of synthesizing these compounds, and their use for the treatment of diseases and / or conditions associated with Pol theta activity. BACKGROUND

[0002] Maintaining the integrity of the genome is crucial for cell survival, as genomic aberrations are a major cause of disease, especially cancer 1 . The genome is constantly challenged by various types of DNA damage, of which double-strand breaks (DSBs) are considered the most toxic, as they cause drastic genomic rearrangements if not repaired or repaired inaccurately 2 .

[0003] DNA polymerase theta (Pol theta, encoded by POLQ) is a multifunctional enzyme, comprising a C-terminal DNA polymerase domain, an N-terminal ATPase / helicase domain, and a low-structured central domain with protein interaction partner binding functions 3 . Both enzyme functions were shown to be mechanistically active in DNA repair processes. The helicase domain disrupts Rad51 nucleofilament formation, removes RPA from single-stranded DNA and stimulates ssDNA annealing. The polymerase domain extends single-stranded DNA ends to close ssDNA gaps.

[0004] Pol theta is essentially not expressed in normal cells, but is upregulated in various cancers, with increased expression correlating with poor prognosis 4,5,6 . In normal mammalian cells, homologous recombination (HR) and non-homologous end joining (NHEJ) are the two main pathways for accurate repair of DSBs. Other alternative pathways, dubbed alternative NHEJ (ALT-NHEJ), are also involved in DSB repair, mainly as a back-up pathway in the absence of HR and NHEJ 7,4,8 . The most characteristic ALT-NHEJ pathway is microhomology-mediated end joining (MMEJ), which relies on microhomologies flanking the break to repair the lesion. In doing so, MMEJ inherently causes deletions, thus leading to genomic instability 9,10 . Pol theta is an important player in MMEJ, which has been shown to process and anneal single-stranded DNA ends, as well as to synthesize DNA to complete repair 11, 12, 13 .

[0005] DNA damage response (DDR) defects, such as the loss of HR, lead to genomic instability and are often associated with cancer. However, DDR-deficient cancers can become critically dependent on backup DNA repair pathways, a lethal vulnerability that can be targeted to eliminate cancer cells. For example, PARP1 inhibitors are selectively lethal in cancer cells lacking components of HR (e.g. ATM, BARD1, PALB2, BRCA1, BRCA2, etc.) 14 .

[0006] Likewise, in the absence of HR and NHEJ, selective lethality is observed when PolQ function is ablated. When HR and NHEJ are available, MMEJ is rarely used 15 , but when the canonical pathways are impaired during oncogenic processes, MMEJ becomes necessary, rendering these cancer cells particularly dependent on PolQ 4,16 .

[0007] PARP inhibitors are used to treat HR-deficient cancers, but their intrinsic or acquired resistance is a major limitation. The two most common resistance mechanisms to PARPi can be counteracted by inhibiting PolQ:

[0008] (i) The primary resistance mechanism observed in clinical samples is the reactivation of HR by back-mutation of the mutations that caused the HR deficiency 17 . A significant fraction of this back-mutated is believed to be acquired through the action of PolQ in MMEJ 18,19 .

[0009] (ii) Restoring HR activity in BRCA1-deficient cancers by loss of the SHLD / 53BP1 complex has been shown to cause PARP inhibitor resistance 20,21,22,23 . PolQ inhibitors are expected to be useful in the treatment of such tumors 24 , and defects in both the SHLD / 53BP1 complex and BRCA1 were shown to cause vulnerability to PolQ inhibition 25,26 .

[0010] In addition to the synthetic lethality observed in HR- and NHEJ-deficient cancers, PolQ loss was reported to sensitize cancer cells to many standard-of-care agents. Depletion of PolQ leads to potentiation of various chemotherapeutics, such as topoisomerase 1 / 2 inhibitors 27 hydroxyurea, platinum agents 28 , bleomycin, and radiotherapy 29,30 . Moreover, PolQ loss also showed an enhanced effect of DNA repair targeting inhibitors: for example, PARP 31 , ATM 27 , ATR 32 , and DNAPK32 .

[0011] Given the wealth of evidence for sensitization to DNA repair related therapies, PolQ is a promising target for combination with established standards of care agents.

[0012] Thus, there is a need for new and improved agents that are capable of targeting PolQ and inhibiting its activity. Furthermore, there is a need for improved agents that have one or more advantageous pharmaceutical properties, e.g., improved potency, improved metabolic stability in humans, improved cellular permeability, or improved solubility. The present invention was designed with the foregoing in mind.

[0013] References

[0014] 1. Helleday T., et al, Nat Rev Genet. (2014); 15:585-98

[0015] 2. Ceccaldi R., et al, Trends Cell Biol. (2016); 26:52-64

[0016] 3. Seki M. et al., Nucleic Acids Res., (2003); 31:6117-26

[0017] 4. Ceccaldi R., et al., Nature (2015); 518:258-62

[0018] 5. Lemée F., et al,. PNAS (2010); 107:13390-5

[0019] 6. Higgins G.S., et al., Oncotarget (2010); 1:175-84

[0020] 7. Kabotyanski E.B., et al, Nucleic Acids Res. (1998); 26:5333-42

[0021] 8. Ahrabi S., et al, Nucleic Acids Res. (2016); 44:5743-57

[0022] 9. McVey M., et al., Trends Genet. (2008); 24:529-38

[0023] 10. Sfeir A., et al, Biochem Sci. (2015); 40:701-14)

[0024] 11. Chan S.H., et al., PLoS Genet. (2010); 6:e1001005

[0025] 12. Wyatt D.W., et al, Mol Cell. (2016); 63:662-673

[0026] 13. Black S.J., et al., Nat Commun. (2019); 10:4423

[0027] 14. Audeh M.W., et al., Lancet (2010); 376 (9737):245-51

[0028] 15. Truong W., et al., PNAS (2013); 110:7720-7725

[0029] 16. Mateos-Gomez P.A., et al., Nature (2015); 518:254-57

[0030] 17. Noordermeer S.M., et al., Trends Cell Biol. (2019); 29:820-834

[0031] 18. Edwards S.L., et al., Nature (2008); 451(7182):1111-5

[0032] 19. Lukashchuk N., et al., J Clin Oncol (2022) 40(16_suppl):5559-5559)

[0033] 20. Jaspers J.E., et al., Cancer Discov. (2013); 3(1):68

[0034] 21. Pettitt S.J., et al., Nat Commun. (2018); 9:1849;

[0035] 22 Noordermeer S.M., et al., Nature (2018) 560:117

[0036] 23. Nacson J., et al, Cell Rep. (2018); 25(5): 1384)

[0037] 24. Higgins G., et al, Science (2018); 359(6381): 1217-1218

[0038] 25. Zatreanu D., et al, Nat Commun. (2021); 12(1):3636

[0039] 26. Feng W., et al, Nat Commun. (2019); 10(1):4286

[0040] 27. Wang ZI et al., J Biol Chem. 2019 Mar 15; 294(11):3909-3919

[0041] 28. Dai CH et al., Oncotarget. 2016; 7(40):65157-65170

[0042] 29. Yousefzadeh MJ et al., PLoS Genet. 2014 Oct 2; 10(10):el004654

[0043] 30. Higgins G et al. Cancer Res. 2010 Apr 1; 70(7):2984-93

[0044] 31. Schrempf et al., Trends Cancer. 2021; 7(2):98-111

[0045] 32. Kumar RJ et al., NAR Cancer. 2020 Dec; 2(4):zcaa038 SUMMARY

[0046] In one aspect, the present application provides a compound of Formula I and / or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0047] In another aspect, the present application provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, and one or more pharmaceutically acceptable excipients.

[0048] In another aspect, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in therapy.

[0049] In another aspect, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition associated with PolQ activity.

[0050] In another aspect, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition associated with PolQ abnormal activity.

[0051] In another aspect, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of cancer or a benign tumor.

[0052] In another aspect, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of cancer.

[0053] In another aspect, the present application provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, for the manufacture of a medicament for the treatment of a disease or condition associated with PolQ activity.

[0054] In another aspect, the present application provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, for the manufacture of a medicament for the treatment of a disease or condition associated with PolQ abnormal activity.

[0055] In another aspect, the present application provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, for the manufacture of a medicament for the treatment of cancer or a benign tumor.

[0056] In another aspect, the present application provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, for the manufacture of a medicament for the treatment of cancer.

[0057] In another aspect, the present application provides a method of treating a disease or condition associated with PolQ activity, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0058] In another aspect, the present application provides a method of treating a disease or condition associated with abnormal activity of PolQ, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0059] In another aspect, the present application provides a method of treating a cancer or a benign tumor, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0060] In another aspect, the present application provides a method of treating a cancer, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0061] In another aspect, the present application provides a combination therapy comprising a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, and one or more additional therapeutic agents.

[0062] In another aspect, the present application provides a method of making a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, with one or more additional therapeutic agents.

[0063] In another aspect, the present application provides the use of a compound of Formula I, or a salt, hydrate, or solvate thereof, for in vitro or in vivo CRISPR gene editing.

[0064] In another aspect, the present application provides the use of a compound of Formula I, or a salt, hydrate, or solvate thereof, for increasing the efficiency of in vitro or in vivo CRISPR gene editing.

[0065] In another aspect, the present application provides a compound of Formula I, or a salt, hydrate, or solvate thereof, for use in in vivo CRISPR gene editing.

[0066] In another aspect, the present application provides a compound of Formula I, or a salt, hydrate, or solvate thereof, for use in increasing the efficiency of in vivo CRISPR gene editing.

[0067] The preferred, suitable, and optional features of any one particular aspect of the application are also preferred, suitable, and optional features of any other aspect. DETAILED DESCRIPTION

[0068] Definitions

[0069] The following terms as used in the specification and claims have the following meanings, unless otherwise indicated.

[0070] It is to be understood that a reference to "treatment" includes prophylaxis as well as the alleviation of established symptoms of a condition. Thus, "treatment" of a state, disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a person who can be predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating a disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0071] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc. of the mammal to be treated.

[0072] "PolQ" refers to DNA polymerase theta (encoded by POLQ).

[0073] Compounds and intermediates described herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature system. It should be understood, unless explicitly stated to the contrary, that the terms "compounds of Formula I", "compounds of the invention", and the more general term "compounds" refer to and encompass any and all compounds described herein by Formula I and / or with reference to Formula I. It should also be understood that these terms encompass all stereoisomers of these compounds, i.e., cis- and trans-isomers, as well as the optical isomers, i.e., R and S enantiomers, in substantially pure form and / or in any mixture of proportions, as described above. This understanding extends to pharmaceutical compositions and methods of treatment using or comprising one or more compounds of Formula I, whether used or comprised alone or in combination with other drugs.

[0074] Unless otherwise indicated, atoms are denoted herein by their chemical symbol as they appear in the IUPAC Periodic Table of the Elements. For example, "C" denotes a carbon atom.

[0075] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0076] In this specification, the term "alkyl" includes straight chain and branched chain alkyl groups. Where a single alkyl group is referred to, e.g. "propyl", this refers only to the straight chain version, and where a single branched chain alkyl group is referred to, e.g. "isopropyl", this refers only to the branched chain version. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl and tert-butyl. Similar conventions apply to other groups, e.g. "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

[0077] An "alkylene" group is an alkyl group which is positioned between two other chemical groups and serves to join them. Thus, a "(1-6C)alkylene" group refers to a straight chain saturated divalent hydrocarbon group of 1-6 carbon atoms or a branched chain saturated divalent hydrocarbon group of 3-6 carbon atoms, e.g. methylene, ethylene, propylene, 2-methylpropylene, pentylene and the like.

[0078] A "(3-6C)cycloalkyl" group refers to a hydrocarbon ring containing 3 to 6 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.

[0079] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0080] "Haloalkyl" and "haloalkyl group" as used herein alone or in combination, refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. Representative examples include, but are not limited to, -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, and -CH2CF3. Suitably, the haloalkyl group is selected from -CHF2and -CF3, suitably -CF3.

[0081] "Haloalkoxy" and "haloalkoxy group" as used herein alone or in combination, refers to an alkoxy group (i.e. O-alkyl) in which one or more hydrogen atoms are replaced by a halogen atom. Representative examples include, but are not limited to, -OCF3, -OCHF2, -OCH2F and -OCF2CF3. Suitably, the haloalkoxy group is selected from -OCHF2and -OCF3, suitably -OCF3.

[0082] The term "heterocyclyl," "heterocyclic" or "heterocycle" refers to non-aromatic saturated or partially saturated monocyclic, fused, bridged or spiro bicyclic ring systems. Monocyclic heterocycles contain about 3 to 12 (suitably 3 to 7) ring atoms with 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain 7 to 17 member atoms in the ring, suitably 7 to 12 member atoms. Bicyclic heterocycles can be fused, spiro or bridged ring systems. Examples of heterocyclyl groups include cyclic ethers such as, but not limited to, oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl and the like. Typical sulfur-containing heterocycles include tetrahydrothiophenyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran and hexahydrothiophene. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolanyl, octahydrobenzofuranyl, octahydrobenzimidazolyl and octahydrobenzothiazolyl. For sulfur-containing heterocycles, oxidized sulfur-containing heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothiophenyl and thiomorpholinyl such as, but not limited to, tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable valence states of heterocyclyl groups bearing 1 or 2 oxo (=0) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyl groups containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person will appreciate, any heterocycle can be attached to another group through any suitable atom, for example through a carbon or nitrogen atom. However, references herein to piperidino or morpholino refer to piperidin-1-yl or morpholin-4-yl rings attached through a ring nitrogen.

[0083] A "bridged ring system" refers to a ring system in which two rings share two or more atoms, see, e.g., Advanced Organic Chemistry, Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane, and quinuclidine.

[0084] A "spiro bicyclic ring system" refers to two ring systems sharing a common spiro carbon atom, i.e., a heterocycle is attached to another carbocycle or heterocycle through a common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0085] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic, or polycyclic ring containing one or more (e.g., 14, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more typically 5 to 10 ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, such as a bicyclic ring structure formed from a fused 5- and 6-membered ring or two fused 6-membered rings. Each ring can contain up to about 4 heteroatoms typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogen. Typically, the number of basic nitrogen atoms present in a heteroaryl group, including any amino substituents on the ring, will be fewer than five.

[0086] Examples of heteroaryl groups include furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenoxazinyl, phenothiazinyl, pyridopyridazinyl, thieno[2,3b]- furanyl-, 2H-furo[3,2b]-pyranyl-, 5H-pyrido[2,3-d]-oxazinyl-, 1H-pyrazolo[4,3-d]- oxazolyl-, 4H-imidazo[4,5d]thiazolyl, pyrazolo[2,3d]pyridazinyl, -imidazo[2,1b]thiazolyl, -imidazo[1,2b][1,2,4]-triazinyl. "Heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more other rings are nonaromatic, saturated or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or -sulfur-. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl.

[0087] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

[0088] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0089] Heteroaryl groups include ring systems such as pyridinone, which can exist in heteroaromatic form, as shown below.

[0090]

[0091] Bicyclic heteroaryl groups can be, for example, a group selected from:

[0092] a 5- or 6-membered ring fused to a benzene ring containing 1, 2, or 3 ring heteroatoms;

[0093] a 5- or 6-membered ring fused to a pyridine ring containing 1, 2, or 3 ring heteroatoms;

[0094] a 5- or 6-membered ring fused to a pyrimidine ring containing 1 or 2 ring heteroatoms;

[0095] a 5- or 6-membered ring fused to a pyrrole ring containing 1, 2, or 3 ring heteroatoms;

[0096] a 5- or 6-membered ring fused to a pyrazole ring containing 1 or 2 ring heteroatoms;

[0097] a 5- or 6-membered ring fused to a pyrazine ring containing 1 or 2 ring heteroatoms;

[0098] a 5- or 6-membered ring fused to an imidazole ring containing 1 or 2 ring heteroatoms;

[0099] a 5- or 6-membered ring fused to an oxazole ring containing 1 or 2 ring heteroatoms;

[0100] a 5- or 6-membered ring fused to an isoxazole ring containing 1 or 2 ring heteroatoms;

[0101] a 5- or 6-membered ring fused to a thiazole ring containing 1 or 2 ring heteroatoms;

[0102] a 5- or 6-membered ring fused to an isothiazole ring containing 1 or 2 ring heteroatoms;

[0103] a 5- or 6-membered ring fused to a thiophene ring containing 1, 2, or 3 ring heteroatoms;

[0104] a 5- or 6-membered ring fused to a furan ring containing 1, 2, or 3 ring heteroatoms;

[0105] a cyclohexane ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms; and

[0106] a cyclopentane ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms.

[0107] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indoxazinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl.

[0108] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanone, isochromanone, benzodioxanyl, quinolyl, benzoxazinyl, benzodiazinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

[0109] The term "aryl" refers to cyclic or polycyclic aromatic rings having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In particular embodiments, the aryl group is phenyl.

[0110] The specification also uses several composite terms to describe groups containing more than one functionality. Those skilled in the art will appreciate that these terms include, for example, heterocyclyl(m-nC)alkyl groups include (m-nC)alkyl groups substituted with a heterocyclyl group.

[0111] The term "aryl(l-2C)alkyl" refers to an aryl group covalently attached to a (l-2C)alkylene group, both of which are defined herein. Examples of aryl(l-2C)alkyl groups include benzyl, phenethyl, and the like.

[0112] "Heteroaryl(l-3C)alkyl" refers to a heteroaryl group covalently attached to a (l-3C)alkylene group, both of which are defined herein. Examples of heteroaryl-alkyl groups include pyrid-3-ylmethyl, 2-(benzofuran-2-yl)ethyl, and the like.

[0113] "Heterocyclyl(l-2C)alkyl" refers to a heterocyclyl group covalently attached to a (l-2C)alkylene group, both of which are defined herein.

[0114] "(3-6C)cycloalkyl-(l-2C)alkyl" refers to a (3-6C)cycloalkyl group covalently attached to a (l-2C)alkylene group, both of which are defined herein.

[0115] The term "optionally substituted" refers to substituted and unsubstituted groups, structures, or molecules. The term "wherein R 1 one / any CH, CH2, CH3group or heteroatom (i.e., NH) in a group is optionally substituted" suitably means that (any) one hydrogen atom in the group is replaced with the relevant specified group. 1 one / any CH, CH2, CH3group or heteroatom (i.e., NH) in a group is optionally substituted" suitably means that (any) one hydrogen atom in the group is replaced with the relevant specified group.

[0116] When an optional substituent is selected from "one or more" groups, it is understood that the definition includes all substituents selected from one of the particular groups or substituents selected from two or more of the particular groups.

[0117] The wave line ( ) is used herein to indicate a point of attachment.

[0118] The phrase "compounds of the invention" refers to those compounds disclosed herein, including those compounds generally and specifically disclosed herein.

[0119] "Pharmaceutically acceptable" as used herein alone or in combination with another term or terms, refers to a material that is generally chemically and / or physically compatible with other ingredients (e.g., for a formulation) and / or generally physiologically compatible with the recipient (e.g., a subject) thereof.

[0120] "Subject" and "patient" as used herein alone or in combination with another term or terms, refer appropriately to a mammal, especially a human.

[0121] Compounds of the invention

[0122] In a first aspect, the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, having structural Formula I as shown below:

[0123]

[0124] wherein:

[0125] Ring A is selected from the group consisting of phenyl and 5- to 10-membered heteroaryl;

[0126] R1is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl, and 6- to 12-membered spiroheterocyclyl, wherein:

[0127] (i) R1is optionally substituted with one or more R 100 substituents; or two R 100 substituents on adjacent ring atoms of R1may be joined to form a fused (3-6C)cycloalkyl ring; or

[0128] (ii) when R1is 5- to 6-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl, and 6- to 12-membered spiroheterocyclyl, it is optionally substituted with oxo;

[0129] and wherein R 100 is selected from the group consisting of halogen, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)haloalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy, -Q 100 -OH, -Q 100 -O-(1-4C)alkyl, -C(O)-(1-4C)alkyl, and -Q 100 -cyano; wherein Q 100 is a bond or (1-4C)alkylene;

[0130] each of the integers a and b is independently 0 or 1 ;

[0131] R2and R3, when present, are each independently selected from the group consisting of halogen, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)hydroxyalkyl, (1-4C)haloalkoxy, -Q1-O-(1-4C)alkyl, and -C(O)OH, wherein Q1is a bond or (1-4C)alkylene;

[0132] X4is selected from CR x4 or N;

[0133] X5is selected from CR x5 or N;

[0134] X6is selected from CR x6 or N;

[0135] X7is selected from CR x7 or N;

[0136] R x4 is hydrogen, fluoro, chloro, methyl, or a group of the formula:

[0137] -Y-Q

[0138] wherein:

[0139] Y is -O-, -S-, -NH-, or -CH2-;

[0140] Q is selected from the group consisting of hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, phenyl, heteroaryl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl, and 6- to 12-membered spiroheterocyclyl, each of which is optionally substituted with one or more R 100 substituents, and (3-8C)cycloalkyl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl, and 6- to 12-membered spiroheterocyclyl is optionally substituted with oxo;

[0141] R x5 or R x6 is selected from the group consisting of:

[0142] hydrogen, halogen, cyano, nitro, or a group of the formula:

[0143] -L1-Y1-L2-Q1

[0144] wherein:

[0145] L1is absent or (1-2C)alkylene;

[0146] Y1is absent or -O-, -S-, -SO-, -SO2-, -S(O)(=NR y1)-, -N(R y1 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R y1 )-, -N(R y1 )C(O)-, -S(O)2N(R y1 )-, -N(R y1 )SO2- or -N(R y1a )C(O)-N(R y1 )-, wherein R y1 and R y1a are selected from hydrogen or (1-2C)alkyl;

[0147] L2is absent or (1-2C)alkylene; and

[0148] Q1is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl and 6- to 12-membered spiroheterocyclyl,

[0149] wherein:

[0150] (i) when Q1is (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl, it is optionally further substituted by one or more substituents independently selected from oxo, halo, cyano or by one or more groups of the formula:

[0151] -Y2-Q2

[0152] wherein:

[0153] Y2is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R y2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R y2 )-, -N(R y2 )C(O)-, -S(O)2N(R y2 )- or -N(R y2 )SO2-, wherein R y2 is selected from hydrogen or (1-2C)alkyl;

[0154] Q2is selected from:

[0155] hydrogen;

[0156] (1-4C)alkyl optionally substituted by one or more substituents selected from halo, hydroxyl, cyano, amino or (1-4C)alkoxy; or

[0157] 4- to 7-membered heterocyclyl optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, (1-4C)alkyl or (1-4C)alkoxy;

[0158] (ii) when Q1is (3-8C)cycloalkyl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl and 6- to 12-membered spiroheterocyclyl, it is optionally further substituted by one or more substituents independently selected from oxo, halogen, cyano or by one or more groups of the formula:

[0159] -Y3-Q3

[0160] wherein:

[0161] Y3is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R y2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R y3 )-, -N(R y3 )C(O)-, -S(O)2N(R y3 )- or -N(R y3 )SO2-, wherein R y3 is selected from hydrogen or (1-2C)alkyl;

[0162] Q3is selected from:

[0163] hydrogen;

[0164] (1-4C)alkyl optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino or (1-4C)alkoxy; or

[0165] 4- to 7-membered heterocyclyl optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, (1-4C)alkyl or (1-4C)alkoxy;

[0166] (iii) when Q1is phenyl or 5- to 6-membered heteroaryl, it is optionally further substituted by one or more substituents independently selected from halogen, cyano or by one or more groups of the formula -Y3-Q3as defined above;

[0167] R x7 is selected from hydrogen, fluorine, chlorine, hydroxy, NH2, methyl or CF3;

[0168] or R x4 and R x5 , R x5 and R x6 or R x6 and R x7together with the carbon atom to which they are attached form a fused (5-6C)cycloalkyl, phenyl, 5 or 6 membered heteroaryl or 5 or 6 membered heterocycle, each of which is optionally substituted with fluorine, chlorine, methyl or hydroxyl;

[0169] provided that:

[0170] (i) when X5is CR x5 and Rx5is a group of the formula -L1-Y1-L2-Q1, then X6is selected from N, C-H, C-F, C-CN, C-Cl or C-Me; and

[0171] (ii) when X6is CR x6 and R x6 is a group of the formula -L1-Y1-L2-Q1, then X5is selected from N, C-H, C-F, C-CN, C-Cl or C-Me.

[0172] In another aspect, the present application relates to a compound, or a pharmaceutically acceptable salt thereof, having the structural Formula I as shown below:

[0173]

[0174] wherein:

[0175] Ring A is selected from the group consisting of phenyl and 5 to 10 membered heteroaryl;

[0176] R1is selected from the group consisting of phenyl, 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, 6 to 10 membered bicyclic heterocyclyl, 6 to 10 membered bridged heterocyclyl and 6 to 12 membered spiroheterocyclyl, wherein:

[0177] (i) R1is optionally substituted with one or more R 100 substituents; or two R 100 substituents on adjacent ring atoms of R1may be joined to form a fused (3-6C)cycloalkyl ring; or

[0178] (ii) when R1is 5 to 6 membered heterocyclyl, 6 to 10 membered bicyclic heterocyclyl, 6 to 10 membered bridged heterocyclyl and 6 to 12 membered spiroheterocyclyl, it is optionally substituted with oxo;

[0179] and wherein R 100 is selected from the group consisting of halogen, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)haloalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy, -Q 100 -OH, -Q 100 -O-(1-4C)alkyl, -C(O)-(1-4C)alkyl and -Q 100 -cyano; wherein Q 100 is a bond or (1-4C)alkylene;

[0180] each of the integers a and b is independently 0 or 1 ;

[0181] R2and R3, when present, are each independently selected from the group consisting of halogen, cyano, -O - , (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)hydroxyalkyl, (1-4C)haloalkoxy, -Q1-O-(1-4C)alkyl, -C(O)OH, -Q1-C(O)-NH2, -Q1-C(O)-NHMe, and -Q1-C(O)-NMe2, wherein Q1is a bond or (1-4C)alkylene;

[0182] X4is selected from CR x4 or N;

[0183] X5is selected from CR x5 or N;

[0184] X6is selected from CR x6 or N;

[0185] X7is selected from CR x7 or N;

[0186] R x4 is hydrogen, fluorine, chlorine, methyl, or a group of the formula:

[0187] -Y-Q

[0188] wherein:

[0189] Y is -O-, -O-CH2-, -S-, -NH-, -CH2-, or -CH2-CH2-;

[0190] Q is selected from hydrogen, (1-6C)alkyl, -C(O)-NH2, -C(O)-NHMe, -C(O)-NMe2, (3-8C)cycloalkyl, phenyl, heteroaryl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl, and 6- to 12-membered spiroheterocyclyl, each of which is optionally substituted with one or more R 100 substituents, and (3-8C)cycloalkyl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl, and 6- to 12-membered spiroheterocyclyl is optionally substituted with oxo;

[0191] R x5 or R x6 is selected from:

[0192] hydrogen, halogen, cyano, nitro, or a group of the formula:

[0193] -L1-Y1-L2-Q1

[0194] in:

[0195] L1 is absent or is a (1-2C) alkylene group;

[0196] Y1 does not exist or is either -O-, -S-, -SO-, -SO2-, or -S(O)(=NR) y1 )-、-N(R y1 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R y1 )-,、-N(R y1 C(O)-、-S(O)2N(R) y1 )-、-N(R y1 SO2- or -N(R) y1a )C(O)-N(R y1 )-, where R y1 and R y1a Selected from hydrogen or (1-2C) alkyl;

[0197] L2 is absent or is a (1-2C) alkylene group; and

[0198] Q1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)ynyl, (3-8C)cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic.

[0199] in:

[0200] (i) When Q1 is (1-6C)alkyl, (2-6C)alkenyl, or (2-6C)ynyl, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula:

[0201] -Y2-Q2

[0202] in:

[0203] Y2 does not exist or is selected from -O-, -S-, -SO-, -SO2-, -N(R) y2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R y2 )-、-N(R y2 C(O)-、-S(O)2N(R) y2 - or -N(R) y2 SO2-, where R y2 Selected from hydrogen or (1-2C) alkyl;

[0204] Q2 is selected from:

[0205] hydrogen;

[0206] (1 -4C)alkyl optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino or (1 -4C)alkoxy; or

[0207] 4 to 7 membered heterocyclyl optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, (1 -4C)alkyl or (1 -4C)alkoxy;

[0208] (ii) when Q1is (3-8C)cycloalkyl, 4 to 7 membered heterocyclyl, 6 to 10 membered bicyclic heterocyclyl, 6 to 10 membered bridged heterocyclyl and 6 to 12 membered spiroheterocyclyl, it is optionally further substituted by one or more substituents independently selected from oxo, halogen, cyano or by one or more groups of the formula:

[0209] -Y3-Q3

[0210] wherein:

[0211] Y3is absent or selected from -0-, -S-, -SO-, -S02-, -N(R y2 )-, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R y3 )-, -N(R y3 )C(O)-, -S(0)2N(R y3 )- or -N(R y3 )S02- wherein R y3 is selected from hydrogen or (1 -2C)alkyl;

[0212] Q3is selected from:

[0213] hydrogen;

[0214] (1 -4C)alkyl optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino or (1 -4C)alkoxy; or

[0215] 4 to 7 membered heterocyclyl optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, (1 -4C)alkyl or (1 -4C)alkoxy;

[0216] (iii) when Q1is phenyl or 5 to 6 membered heteroaryl, it is optionally further substituted by one or more substituents independently selected from halogen, cyano or by one or more groups of the formula -Y3-Q3as defined above;

[0217] R x7 is selected from hydrogen, fluorine, chlorine, hydroxyl, NH2, methyl or CF3;

[0218] or R x4 and R x5 , Rx5 and R x6 or R x6 and R x7 are linked such that they, together with the carbon atom to which they are attached, form a fused (5-6C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 5- or 6-membered heterocycle, each of which is optionally substituted with fluorine, chlorine, methyl or hydroxyl;

[0219] provided that:

[0220] (i) when X5is CR x5 and Rx5is a group of the formula -L1-Y1-L2-Q1, then X6is selected from N, C-H, C-F, C-CN, C-Cl or C-Me; and

[0221] (ii) when X6is CR x6 and R x6 is a group of the formula -L1-Y1-L2-Q1, then X5is selected from N, C-H, C-F, C-CN, C-Cl or C-Me.

[0222] Suitably, when X5is CR x5 and R x5 is cyano or a group of the formula -L1-Y1-L2-Q1, then:

[0223] X4is selected from N, C-H, C-F, C-Cl or C-Me;

[0224] X6is selected from N, C-H, C-F, C-CN, C-Cl or C-Me;

[0225] X7is selected from N, C-H, C-F, C-Cl or C-Me.

[0226] In one embodiment, when X5is CR x5 and R x5 is cyano or a group of the formula -L1-Y1-L2-Q1, then:

[0227] X4is selected from N, C-H or C-F;

[0228] X6is selected from N, C-H, C-F, C-Cl or C-Me;

[0229] X7is selected from N, C-H or C-F.

[0230] In another embodiment, when X5is CR x5 and R x5 is cyano or a group of the formula -L1-Y1-L2-Q1, then:

[0231] X4is selected from N or C-H or C-F;

[0232] X6is selected from N, C-H, C-F, C-Cl or C-Me;

[0233] X7is selected from N or C-H.

[0234] In another embodiment, when X5is CR x5 and R x5 is cyano or a group of the formula -L1-Y1-L2-Q1, then:

[0235] X4is C-H;

[0236] X6is selected from N, C-H, C-F, C-Cl or C-Me;

[0237] X7is selected from N or C-H.

[0238] In another embodiment, when X5is CR x5 and R x5 is cyano or a group of the formula -L1-Y1-L2-Q1, then:

[0239] X4is C-H;

[0240] X6is C-H;

[0241] X7is N or C-H.

[0242] In another embodiment, when X5is CR x5 and R x5 is cyano or a group of the formula -L1-Y1-L2-Q1, then:

[0243] X4is C-H;

[0244] X6is C-H;

[0245] X7is C-H.

[0246] Suitably, when X6is CR x6 and R x6 is cyano or a group of the formula -L1-Y1-L2-Q1, then:

[0247] X4is selected from N, C-H or C-F;

[0248] X5is selected from N, C-H, C-F, C-Cl or C-Me;

[0249] X7is selected from N, C-H or C-F.

[0250] In one embodiment, when X6is CR x6 and R x6 is cyano or a group of the formula -L1-Y1-L2-Q1, then:

[0251] X4is selected from N, C-H or C-F;

[0252] X5is selected from N, C-H or C-F;

[0253] X7is selected from N, C-H or C-F.

[0254] In another embodiment, when X6is CR x6 and R x6 is cyano or a group of the formula -L1-Y1-L2-Q1, then:

[0255] X4is selected from N, C-H or C-F;

[0256] X5is selected from N, C-H or C-F;

[0257] X7is selected from N, C-H or C-F.

[0258] In another embodiment, when X6is CR x6 and R x6 is cyano or a group of the formula -L1-Y1-L2-Q1, then:

[0259] X4is selected from N or C-H;

[0260] X5is selected from N, C-H or C-F;

[0261] X7is selected from N or C-H.

[0262] In another embodiment, when X6is CR x6 and R x6 is cyano or a group of the formula -L1-Y1-L2-Q1, then:

[0263] X4is C-H;

[0264] X5is selected from N or C-H;

[0265] X7is selected from N or C-H.

[0266] Specific compounds of the application include, for example, compounds of the formula I, or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein ring A, R1, R 100 , R2, R3, the integer a, the integer b, X4, X5, X6, X7, R x4 , R x5 , R x6 , R x7 , X8, the integer c, R 100a , the integer d, R 100b , the integer e and R 100c each have any of the meanings defined hereinbefore or as defined in any one of paragraphs (1) to (89) hereinafter: -

[0267] (1) Ring A is selected from phenyl or 5-, 6-, 9- or 10-membered heteroaryl;

[0268] (2) Ring A is selected from phenyl or 5- or 6-membered heteroaryl;

[0269] (3) Ring A is selected from phenyl or 6-membered heteroaryl;

[0270] (4) Ring A is 5-, 6-, 9- or 10-membered heteroaryl;

[0271] (5) Ring A is 5- or 6-membered heteroaryl;

[0272] (6) Ring A is phenyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, imidazo[l,2-a]pyridinyl, [l,2,3]triazolo[l,5-a]pyridinyl, imidazo[l,5-a]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrazolo[l,5-a]pyridinyl, [l,2,4]triazolo[l,5-a]pyridinyl, 1,6-naphthyridinyl or 1,7-naphthyridinyl;

[0273] (7) Ring A is phenyl, pyridyl, pyrimidinyl and imidazo[l,2-a]pyridinyl, 1,2,3-triazolyl, pyrazolyl, isoxazolyl, imidazo[l,5-a]pyridinyl

[0274] (8) Ring A is phenyl, pyridyl, pyrimidinyl and imidazo[l,2-a]pyridinyl

[0275] (9) Ring A is phenyl or pyridyl;

[0276] (10) Ring A is phenyl;

[0277] (11) Ring A is pyridyl;

[0278] (12) Ring A is selected from:

[0279] ; ; ; ; ; ; ; ; or

[0280] wherein represents the point of attachment to the amide group of Formula I; and R1, R2, R3, a and b are each as defined herein;

[0281] (13) Ring A is selected from:

[0282] ; ; or ;

[0283] wherein represents the point of attachment to the amide group of Formula I; and each of R1, R2, R3, a, and b is as defined herein;

[0284] (14) Ring A is selected from:

[0285] ; or ;

[0286] wherein represents the point of attachment to the amide group of Formula I; and each of R1, R2, R3, a, and b is as defined herein;

[0287] (15) Ring A is selected from:

[0288] ; ; or ; or

[0289] wherein represents the point of attachment to the amide group of Formula I; and each of R1, R2, R3, a, and b is as defined herein;

[0290] (16) Ring A is selected from:

[0291] ; or ;

[0292] wherein represents the point of attachment to the amide group of Formula I; and each of R1, R2, R3, a, and b is as defined herein;

[0293] (17) Ring A is:

[0294]

[0295] wherein represents the point of attachment to the amide group of Formula I; and each of R1, R2, R3, a, and b is as defined herein;

[0296] (18) Ring A is:

[0297]

[0298] wherein represents the point of attachment to the amide group of Formula I; and each of R1, R2, R3, a, and b is as defined herein;

[0299] (19) R1is selected from phenyl or 5- to 6-membered heteroaryl, each optionally substituted with one or more R 100 ; or two R 100 substituents on adjacent ring atoms in R1may be joined to form a fused (3-6C)cycloalkyl ring;

[0300] (20) R1is selected from phenyl or 6-membered heteroaryl, each optionally substituted with one or more R 100 ; or two R 100 substituents on adjacent ring atoms in R1may be joined to form a fused (3-6C)cycloalkyl ring;

[0301] (21) R1is a group of the formula:

[0302] or

[0303] wherein:

[0304] represents the point of attachment to ring A of formula I;

[0305] X8is CH or N;

[0306] R 100a , R 100b , and R 100c are substituents R 100 as defined in any one of the preceding paragraphs (25) to (31); and

[0307] the integers c, d, and e are 0, 1, or 2;

[0308] (22) R1is a group of the formula:

[0309] , , , or

[0310] wherein:

[0311] represents the point of attachment to ring A of formula I;

[0312] X8is CH or N;

[0313] R 100a , R 100b , and R 100c are substituents R 100; and

[0314] The integers d and e are 0 or 1 ;

[0315] (23) R1is a group of the formula:

[0316] , or

[0317] wherein:

[0318] denotes the point of attachment to ring A of formula I;

[0319] R 100b is methyl, fluoro or chloro;

[0320] R 100c is fluoro or chloro, especially fluoro;

[0321] (24) R1is a group of the formula:

[0322]

[0323] wherein:

[0324] denotes the point of attachment to ring A of formula I.

[0325] (25) R 100 is selected from halo, (1-3C)alkyl, (1-3C)haloalkyl, (1-3C)haloalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy, -Q 100 -OH, -Q 100 -O-(1-3C)alkyl, -C(O)-(1-3C)alkyl and -Q 100 -cyano; wherein Q 100 is a bond or (1-3C)alkylene;

[0326] (26) R 100 is selected from halo, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)haloalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy, -Q 100 -OH, -Q 100 -O-(1-2C)alkyl, -C(O)-(1-2C)alkyl and -Q 100 -cyano; wherein Q 100 is a bond or (1-2C)alkylene;

[0327] (27) R 100selected from halogen, (1-2C)alkyl, (1-2C)fluoroalkyl, (1-2C)fluoroalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy, -Q 100 -OH, -Q 100 -O-(1-2C)alkyl, -C(O)-(1-2C)alkyl and -Q 100 -cyano; wherein Q 100 is a bond or (1-2C)alkylene;

[0328] (28) R 100 selected from halogen, (1-2C)alkyl, (1-2C)fluoroalkyl, -Q 100 -OH and -Q 100 -O-(1-2C)alkyl; wherein Q 100 is a bond or (1-2C)alkylene; 100

[0329] (29) R 100 selected from halogen, (1-2C)alkyl, (1-2C)fluoroalkyl, -Q 100 -OH and -Q 100 -O-(1-2C)alkyl; wherein Q 100 is a bond or (1-2C)alkylene;

[0330] (30) R 100 selected from fluorine, chlorine, (1-2C)alkyl, (1-2C)fluoroalkyl, -Q 100 -OH and -Q 100 -O-(1-2C)alkyl; wherein Q 100 is a bond or (1-2C)alkylene;

[0331] (31) R 100 selected from fluorine, chlorine, methyl, (1-2C)fluoromethyl and -Q 100 -O-(1-2C)alkyl; wherein Q 100 is a bond or methylene.

[0332] (32) integer a is 0 or 1 and integer b is 0;

[0333] (33) integer a is 0 and integer b is 0;

[0334] (34) integer a is 1 and integer b is 0;

[0335] ​(35) R2 and R3, when present, are each independently selected from the group consisting of fluorine, chlorine, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkoxy, -Q1-O-(1-2C)alkyl and -C(O)OH, wherein Q1 is a bond or (1-2C)alkylene;

[0336] (36) R2 and R3, when present, are each independently selected from the group consisting of fluorine, chlorine, (1-2C) alkyl, (1-2C) alkoxy or (1-2C) haloalkyl;

[0337] (37) R2 and R3, when present, are each independently selected from the group consisting of fluorine, (1-2C)alkyl or (1-2C)alkoxy;

[0338] (38) R2 and R3 are methyl groups when present;

[0339] (39)X4 is selected from CR x4 X5 is selected from CR x5 Or N; X6 is selected from CR x6 X7 is selected from CR x7 Or N; where R x4 R x5 R x6 and R x7 Each as defined above, or R x4 As defined in any of paragraphs (50) to (58); R x5 As defined in any of paragraphs (59) to (62); R x6 As defined in any of paragraphs (59) to (62); or R x7 As defined in either paragraph (63) or (64);

[0340] (40)X4 is selected from CR x4 X5 is selected from CR x5 Or N; X6 is selected from CR x6 X7 is selected from CH or N; where R x4 R x5 and R x6 Each as defined above, or R x4 As defined in any of paragraphs (50) to (58); R x5 As defined in any of paragraphs (59) to (62); R x6 As defined in any of paragraphs (59) to (62);

[0341] (41) X4 is selected from CH; X5 is selected from CR x5 Or N; X6 is selected from CR x6 X7 is selected from CH or N; where Rx5 and R x6 Each as defined above, or R x5 As defined in any of paragraphs (59) to (62) and R x6 As defined in any of paragraphs (59) to (62);

[0342] (42) X4 is selected from CH; X5 is selected from CH or N; X6 is selected from CR. x6 X7 is selected from CH or N; where R x6 As defined above or in any of paragraphs (59) to (62);

[0343] (43) X4 is selected from CH; X5 is selected from CH; X6 is selected from CR x6 X7 is selected from CH or N; where R x6 As defined above or in any of paragraphs (59) to (62);

[0344] (44) X4 is selected from CH; X5 is selected from CH or N; X6 is selected from CR. x6 X7 is selected from CH; where R x6 As defined above or in any of paragraphs (59) to (62);

[0345] (45) X4 is selected from CH; X5 is selected from CH; X6 is selected from CR x6 X7 is selected from CH; where R x6 As defined above or in any of paragraphs (59) to (62);

[0346] (46) X4 is selected from CH; X5 is selected from N; X6 is selected from CR x6 X7 is selected from CH; where R x6 As defined above or in any of paragraphs (59) to (62);

[0347] (47) X4 is selected from CH; X5 is selected from CH; X6 is selected from CR x6 X7 is selected from N; where R x6 As defined above or in any of paragraphs (59) to (62);

[0348] (48) X4 is selected from CH; X5 is selected from N; X6 is selected from CR. x6 X7 is selected from N; where R x6 As defined above or in any of paragraphs (59) to (62);

[0349] (49) X4 is selected from CH or N; X5 is selected from CR x5 X6 is selected from CH or N; X7 is selected from CH or N; where R x5As defined above or in any of paragraphs (59) to (62);

[0350] (50) X4 is selected from CH; X5 is selected from CR x5 X6 is selected from CH; X7 is selected from CH; where R x5 As defined above or in any of paragraphs (59) to (62);

[0351] (51) X4 is selected from CH; X5 is selected from CR x5 X6 is selected from N; X7 is selected from CH; where R x5 As defined above or in any of paragraphs (59) to (62);

[0352] (52) X4 is selected from CH; X5 is selected from CR x5 X6 is selected from CH; X7 is selected from N; where R x5 As defined above or in any of paragraphs (59) to (62);

[0353] (53) X4 is selected from N; X5 is selected from CR x5 X6 is selected from CH; X7 is selected from CH; where R x5 As defined above or in any of paragraphs (59) to (62);

[0354] (54) X4 is selected from N; X5 is selected from CR x5 X6 is selected from N; X7 is selected from CH; where R x5 As defined above or in any of paragraphs (59) to (62);

[0355] (55)R x4 Selected from hydrogen, fluorine, chlorine, methyl, or groups of the following formula:

[0356] -YQ

[0357] in:

[0358] Y is -O-, -S-, -NH-, or -CH2-;

[0359] Q is selected from hydrogen (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclic, each optionally bound by one or more R 100 Substituents and (3-8C) cycloalkyl substitutions, and optional 4- to 7-membered heterocyclic groups are oxysubstituted;

[0360] (56)R x4 Selected from hydrogen, fluorine, methyl, or groups of the following formula:

[0361] -YQ

[0362] in:

[0363] Y is -O-, -S-, -NH-, or -CH2-;

[0364] Q is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 5 or 6-membered heteroaryl, 4 to 7-membered heterocyclic group;

[0365] (57)R x4 Selected from hydrogen, fluorine, chlorine, or methyl;

[0366] (58)R x4 It is hydrogen;

[0367] (59)R x5 Or R x6 Selected from hydrogen, halogen, cyano, nitro or groups of the following formula:

[0368] -L1-Y1-L2-Q1

[0369] in:

[0370] L1 is absent or is a (1-2C) alkylene group;

[0371] Y1 does not exist or is either -O-, -S-, -SO-, -SO2-, or -S(O)(=NR) y1 )-、-N(R y1 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R y1 )-,、-N(R y1 C(O)-、-S(O)2N(R) y1 )-、-N(R y1 SO2- or -N(R) y1a )C(O)-N(R y1 )-, where R y1 and R y1a Selected from hydrogen or (1-2C) alkyl;

[0372] L2 is absent or is a (1-2C) alkylene group; and

[0373] Q1 is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic.

[0374] in:

[0375] (i) When Q1 is (1-6C)alkyl, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula:

[0376] -Y2-Q2

[0377] in:

[0378] Y2 does not exist or is selected from -O-, -SO2-, or -N(R). y2 -, -C(O)-, -C(O)N(R) y2 )-、-N(R y2 C(O)-、-S(O)2N(R) y2 - or -N(R) y2 SO2-, where R y2 Selected from hydrogen or methyl;

[0379] Q2 is selected from:

[0380] hydrogen;

[0381] Optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, or (1-4C)alkoxy; or

[0382] Optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, (1-4C)alkyl or (1-4C)alkoxy, a 4- to 7-membered heterocycle;

[0383] (ii) When Q1 is a (3-8C)cycloalkyl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula:

[0384] -Y3-Q3

[0385] in:

[0386] Y3 does not exist or is selected from -O-, -SO2-, or -N(R). y3 -, -C(O)-, -C(O)N(R) y3 )-、-N(R y3 C(O)-、-S(O)2N(R) y3 - or -N(R) y3 SO2-, where R y3 Selected from hydrogen or methyl;

[0387] Q3 is selected from:

[0388] hydrogen;

[0389] Optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, or (1-4C)alkoxy; or

[0390] Optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, (1-4C)alkyl or (1-4C)alkoxy, a 4- to 7-membered heterocycle;

[0391] (iii) When Q1 is phenyl or a 5- to 6-membered heteroaryl group, it may optionally be further substituted by one or more substituents independently selected from halogens, cyano groups, or by one or more groups of the formula -Y3-Q3 as defined above.

[0392] (60)R x5 or R x6 Selected from hydrogen, halogen, cyano, nitro or groups of the following formula:

[0393] -L1-Y1-L2-Q1

[0394] in:

[0395] L1 is absent or is methylene;

[0396] Y1 does not exist or is -O-, -SO2-, or -S(O) (=NR) y1 )-、-N(R y1 )-、-C(O)N(R y1 )-、-N(R y1 C(O)-、-S(O)2N(R) y1 - or -N(R) y1 SO2-, where R y1 and R y1a Selected from hydrogen or (1-2C) alkyl;

[0397] L2 is absent or methylene; and

[0398] Q1 is hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic.

[0399] in:

[0400] (i) When Q1 is (1-4C)alkyl, it may optionally be further substituted by one or more substituents independently selected from halogens, cyano groups, or by one or more groups of the following formula:

[0401] -Y2-Q2

[0402] in:

[0403] Y2 does not exist or is selected from -O-, -SO2-, or -N(R). y2 -, -C(O)-, -C(O)N(R) y2 - or -N(R) y2C(O)-、-S(O)2N(R) y2 - or -N(R) y2 SO2-, where R y2 Selected from hydrogen or methyl;

[0404] Q2 is selected from:

[0405] hydrogen;

[0406] (1-4C) alkyl groups optionally substituted with one or more halogens; or

[0407] 4- to 7-membered heterocyclic rings;

[0408] (ii) When Q1 is a (3-6C)cycloalkyl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula:

[0409] -Y3-Q3

[0410] in:

[0411] Y3 does not exist or is selected from -O-, -SO2-, or -N(R). y3 -, -C(O)-, -C(O)N(R) y3 )-、-N(R y3 C(O)-、-S(O)2N(R) y3 - or -N(R) y3 SO2-, where R y3 Selected from hydrogen or methyl;

[0412] Q3 is selected from:

[0413] hydrogen;

[0414] (1-4C) alkyl groups optionally substituted with one or more halogens; or

[0415] 4- to 7-membered heterocyclic rings;

[0416] (iii) When Q1 is phenyl or 5 to 6-membered heteroaryl, it may optionally be further substituted by one or more substituents independently selected from halogens, cyano groups or by one or more groups of the formula -Y3-Q3 as defined above;

[0417] (61)R x5 Or R x6 Selected from hydrogen, halogen, cyano, nitro or groups of the following formula:

[0418] -L1-Y1-L2-Q1

[0419] in:

[0420] L1 is absent or is methylene;

[0421] Y1 does not exist or is -O-, -SO2-, or -S(O) (=NR) y1 )-、-N(R y1 )-、-C(O)N(R y1 )-、-N(R y1 C(O)-、-S(O)2N(R) y1 - or -N(R) y1 SO2-, where R y1 and R y1a Selected from hydrogen or (1-2C) alkyl;

[0422] L2 is absent or methylene; and

[0423] Q1 is hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic.

[0424] in:

[0425] (i) When Q1 is (1-4C)alkyl, it may optionally be further substituted by one or more substituents independently selected from halogens, cyano groups, or by one or more groups of the following formula:

[0426] -Y2-Q2

[0427] in:

[0428] Y2 does not exist or is selected from -O-, -SO2-, or -N(R) y2 )-, where R y2 Selected from hydrogen or methyl;

[0429] Q2 is selected from:

[0430] hydrogen;

[0431] (1-4C) alkyl groups optionally substituted with one or more halogens; or

[0432] 4- to 7-membered heterocyclic rings;

[0433] (ii) When Q1 is a (3-6C)cycloalkyl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula:

[0434] -Y3-Q3

[0435] in:

[0436] Y3 does not exist or is selected from -O-, -SO2-, or -N(R) y3 )-, where R y3 Selected from hydrogen or methyl;

[0437] Q3 is selected from:

[0438] hydrogen;

[0439] (1-4C) alkyl groups optionally substituted with one or more halogens; or

[0440] 4- to 7-membered heterocyclic rings;

[0441] (iii) When Q1 is phenyl or 5 to 6-membered heteroaryl, it may optionally be further substituted by one or more substituents independently selected from halogens, cyano groups or by one or more groups of the formula -Y3-Q3 as defined above;

[0442] (62)R x5 Or R x6 Selected from hydrogen, halogen, cyano, nitro or groups of the following formula:

[0443] -L1-Y1-L2-Q1

[0444] in:

[0445] L1 does not exist;

[0446] Y1 does not exist or is -O-, -SO2-, or -S(O) (=NR) y1 )-、-N(R y1 )-、-C(O)N(R y1 )-、-N(R y1 C(O)-、-S(O)2N(R) y1 - or -N(R) y1 SO2-, where R y1 and R y1a Selected from hydrogen or (1-2C) alkyl;

[0447] L2 is absent or methylene; and

[0448] Q1 is hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic.

[0449] in:

[0450] (i) When Q1 is (1-4C)alkyl, it may optionally be further substituted by one or more substituents independently selected from halogens, cyano groups, or by one or more groups of the following formula:

[0451] -Y2-Q2

[0452] in:

[0453] Y2 does not exist or is -O-;

[0454] Q2 is selected from:

[0455] hydrogen;

[0456] (1-4C) alkyl groups optionally substituted with one or more halogens; or

[0457] 4- to 7-membered heterocyclic rings;

[0458] (ii) When Q1 is a (3-6C)cycloalkyl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula:

[0459] -Y3-Q3

[0460] in:

[0461] Y3 does not exist or is -O-;

[0462] Q3 is selected from:

[0463] hydrogen;

[0464] (1-4C) alkyl groups optionally substituted with one or more halogens; or

[0465] 4- to 7-membered heterocyclic rings;

[0466] (iii) When Q1 is phenyl or 5 to 6-membered heteroaryl, it may optionally be further substituted by one or more substituents independently selected from halogens, cyano groups or by one or more groups of the formula -Y3-Q3 as defined above;

[0467] (63)R x7 Selected from hydrogen, fluorine, chlorine, or methyl;

[0468] (64)R x7 It is hydrogen;

[0469] (65)X8 is N;

[0470] (66)X8 is CH;

[0471] (67) Integer c is 1, and integer d is 0 or 1;

[0472] (68)R 100a and R 100b All are R as defined above 100 ;

[0473] (69)R 100a and R 100b All of them are R as defined in the previous paragraph (25). 100 ;

[0474] (70)R 100a and R 100b All of them are R as defined in the previous paragraph (26). 100 ;

[0475] (71)R 100a and R 100b All of them are R as defined in paragraph (27) above. 100 ;

[0476] (72)R 100a and R 100b All of them are R as defined in the previous paragraph (28). 100 ;

[0477] (73)R 100a and R 100b All of them are R as defined in the previous paragraph (29). 100 ;

[0478] (74)R 100a and R 100b All of them are R as defined in the previous paragraph (30). 100 ;

[0479] (75)R 100a and R 100b All of them are R as defined in the previous paragraph (31). 100 ;

[0480] (76) The integer e is 0 or 1;

[0481] (77)R 100c As defined in paragraph (23) above;

[0482] (78)R 100c As defined in paragraph (26) above;

[0483] (79)R 100c As defined in paragraph (27) above;

[0484] (80)R 100c As defined in paragraph (28) above;

[0485] (81)R 100c As defined in paragraph (29) above;

[0486] (82)R 100c As defined in paragraph (30) above;

[0487] (83)R 100c As defined in paragraph (31) above;

[0488] (84) R2 and R3, when present, are each independently selected from the group consisting of fluorine, oxo, (1-2C)alkyl, (1-2C)alkoxy, -CH2-C(O)-NH2, -CH2-C(O)-NHMe or -CH2-C(O)-NMe;

[0489] (85) R2 and R3 are methyl, oxo or -CH2-C(O)-NMe2 when present;

[0490] (86)R x4 Selected from hydrogen, fluorine, chlorine, bromine, methyl, or groups of the following formula:

[0491] -YQ

[0492] in:

[0493] Y is -O-, -O-CH2-, -S-, -NH-, -CH2-, or -CH2-CH2-;

[0494] Q is selected from hydrogen, (1-4C)alkyl, -C(O)-NH2, -C(O)-NHMe, -C(O)-NMe2, (3-6C)cycloalkyl, phenyl, 5 or 6-membered heteroaryl, 4 to 7-membered heterocyclic group;

[0495] (87)R x4 Selected from hydrogen, fluorine, chlorine, bromine, or methyl;

[0496] (88)R x5 Or R x6 Selected from hydrogen, halogen, cyano, nitro or groups of the following formula:

[0497] -L1-Y1-L2-Q1

[0498] in:

[0499] L1 is absent or is methylene;

[0500] Y1 does not exist or is -O-, -SO2-, or -S(O) (=NR) y1 )-、-N(R y1 )-、-C(O)N(R y1 )-、-N(R y1 C(O)-、-S(O)2N(R) y1 - or -N(R) y1 SO2-, where R y1 and R y1a Selected from hydrogen or (1-2C) alkyl;

[0501] L2 is absent or is a (1-2C) alkylene group; and

[0502] Q1 is hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic.

[0503] in:

[0504] (i) When Q1 is (1-4C)alkyl, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula:

[0505] -Y2-Q2

[0506] in:

[0507] Y2 is absent or selected from -O-, -SO2-, -OC(O)-, -N(Ry2)-, -C(O)N(Ry2)- or -N(Ry2)C(O)-, where Ry2 is selected from hydrogen or methyl;

[0508] Q2 is selected from:

[0509] hydrogen;

[0510] (1-4C) alkyl groups optionally substituted with one or more halogens; or

[0511] 4- to 7-membered heterocyclic rings;

[0512] (ii) When Q1 is a (3-6C)cycloalkyl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula:

[0513] -Y3-Q3

[0514] in:

[0515] Y3 does not exist or is selected from -O-, -SO2-, or -N(R) y3 )-, where R y3 Selected from hydrogen or methyl;

[0516] Q3 is selected from:

[0517] hydrogen;

[0518] (1-4C) alkyl groups optionally substituted with one or more halogens; or

[0519] 4- to 7-membered heterocyclic rings;

[0520] (iii) When Q1 is phenyl or 5 to 6-membered heteroaryl, it may optionally be further substituted by one or more substituents independently selected from halogens, cyano groups or by one or more groups of the formula -Y3-Q3 as defined above;

[0521] (89)R x5 or R x6 Selected from hydrogen, halogen, cyano, nitro or groups of the following formula:

[0522] -L1-Y1-L2-Q1

[0523] in:

[0524] L1 does not exist;

[0525] Y1 does not exist or is -O-, -SO2-, or -S(O) (=NR) y1 )-、-N(R y1 )-、-C(O)N(R y1 )-、-N(R y1 C(O)-、-S(O)2N(R) y1 - or -N(R) y1 SO2-, where R y1 and R y1a Selected from hydrogen or (1-2C) alkyl;

[0526] L2 is absent or is a (1-2C) alkylene group; and

[0527] Q1 is hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic.

[0528] in:

[0529] (i) When Q1 is (1-4C)alkyl, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula:

[0530] -Y2-Q2

[0531] in:

[0532] Y2 does not exist; it is -O-, -OC(O)-, -C(O)NH-, or -C(O)NMe-.

[0533] Q2 is selected from:

[0534] hydrogen;

[0535] (1-4C) alkyl groups optionally substituted with one or more halogens; or

[0536] 4- to 7-membered heterocyclic rings;

[0537] (ii) When Q1 is a (3-6C)cycloalkyl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula:

[0538] -Y3-Q3

[0539] in:

[0540] Y3 does not exist or is -O-;

[0541] Q3 is selected from:

[0542] hydrogen;

[0543] (1-4C) alkyl groups optionally substituted with one or more halogens; or

[0544] 4- to 7-membered heterocyclic rings;

[0545] (iii) When Q1 is phenyl or a 5- to 6-membered heteroaryl group, it may optionally be further substituted by one or more substituents independently selected from halogens, cyano groups or by one or more groups of the formula -Y3-Q3 as defined above.

[0546] Suitablely, in compounds of formula I, ring A is as defined above or as defined in any of paragraphs (1) to (18) above. More suitablely, ring A is as defined in paragraphs (12) to (18) above. Most suitablely, ring A is as defined in paragraph (15) or paragraph (16) above.

[0547] Suitablely, in compounds of formula I, R1 is as defined above or as defined in any of paragraphs (19) to (24) above. More suitablely, R1 is as defined in paragraphs (21) to (23) above. Most suitablely, R1 is as defined in paragraph (22) or paragraph (23) above.

[0548] Suitablely, in compounds of formula I, R 100 As defined above or as defined in any of paragraphs (25) to (31) above. More appropriately, R 100 As defined in paragraphs (27) to (31) above. Most appropriately, R 100 As defined in paragraph (27) or paragraph (30) above.

[0549] Suitablely, in compounds of formula I, integers a and b are as defined above or as defined in any of paragraphs (32) to (34) above. More suitablely, integers a and b are as defined in paragraph (32) or paragraph (33) above. Most suitablely, integers a and b are as defined in paragraph (32) above.

[0550] Suitablely, in compounds of formula I, R2 and R3 are as defined above or as defined in any of paragraphs (35) to (38), (84), or (85) above. More suitablely, R2 and R3 are as defined in paragraphs (36) to (38) or (85) above. Most suitablely, R2 and R3 are as defined in paragraph (36) or paragraph (37) above.

[0551] Suitablely, in compounds of formula I, X4, X5, X6, and X7 are as defined above or as defined in any of paragraphs (39) to (54) above. More suitablely, X4, X5, X6, and X7 are as defined in paragraph (40) above. Most suitablely, X4, X5, X6, and X7 are as defined in paragraphs (41), (42), (49), or (50) above.

[0552] Suitablely, in compounds of formula I, R x4 As defined above, or as defined in any of paragraphs (55) through (58), (86), or (87) above. More appropriately, R x4 As defined in paragraphs (56) through (58) or (87) above. Most appropriately, R x4 As defined in paragraph (57) or paragraph (58) above.

[0553] Suitablely, in compounds of formula I, R x5 As defined above or as defined in any of paragraphs (59) to (62), (88), or (89) above. More appropriately, R x5 As defined in paragraphs (60) or (89) above. Most appropriately, R x5 As defined in paragraph (61) or paragraph (62) above.

[0554] Suitablely, in compounds of formula I, R x6 As defined above or as defined in any of paragraphs (59) to (62), (88), or (89) above. More appropriately, R x6 As defined in paragraphs (60) or (89) above. Most appropriately, R x6 As defined in paragraph (61) or paragraph (62) above.

[0555] Appropriately, R x5 and R x6 At least one of them is not hydrogen. In one implementation, when Rx5 and R x6 If both exist, then R x6 It is not hydrogen. In another implementation, when R x5 and R x6 If both exist, then R x5 It is not hydrogen. In one implementation, when R x5 and R x6 Both exist and R x5 When it is hydrogen, then R x6 It is not hydrogen. In one implementation, when R x5 and R x6 Both exist and R x6 When it is hydrogen, then R x5 It's not hydrogen.

[0556] In one implementation, R x5 and R x6 As defined above, the condition is R. x5 and R x6 At least one of them is not hydrogen. In another embodiment, R x5 and R x6 As defined in paragraph (59) above, the condition is R x5 and R x6 At least one of them is not hydrogen. In another embodiment, R x5 and R x6 As defined in paragraph (60) above, the condition is R x5 and R x6 At least one of them is not hydrogen. In another embodiment, R x5 and R x6 As defined in paragraph (61) above, the condition is R x5 and R x6 At least one of them is not hydrogen. In another embodiment, R x5 and R x6 As defined in paragraph (62) above, the condition is R x5 and R x6 At least one of them is not hydrogen. In another embodiment, R x6 As defined in paragraph (59) above, the condition is R x6 It is not hydrogen. In another implementation, R x6 As defined in paragraph (60) above, the condition is R x6 It is not hydrogen. In another implementation, R x6 As defined in paragraph (61) above, the condition is R x6 It is not hydrogen. In another implementation, R x6 As defined in paragraph (62) above, the condition is R x6It is not hydrogen. In another implementation, R x5 and R x6 As defined in paragraph (88) above, the condition is R x5 and R x6 At least one of them is not hydrogen. In another embodiment, R x5 and R x6 As defined in paragraph (89) above, the condition is R x5 and R x6 At least one of them is not hydrogen. In another embodiment, R x6 As defined in paragraph (88) above, the condition is R x6 It is not hydrogen. In another implementation, R x6 As defined in paragraph (89) above, the condition is R x6 It's not hydrogen.

[0557] Suitablely, in compounds of formula I, R x7 As defined above or as defined in any of paragraphs (63) or (64) above. More appropriately, R x7 As defined in paragraph (63) above. Most appropriately, R x7 As defined in paragraph (64) above.

[0558] Suitablely, in compounds of formula I, X8 is as defined above or as defined in either paragraph (65) or (66) above. More suitably, X8 is as defined in paragraph (65) above.

[0559] Appropriately, in compounds of formula I, integers c and d are as defined above or as defined in any of paragraphs (67) above.

[0560] Appropriately, in compounds of formula I, the integer e is as defined above or as defined in any of the paragraphs above (76).

[0561] Suitablely, in compounds of formula I, R 100a and R 100b As defined above or as defined in any of paragraphs (68) to (75) above. More appropriately, R 100a and R 100b As defined in paragraph (70). Most appropriately, R 100a and R 100b As defined in paragraph (72) or paragraph (73) above.

[0562] Suitablely, in compounds of formula I, R 100c As defined in paragraph (23) above.

[0563] In a specific group of compounds of formula I, the compound or a pharmaceutically acceptable salt thereof has one of the following structural formulas Ia to Iam:

[0564]

[0565]

[0566]

[0567]

[0568]

[0569] in:

[0570] Ring A, R1, R 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, integer c, R 100a Integers d and R 100b Integers e and R 100c It has any meaning as defined above, or as defined in any of the paragraphs (1) to (89) above.

[0571] Among a specific set of compounds of the present invention, these compounds have the structural formula Ia shown above.

[0572] Among a specific set of compounds of the present invention, these compounds have the structural formula Ib shown above.

[0573] Among a specific set of compounds of the present invention, these compounds have the structural formula Ic shown above.

[0574] Among a specific set of compounds of the present invention, these compounds have the structural formula Id shown above.

[0575] Among a specific set of compounds of the present invention, these compounds have the structural formula Ie shown above.

[0576] Among a specific set of compounds of the present invention, these compounds have the structural formula If as shown above.

[0577] Among a specific set of compounds of the present invention, these compounds have the structural formula Ig as shown above.

[0578] Among a specific set of compounds of the present invention, these compounds have the structural formula Ih as shown above.

[0579] Among a specific set of compounds of the present invention, these compounds have the structural formula Ii shown above.

[0580] Among a specific set of compounds of the present invention, these compounds have the structural formula Ij shown above.

[0581] Among a specific set of compounds of the present invention, these compounds have the structural formula Ik as shown above.

[0582] Among a specific set of compounds of the present invention, these compounds have the structural formula Im as shown above.

[0583] Among a specific set of compounds of the present invention, these compounds have the structural formula In as shown above.

[0584] Among a specific set of compounds of the present invention, these compounds have the structural formula Io as shown above.

[0585] Among a specific set of compounds of the present invention, these compounds have the structural formula Ip as shown above.

[0586] Among a specific set of compounds of the present invention, these compounds have the structural formula Iq as shown above.

[0587] Among a specific set of compounds of the present invention, these compounds have the structural formula Ir as shown above.

[0588] Among a specific set of compounds of the present invention, these compounds have the structural formula Is as shown above.

[0589] Among a specific set of compounds of the present invention, these compounds have the structural formula It as shown above.

[0590] Among a specific set of compounds of the present invention, these compounds have the structural formula Iu as shown above.

[0591] Among a specific set of compounds of the present invention, these compounds have the structural formula Iv as shown above.

[0592] Among a specific set of compounds of the present invention, these compounds have the structural formula Iw as shown above.

[0593] Among a specific set of compounds of the present invention, these compounds have the structural formula Ix as shown above.

[0594] Among a specific set of compounds of the present invention, these compounds have the structural formula Iy as shown above.

[0595] Among a specific set of compounds of the present invention, these compounds have the structural formula Iz shown above.

[0596] Among a specific set of compounds of the present invention, these compounds have the structural formula Iaa as shown above.

[0597] Among a specific set of compounds of the present invention, these compounds have the structural formula Iab as shown above.

[0598] Among a specific set of compounds of the present invention, these compounds have the structural formula Iac as shown above.

[0599] Among a specific set of compounds of the present invention, these compounds have the structural formula Iad as shown above.

[0600] Among a specific set of compounds of the present invention, these compounds have the structural formula Iae as shown above.

[0601] Among a specific set of compounds of the present invention, these compounds have the structural formula Iaf as shown above.

[0602] Among a specific set of compounds of the present invention, these compounds have the structural formula Iag as shown above.

[0603] Among a specific set of compounds of the present invention, these compounds have the structural formula Iah as shown above.

[0604] Among a specific set of compounds of the present invention, these compounds have the structural formula Iai as shown above.

[0605] Among a specific set of compounds of the present invention, these compounds have the structural formula Iaj as shown above.

[0606] Among a specific set of compounds of the present invention, these compounds have the structural formula Iak as shown above.

[0607] Among a specific set of compounds of the present invention, these compounds have the structural formula Ial as shown above.

[0608] Among a specific set of compounds of the present invention, these compounds have the structural formula Iam as shown above.

[0609] A specific group of compounds has any one of the formulas Ia to Iam above, wherein, and when rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has the following definition:

[0610] Ring A is as defined in paragraph (1) above;

[0611] R1 is defined as in paragraph (19) above;

[0612] R 100 As defined in paragraph (25) above;

[0613] R2 is defined as in paragraph (35) above;

[0614] R3 is defined as in paragraph (35) above;

[0615] The integer a is defined as in paragraph (32) above;

[0616] The integer b is defined as in paragraph (32) above;

[0617] X4 is defined in paragraph (39) above;

[0618] X5 is defined as in paragraph (39) above;

[0619] X6 is defined as in paragraph (39) above;

[0620] X7 is as defined in paragraph (39) above;

[0621] R x4 As defined in paragraph (55) above;

[0622] R x5 As defined in paragraph (59) above;

[0623] R x6 As defined in paragraph (59) above;

[0624] R x7 As defined in paragraph (63) above;

[0625] X8 is as defined in paragraph (65) above;

[0626] The integer c is defined as in paragraph (67) above;

[0627] The integer d is defined as in paragraph (67) above;

[0628] R 100a As defined in paragraph (69) above;

[0629] R 100b As defined in paragraph (69) above;

[0630] The integer e is defined as in paragraph (76) above;

[0631] R 100c As defined in paragraph (78) above.

[0632] A specific group of compounds has any one of the formulas Ia to Iam above, wherein, and when rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has the following definition:

[0633] Ring A is as defined in paragraph (3) above;

[0634] R1 is defined as in paragraph (18) above;

[0635] R 100 As defined in paragraph (26) above;

[0636] R2 is defined as in paragraph (36) above;

[0637] R3 is defined as in paragraph (36) above;

[0638] The integer a is defined as in paragraph (32) above;

[0639] The integer b is defined as in paragraph (32) above;

[0640] X4 is defined in paragraph (39) above;

[0641] X5 is defined as in paragraph (39) above;

[0642] X6 is defined as in paragraph (39) above;

[0643] X7 is as defined in paragraph (39) above;

[0644] R x4 As defined in paragraph (56) above;

[0645] R x5 As defined in paragraph (60) above;

[0646] R x6 As defined in paragraph (60) above;

[0647] R x7 As defined in paragraph (63) above;

[0648] X8 is as defined in paragraph (65) above;

[0649] The integer c is defined as in paragraph (67) above;

[0650] The integer d is defined as in paragraph (67) above;

[0651] R 100a As defined in paragraph (70) above;

[0652] R 100b As defined in paragraph (70) above;

[0653] The integer e is defined as in paragraph (76) above;

[0654] R 100c As defined in paragraph (23) above.

[0655] A specific group of compounds has any one of the formulas Ia to Iam above, wherein, and when rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has the following definition:

[0656] Ring A is as defined in paragraph (12) above;

[0657] R1 is defined as in paragraph (21) above;

[0658] R 100 As defined in paragraph (27) above;

[0659] R2 is defined as in paragraph (36) above;

[0660] R3 is defined as in paragraph (36) above;

[0661] The integer a is defined as in paragraph (32) above;

[0662] The integer b is defined as in paragraph (32) above;

[0663] X4 is defined as in paragraph (41) above;

[0664] X5 is as defined in paragraph (41) above;

[0665] X6 is defined as in paragraph (41) above;

[0666] X7 is as defined in paragraph (41) above;

[0667] R x5 As defined in paragraph (60) above;

[0668] R x6As defined in paragraph (60) above;

[0669] X8 is as defined in paragraph (65) above;

[0670] The integer c is defined as in paragraph (67) above;

[0671] The integer d is defined as in paragraph (67) above;

[0672] R 100a As defined in paragraph (72) above;

[0673] R 100b As defined in paragraph (72) above;

[0674] The integer e is defined as in paragraph (76) above;

[0675] R 100c As defined in paragraph (23) above.

[0676] A specific group of compounds has any one of the formulas Ia to Iam above, wherein, and when rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has the following definition:

[0677] Ring A is as defined in paragraph (15) above;

[0678] R1 is defined as in paragraph (22) above;

[0679] R 100 As defined in paragraph (30) above;

[0680] R2 is defined as in paragraph (37) above;

[0681] R3 is defined as in paragraph (37) above;

[0682] The integer a is defined as in paragraph (32) above;

[0683] The integer b is defined as in paragraph (32) above;

[0684] X4 is defined as in paragraph (41) above;

[0685] X5 is as defined in paragraph (41) above;

[0686] X6 is defined as in paragraph (41) above;

[0687] X7 is as defined in paragraph (41) above;

[0688] R x5 As defined in paragraph (61) above;

[0689] R x6 As defined in paragraph (61) above;

[0690] X8 is as defined in paragraph (65) above;

[0691] The integer c is defined as in paragraph (67) above;

[0692] The integer d is defined as in paragraph (67) above;

[0693] R 100a As defined in paragraph (73) above;

[0694] R 100b As defined in paragraph (73) above;

[0695] The integer e is defined as in paragraph (76) above;

[0696] R 100c As defined in paragraph (23) above.

[0697] A specific group of compounds has any one of the formulas Ia to Iam above, wherein, and when rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has the following definition:

[0698] Ring A is as defined in paragraph (16) above;

[0699] R1 is defined as in paragraph (23) above;

[0700] R 100 As defined in paragraph (30) above;

[0701] R2 is defined as in paragraph (37) above;

[0702] R3 is defined as in paragraph (37) above;

[0703] The integer a is defined as in paragraph (32) above;

[0704] The integer b is defined as in paragraph (32) above;

[0705] X4 is defined as in paragraph (41) above;

[0706] X5 is as defined in paragraph (41) above;

[0707] X6 is defined as in paragraph (41) above;

[0708] X7 is as defined in paragraph (41) above;

[0709] R x5 As defined in paragraph (61) above;

[0710] R x6 As defined in paragraph (61) above;

[0711] X8 is as defined in paragraph (65) above;

[0712] The integer c is defined as in paragraph (67) above;

[0713] The integer d is defined as in paragraph (67) above;

[0714] R 100a As defined in paragraph (73) above;

[0715] R 100b As defined in paragraph (73) above;

[0716] The integer e is defined as in paragraph (76) above;

[0717] R 100c As defined in paragraph (23) above.

[0718] A specific group of compounds has any one of the formulas Ia to Iam above, wherein, and when rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has the following definition:

[0719] Ring A is as defined in paragraph (1) above;

[0720] R1 is defined as in paragraph (19) above;

[0721] R 100 As defined in paragraph (25) above;

[0722] R2 is defined as in paragraph (84) above;

[0723] R3 is defined as in paragraph (84) above;

[0724] The integer a is defined as in paragraph (32) above;

[0725] The integer b is defined as in paragraph (32) above;

[0726] X4 is defined in paragraph (39) above;

[0727] X5 is defined as in paragraph (39) above;

[0728] X6 is defined as in paragraph (39) above;

[0729] X7 is as defined in paragraph (39) above;

[0730] R x4 As defined in paragraph (86) above;

[0731] R x5 As defined in paragraph (88) above;

[0732] R x6 As defined in paragraph (88) above;

[0733] R x7 As defined in paragraph (63) above;

[0734] X8 is as defined in paragraph (65) above;

[0735] The integer c is defined as in paragraph (67) above;

[0736] The integer d is defined as in paragraph (67) above;

[0737] R 100a As defined in paragraph (69) above;

[0738] R 100b As defined in paragraph (69) above;

[0739] The integer e is defined as in paragraph (76) above;

[0740] R 100c As defined in paragraph (78) above.

[0741] A specific group of compounds has any one of the formulas Ia to Iam above, wherein, and when rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R100a and R 100b When they exist, each has the following definition:

[0742] Ring A is as defined in paragraph (3) above;

[0743] R1 is defined as in paragraph (19) above;

[0744] R 100 As defined in paragraph (26) above;

[0745] R2 is defined as in paragraph (85) above;

[0746] R3 is defined as in paragraph (85) above;

[0747] The integer a is defined as in paragraph (32) above;

[0748] The integer b is defined as in paragraph (32) above;

[0749] X4 is defined in paragraph (39) above;

[0750] X5 is defined as in paragraph (39) above;

[0751] X6 is defined as in paragraph (39) above;

[0752] X7 is as defined in paragraph (39) above;

[0753] R x4 As defined in paragraph (87) above;

[0754] R x5 As defined in paragraph (89) above;

[0755] R x6 As defined in paragraph (89) above;

[0756] R x7 As defined in paragraph (63) above;

[0757] X8 is as defined in paragraph (65) above;

[0758] The integer c is defined as in paragraph (67) above;

[0759] The integer d is defined as in paragraph (67) above;

[0760] R 100a As defined in paragraph (70) above;

[0761] R 100b As defined in paragraph (70) above;

[0762] The integer e is defined as in paragraph (76) above;

[0763] R 100c As defined in paragraph (23) above.

[0764] A specific group of compounds has any one of the formulas Ia to Iam above, wherein, and when rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has the following definition:

[0765] Ring A is as defined in paragraph (12) above;

[0766] R1 is defined as in paragraph (21) above;

[0767] R 100 As defined in paragraph (27) above;

[0768] R2 is defined as in paragraph (85) above;

[0769] R3 is defined as in paragraph (85) above;

[0770] The integer a is defined as in paragraph (32) above;

[0771] The integer b is defined as in paragraph (32) above;

[0772] X4 is defined as in paragraph (41) above;

[0773] X5 is as defined in paragraph (41) above;

[0774] X6 is defined as in paragraph (41) above;

[0775] X7 is as defined in paragraph (41) above;

[0776] R x5 As defined in paragraph (89) above;

[0777] R x6 As defined in paragraph (89) above;

[0778] X8 is as defined in paragraph (65) above;

[0779] The integer c is defined as in paragraph (67) above;

[0780] The integer d is defined as in paragraph (67) above;

[0781] R 100a As defined in paragraph (72) above;

[0782] R 100b As defined in paragraph (72) above;

[0783] The integer e is defined as in paragraph (76) above;

[0784] R 100c As defined in paragraph (23) above.

[0785] A specific group of compounds has any one of the formulas Ia to Iam above, wherein, and when rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has the following definition:

[0786] Ring A is as defined in paragraph (15) above;

[0787] R1 is defined as in paragraph (22) above;

[0788] R 100 As defined in paragraph (30) above;

[0789] R2 is defined as in paragraph (85) above;

[0790] R3 is defined as in paragraph (85) above;

[0791] The integer a is defined as in paragraph (32) above;

[0792] The integer b is defined as in paragraph (32) above;

[0793] X4 is defined as in paragraph (41) above;

[0794] X5 is as defined in paragraph (41) above;

[0795] X6 is defined as in paragraph (41) above;

[0796] X7 is as defined in paragraph (41) above;

[0797] R x5 As defined in paragraph (89) above;

[0798] R x6 As defined in paragraph (89) above;

[0799] X8 is as defined in paragraph (65) above;

[0800] The integer c is defined as in paragraph (67) above;

[0801] The integer d is defined as in paragraph (67) above;

[0802] R 100a As defined in paragraph (73) above;

[0803] R 100b As defined in paragraph (73) above;

[0804] The integer e is defined as in paragraph (76) above;

[0805] R 100c As defined in paragraph (23) above.

[0806] A specific group of compounds has any one of the formulas Ia to Iam above, wherein, and when rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has the following definition:

[0807] Ring A is as defined in paragraph (16) above;

[0808] R1 is defined as in paragraph (23) above;

[0809] R 100 As defined in paragraph (30) above;

[0810] R2 is defined as in paragraph (85) above;

[0811] R3 is defined as in paragraph (85) above;

[0812] The integer a is defined as in paragraph (32) above;

[0813] The integer b is defined as in paragraph (32) above;

[0814] X4 is defined as in paragraph (41) above;

[0815] X5 is as defined in paragraph (41) above;

[0816] X6 is defined as in paragraph (41) above;

[0817] X7 is as defined in paragraph (41) above;

[0818] R x5 As defined in paragraph (89) above;

[0819] R x6 As defined in paragraph (89) above;

[0820] X8 is as defined in paragraph (65) above;

[0821] The integer c is defined as in paragraph (67) above;

[0822] The integer d is defined as in paragraph (67) above;

[0823] R 100a As defined in paragraph (73) above;

[0824] R 100b As defined in paragraph (73) above;

[0825] The integer e is defined as in paragraph (76) above;

[0826] R 100c As defined in paragraph (23) above.

[0827] A specific group of compounds has any one of the above formulas Ia to Iam, where, and when R 100 R2, R3, integer a, integer b, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has any of the definitions described herein, and when rings A, R1, X4, X5, X6, and X7 exist, each has the following definitions:

[0828] Ring A is as defined in paragraph (12) above;

[0829] R1 is defined as in paragraph (21) above;

[0830] X4 is selected from CH;

[0831] X5 is selected from N;

[0832] X6 is selected from CR x6 ;and

[0833] X7 is selected from N or CH.

[0834] A specific group of compounds has any one of the above formulas Ia to Iam, where, and when R 100R2, R3, integer a, integer b, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has any of the definitions described herein, and when rings A, R1, X4, X5, X6, and X7 exist, each has the following definitions:

[0835] Ring A is as defined in paragraph (15) above;

[0836] R1 is defined as in paragraph (22) above;

[0837] X4 is selected from CH;

[0838] X5 is selected from N;

[0839] X6 is selected from CR x6 ;and

[0840] X7 is selected from N or CH.

[0841] A specific group of compounds has any one of the above formulas Ia to Iam, where, and when R 100 R2, R3, integer a, integer b, R x4 R x5 R x6 R x7 X8, R 100a and R 100b When they exist, each has any of the definitions described herein, and when rings A, R1, X4, X5, X6, and X7 exist, each has the following definitions:

[0842] Ring A is as defined in paragraph (17) above;

[0843] R1 is defined as in paragraph (23) above;

[0844] X4 is selected from CH;

[0845] X5 is selected from N;

[0846] X6 is selected from CR x6 ;and

[0847] X7 is selected from N or CH.

[0848] A specific group of compounds has any one of the above formulas Ia to Iam, where, and when R 100 R2, R3, integer a, integer b, R x4 R x5 R x6 R x7X8, R 100a and R 100b When they exist, each has any of the definitions described herein, and when rings A, R1, X4, X5, X6, and X7 exist, each has the following definitions:

[0849] Ring A is as defined in paragraph (18) above;

[0850] R1 is defined as in paragraph (24) above;

[0851] X4 is selected from CH;

[0852] X5 is selected from N;

[0853] X6 is selected from CR x6 ;and

[0854] X7 is selected from N or CH.

[0855] In the group of compounds of the present invention, including compounds of formula I as defined above and any one of formulas Ia to Iam, R x4 and R x5 R x5 and R x6 Or R x6 and R x7 They can be linked to form fused (5-6C) cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocycles together with the carbon atoms to which they are attached, each optionally substituted with fluorine, chlorine, methyl, or hydroxyl. In these compounds, all other variable groups may have any of the definitions described herein.

[0856] Among these compounds, R is suitable. x4 and R x5 They are linked together to form fused 5- or 6-membered heteroaryl or 5- or 6-membered heterocycles together with the carbon atoms to which they are attached, each of which is optionally substituted with fluorine, chlorine, methyl or hydroxyl.

[0857] In a specific set of compounds of the present invention, including compounds of formula I as defined above and any one of formulas Ia to Iam, R x4 and R x5 They can be linked together to form fused (5-6C) cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocycles together with the carbon atoms to which they are attached, each of which may optionally be substituted with fluorine, chlorine, methyl, or hydroxyl.

[0858] Among these compounds, R is suitable. x4 and R x5 They are linked together to form fused 5- or 6-membered heteroaryl or 5- or 6-membered heterocycles together with the carbon atoms to which they are attached, each of which is optionally substituted with fluorine, chlorine, methyl or hydroxyl.

[0859] Specific compounds of the present invention include any of the compounds described in the Examples section of this application, or pharmaceutically acceptable salts thereof, particularly any of the following compounds, or pharmaceutically acceptable salts thereof:

[0860] N-(6-chloro-1,3-benzothiazo-2-yl)-4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3-carboxamide;

[0861] 2'-Chloro-N-(6-methanesulfonyl-1,3-benzothiazolyl-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0862] 2'-Chloro-N-(6-cyano-1,3-benzothiazo-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0863] 2'-Chloro-N-(6-iodo-1,3-benzothiazolyl-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0864] N-(6-bromo-1,3-benzothiazo-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0865] 2'-Chloro-N-{5-chloro-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0866] 2'-Chloro-N-{5-chloro-[1,3]thiazo[5,4-b]pyridin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0867] 3-(2-methoxyphenyl)-N-{[1,3]thiazo[5,4-d]pyrimidin-2-yl}pyridine-4-carboxamide;

[0868] N-(6-bromo-1,3-benzothiazo-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide;

[0869] 3-(2-methoxyphenyl)-N-{[1,3]thiazo[4,5-c]pyridin-2-yl}pyridine-4-carboxamide;

[0870] 3-(2-methoxyphenyl)-N-{[1,3]thiazo[4,5-b]pyridin-2-yl}pyridine-4-carboxamide;

[0871] 3-(2-methoxyphenyl)-N-[5-(trifluoromethyl)-1,3-benzothiazo-2-yl]pyridine-4-carboxamide;

[0872] N-(5-chloro-1,3-benzothiazo-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide;

[0873] 3-(2-methoxyphenyl)-N-{[1,3]thiazo[5,4-b]pyridin-2-yl}pyridine-4-carboxamide;

[0874] N-(1,3-benzothiazo-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide;

[0875] N-(5-cyano-1,3-benzothiazo-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide;

[0876] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-1,3-benzothiazo-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0877] 2'-Chloro-5'-methoxy-6-methyl-N-(6-nitro-1,3-benzothiazo-2-yl)-[4,4'-bipyridine]-3-carboxamide;

[0878] 4-(2-chloro-5-methoxy-4-pyridyl)-N-[5-[(3R)-3-hydroxypyrrolidine-1-yl]thiazo[5,4-d]pyrimidin-2-yl]-6-methyl-pyridine-3-carboxamide;

[0879] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(piperidin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0880] 2'-Chloro-N-[5-(4,4-difluoropiperidin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0881] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0882] 2'-Chloro-N-{5-[(3S)-3-hydroxypyrrolidone-1-yl]-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0883] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(pyrrolidone-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0884] 2'-Chloro-N-[5-(3,3-difluoropyrrolidone-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0885] 2'-Chloro-N-{5-[(3R)-3-hydroxypyrrolidone-1-yl]-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0886] 2'-Chloro-N-[5-(1,1-dioxo-1λ) 6 -Thiomorpholino-4-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0887] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(4-methylpiperazin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0888] 2'-Chloro-5'-methoxy-6-methyl-N-(5-{2-oxa-6-azaspiro[3.3]hept-6-yl}-[1,3]thiazo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide;

[0889] 2'-Chloro-5'-methoxy-N-{5-[(2-methoxyethyl)amino]-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0890] 2'-Chloro-N-[5-(3-hydroxyazacyclobutane-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0891] 2'-Chloro-5'-methoxy-N-[5-(3-methoxypyrrolidone-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0892] 2'-Chloro-N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0893] 2'-Chloro-5'-methoxy-6-methyl-N-{5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide;

[0894] 2'-Chloro-N-[5-(3-cyanopiperidin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0895] N-(6-amino-1,3-benzothiazo-2-yl)-4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3-carboxamide;

[0896] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(2-oxopiperidin-1-yl)-1,3-benzothiazo-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0897] 4-(2-chloro-5-methoxy-4-pyridinyl)-N-[5-(3,6-dihydro-2H-pyran-5-yl)thiazo[5,4-b]pyridin-2-yl]-6-methyl-pyridin-3-carboxamide;

[0898] 4-(2-chloro-5-methoxy-4-pyridinyl)-N-[6-(5-chloro-2-pyridinyl)-1,3-benzothiazolyl-2-yl]-6-methylpyridin-3-carboxamide;

[0899] N-[6-(5-chloropyridin-2-yl)-1,3-benzothiazo-2-yl]-3-(2-methoxyphenyl)pyridine-4-carboxamide;

[0900] 2'-Chloro-N-[6-(3-hydroxyoxacyclopentan-3-yl)-1,3-benzothiazo-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0901] 2'-Chloro-N-(6-methanesulfonamido-1,3-benzothiazo-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0902] 2'-Chloro-5'-methoxy-6-methyl-N-{[1,3]thiazo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide;

[0903] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(methylthio)-1,3-benzothiazo-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0904] 2'-Chloro-5'-methoxy-6-methyl-N-{[1,3]thiazo[5,4-c]pyridin-2-yl}-[4,4'-bipyridine]-3-carboxamide;

[0905] N-[5-(4-acetylpiperazin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0906] 2'-Chloro-N-{5-[(2-hydroxyethyl)amino]-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0907] 2'-Chloro-5'-methoxy-N-[5-(3-methoxyazacyclobutane-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0908] 2'-Chloro-N-{5-[(4-hydroxycyclohexyl)amino]-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0909] Racemic-2'-chloro-N-(5-{[(1R,3S)-3-hydroxycyclopentyl]amino}-[1,3]thiazo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0910] 2'-Chloro-5'-methoxy-6-methyl-N-{5-[(3R)-3-methylmorpholin-4-yl]-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide;

[0911] 2'-Chloro-5'-methoxy-6-methyl-N-{5-[(3S)-3-methylmorpholin-4-yl]-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide;

[0912] 2'-Chloro-5'-methoxy-6-methyl-N-{5-[(propyl-2-yl)amino]-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0913] 2'-Chloro-5'-methoxy-6-methyl-N-(5-{2-oxa-7-azaspiro[3.5]non-7-yl}-[1,3]thiazo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide;

[0914] 2'-Chloro-N-(5-{3,8-diazabicyclo[3.2.1]oct-3-yl}-[1,3]thiazo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0915] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(piperazin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0916] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(2-oxopyrrolidone-1-yl)-1,3-benzothiazolyl-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0917] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(3-oxomorpholin-4-yl)-1,3-benzothiazo-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0918] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(3-methyl-2-oxoimidazolidine-1-yl)-1,3-benzothiazolyl-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0919] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(2-oxo-1,3-oxazolidin-3-yl)-1,3-benzothiazo-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0920] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(2-oxoimidazolidine-1-yl)-1,3-benzothiazolyl-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0921] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(2-oxopiperidin-1-yl)-[1,3]thiazo[4,5-c]pyridin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0922] 2'-Chloro-5'-methoxy-6-methyl-N-{[1,3]thiazo[4,5-c]pyridin-2-yl}-[4,4'-bipyridine]-3-carboxamide;

[0923] 2'-Chloro-N-{6-chloro-[1,3]thiazo[5,4-c]pyridin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0924] 2'-Chloro-N-{6-chloro-[1,3]thiazo[4,5-c]pyridin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0925] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-[1,3]thiazo[4,5-c]pyridin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0926] 2'-Chloro-N-[6-(dimethylaminosulfonyl)-1,3-benzothiazo-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0927] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-[1,3]thiazo[4,5-b]pyridin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0928] 2'-Chloro-N-[6-(4-hydroxypiperidin-1-yl)-[1,3]thiazo[4,5-c]pyridin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0929] N-(1,3-benzothiazo-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0930] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(2-oxopiperidin-1-yl)-[1,3]thiazo[4,5-b]pyridin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0931] 2'-Chloro-N-[6-(4-hydroxypiperidin-1-yl)-[1,3]thiazo[4,5-b]pyridin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0932] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazo[5,4-b]pyridin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0933] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(2-oxopiperidin-1-yl)-[1,3]thiazo[5,4-b]pyridin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0934] 2'-Chloro-N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazo[5,4-b]pyridin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0935] 2'-Chloro-5'-methoxy-N-{5-methoxy-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0936] 2'-Chloro-5'-methoxy-6-methyl-N-(5-{2-oxa-6-azaspiro[3.4]oct-6-yl}-[1,3]thiazo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide;

[0937] 2'-Chloro-N-{5-[(2-hydroxy-2-methylpropyl)amino]-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0938] 2'-Chloro-5'-methoxy-6-methyl-N-{5-[(2-methylpropyl)amino]-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide;

[0939] 2'-Chloro-N-[5-(cyclobutanoamino)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0940] 2'-Chloro-5'-methoxy-N-[5-(4-methoxypiperidin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0941] 2'-Chloro-N-(5-{6-hydroxy-2-azaspiro[3.3]hept-2-yl}-[1,3]thiazo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0942] 2'-Chloro-5'-methoxy-6-methyl-N-(5-{6-oxa-2-azaspiro[3.4]oct-2-yl}-[1,3]thiazo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide;

[0943] 2'-Chloro-N-{6-[imino(methyl)oxo-λ 6 [-thioalkyl]-1,3-benzothiazolyl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0944] 2'-Chloro-N-[6-(1,1-dioxo-1λ) 6 [2-Thiazolidin-2-yl]-1,3-benzothiazolidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0945] 2'-Chloro-N-{6-[(4R)-4-hydroxy-2-oxopiperidin-1-yl]-1,3-benzothiazo-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0946] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(4-methyl-2-oxoperazin-1-yl)-1,3-benzothiazo-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0947] 2'-Chloro-N-[5-(3,6-dihydro-2H-pyran-4-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0948] N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxamide;

[0949] N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxamide;

[0950] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(trifluoromethyl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0951] 2'-Chloro-5'-methoxy-6-methyl-N-{5-methyl-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide;

[0952] 5'-Methoxy-2',6-Dimethyl-N-[5-(morpholin-4-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0953] 2'-Fluoro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0954] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(2-oxopiperidin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0955] 2'-Chloro-N-(5-{[(2R)-2-hydroxypropyl]amino}-[1,3]thiazo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0956] 2'-Chloro-N-(5-{[(2S)-2-hydroxypropyl]amino}-[1,3]thiazo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0957] 2'-Chloro-5'-methoxy-N-[5-(3-methoxy-3-methylazacyclobutane-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0958] N-(4-bromo-1,3-benzothiazo-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0959] 2'-Chloro-N-{4-[2-(dimethylcarbamoyl)ethyl]-1,3-benzothiazolyl-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0960] 2'-Chloro-N-[5-(cyanomethoxy)-1,3-benzothiazolyl-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0961] 2'-Chloro-N-{5-[difluoro(methylcarbamoyl)methoxy]-1,3-benzothiazolyl-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0962] N-(5-bromo-1,3-benzothiazo-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0963] 2'-Chloro-N-{5-[(dimethylcarbamoyl)difluoromethoxy]-1,3-benzothiazolyl-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0964] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(methylcarbamoyl)-1,3-benzothiazo-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0965] 2'-Chloro-5'-methoxy-N-(5-methoxy-1,3-benzothiazo-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0966] 2'-Chloro-5'-methoxy-N-{5-[(2-methoxyethyl)carbamoyl]-1,3-benzothiazo-2-yl}-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0967] 2'-Chloro-N-{7-[(dimethylcarbamoyl)methoxy]-[1,3]thiazo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0968] N-{5-[(1-acetylpiperidin-4-yl)methoxy]-1,3-benzothiazo-2-yl}-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0969] 2'-Chloro-N-{5-[(dimethylcarbamoyl)methoxy]-1,3-benzothiazolyl-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0970] 2'-Chloro-5'-methoxy-6-methyl-N-{5-[2-(morpholin-4-yl)ethoxy]-1,3-benzothiazo-2-yl}-[4,4'-bipyridine]-3-carboxamide;

[0971] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(propyl-2-yloxy)-1,3-benzothiazo-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0972] 2'-Chloro-N-{5-[(1,1-dioxo-1-λ6-thionylbutane-3-yl)methoxy]-1,3-benzothiazo-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0973] 2'-Chloro-N-(5-ethoxy-1,3-benzothiazolyl-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0974] 2'-Chloro-5'-methoxy-6-methyl-N-{5-[2-(trifluoromethoxy)ethoxy]-1,3-benzothiazolyl-2-yl}-[4,4'-bipyridine]-3-carboxamide;

[0975] 2'-Chloro-5'-methoxy-N-[6-(3-methoxyazacyclobutane-1-yl)-[1,3]thiazo[4,5-c]pyridin-2-yl]-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0976] 2'-Chloro-N-{6-[(2-hydroxy-2-methylpropyl)amino]-[1,3]thiazo[4,5-c]pyridin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0977] 2'-Chloro-5'-methoxy-N-[6-(3-methoxy-3-methylazacyclobutane-1-yl)-[1,3]thiazo[4,5-c]pyridin-2-yl]-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0978] 6-[(dimethylcarbamoyl)methyl]-5'-methoxy-N-{[1,3]thiazo[5,4d]pyrimidin-2-yl}-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxamide;

[0979] N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide;

[0980] 2'-Chloro-5'-methoxy-6-methyl-N-[5-(2-oxopiperidin-1-yl)-[1,3]thiazo[5,4-b]pyridin-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0981] 5-[(2-{2'-chloro-5'-methoxy-6-methyl]-[4,4'-bipyridine]-3-amino}-[1,3]thiazo[4,5-c]pyridin-6-yl)amino]valerate;

[0982] 5-[(2-{2'-chloro-5'-methoxy-6-methyl]-[4,4'-bipyridine]-3-amino}-[1,3]thiazo[5,4-b]pyridin-5-yl)amino]valerate;

[0983] 2'-Chloro-5'-methoxy-6-methyl-N-{5-[(2H-1,2,3,4-tetrazol-5-yl)methoxy]-1,3-benzothiazolyl-2-yl}-[4,4'-bipyridine]-3-carboxamide;

[0984] 2'-Chloro-N-(5-hydroxy-1,3-benzothiazolyl-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0985] 2-[(2-{2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-amino}-1,3-benzothiazolyl-5-yl)oxy]ethyl acetate;

[0986] 2'-Chloro-N-[5-(2-hydroxyethoxy)-1,3-benzothiazolyl-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0987] 2'-Chloro-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxylic acid 5-(4-hydroxypiperidin-1-yl)-[1,3]thiazo[5,4-d]pyrimidin-2-yl ester;

[0988] 2'-Chloro-N-[7-(cyanomethoxy)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0989] N-[7-(carbamoylmethoxy)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0990] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(morpholin-3-yl)-1,3-benzothiazo-2-yl]-[4,4'-bipyridine]-3-carboxamide;

[0991] 2'-Chloro-N-[5-(4-hydroxypiperidin-1-yl)-7-methyl-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;

[0992] 2'-Chloro-N-[5-(2-hydroxy-2-methylpropoxy)-[1,3]thiazo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide,

[0993] Or its pharmaceutically acceptable salt.

[0994] While the invention may relate to any compound or particular group of compounds as defined herein by optional, preferred or suitable features, or according to a particular embodiment, the invention may also relate to any compound or particular group of compounds that explicitly excludes the optional, preferred or suitable features or particular embodiments.

[0995] Suitablely, the present invention excludes any single compound that does not have the biological activity defined herein.

[0996] Salts and solvates

[0997] The compounds described herein (including final products and intermediates) may be isolated and used on their own, or may be isolated in the form of salts, suitably, pharmaceutically acceptable salts. It should be understood that, unless otherwise stated, the terms “salt” and “salt form” used alone or in combination with another term or terms include all inorganic and organic salts, including industrially acceptable salts and pharmaceutically acceptable salts as defined herein. As used herein, an industrially acceptable salt is a salt generally suitable for manufacture and / or processing (including purification) and for transport and storage, but may not be a salt generally intended for clinical or therapeutic use. Industrially acceptable salts can be prepared on a laboratory scale, i.e., a few grams or less, or on a larger scale, i.e., up to and including one kilogram or more.

[0998] As used herein, a pharmaceutically acceptable salt is a salt that is generally chemically and / or physically compatible with other components of a formulation, and / or generally physiologically compatible with its recipient. Pharmaceutically acceptable salts can be prepared on a laboratory scale, i.e., a few grams or less, or on a larger scale, i.e., up to and including one kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are generally administered or approved by the FDA or an equivalent foreign regulatory agency for human clinical or therapeutic use. Practitioners of ordinary skill will readily understand that some salts are both industrially acceptable and pharmaceutically acceptable. It should be understood that all such salts, including mixed salt forms, are within the scope of this application.

[0999] In one embodiment, compounds of Formula I and its subforms are isolated in the form of pharmaceutically acceptable salts.

[1000] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention having sufficient basicity, such as acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of the present invention having sufficient acidity are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tri-(2-hydroxyethyl)amine.

[1001] Typically, the salts of this application can be prepared in situ during the separation and / or purification of compounds (including intermediates), or by reacting the compound (or intermediate) alone with a suitable organic or inorganic acid or base (if appropriate) and separating the resulting salt. The degree of ionization in the salt can vary from fully ionized to almost unionized. In practice, various salts can be precipitated (with or without one or more cosolvents and / or antisolvents) and collected by filtration, or the salt can be recovered by evaporating the solvent. The salts of this application can also be formed by "salt conversion" or ion exchange / double displacement reactions (i.e., reactions in which one ion is completely or partially replaced by another ion with the same charge). Those skilled in the art will understand that salts can be prepared and / or separated using a single method or a combination of methods.

[1002] Representative salts include, but are not limited to, acetates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, hydrogen sulfates / sulfates, borates, camphor sulfonates, citrates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, hexafluorophosphates, phenoxylates, hydrochlorides / chlorides, hydrobromates / bromines, hydroiodates / iodides, hydroxyethyl sulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthalene sulfonates, 2-naphthalene sulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, sucroseates, stearates, succinates, tartrates, toluenesulfonates, trifluoroacetates, etc. Other examples of representative salts include alkali metal or alkaline earth metal cations, such as, but not limited to, sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine penicillin, choline, tromethamine, diethanolamine, glycine, meglumine, ethanolamine, etc.

[1003] Some compounds of Formula I and its subforms can exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that this invention covers all solvated forms having the biological activities described herein.

[1004] Polymorphs

[1005] It should also be understood that some compounds of Formula I and its subforms may exhibit polymorphism, and the present invention covers all such forms having the biological activities described herein.

[1006] N-oxides

[1007] Compounds of formula I and its derivatives containing amine functional groups can also form N-oxides. The compounds of formula I and its derivatives containing amine functional groups mentioned herein also include N-oxides. When a compound contains multiple amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as, but not limited to, hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as, but not limited to, dichloromethane.

[1008] Tautomers

[1009] Compounds of Formula I and its subforms can exist in many different tautomer forms, and references to Formula I and its subforms include all such forms. To avoid ambiguity, when a compound can exist in one of many tautomer forms, and only one is specifically described or shown, all other forms are included in Formula I and its subforms. Examples of tautomer forms include ketone, enol, and enol salt forms, such as the following tautomer pairs: ketone / enol (as shown below), pyrimidinone / hydroxypyrimidine, imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acidic nitro.

[1010]

[1011] Note: keto = ketone, enol = enol, enolate = enol compound.

[1012] Isomers

[1013] Compounds with the same molecular formula but different atomic bonding properties, sequences, or spatial arrangements are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while mirror images that do not overlap are called "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S sequence rules of Cahn and Prelog, or by rotating the molecular plane of polarized light, and are named dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[1014] Certain compounds of Formula I and their derivatives may have one or more asymmetric centers, and thus may exist in a variety of stereoisomers. Therefore, such compounds can be synthesized and / or isolated as mixtures and / or individual (pure) enantiomers, and in the case of two or more asymmetric centers, can be synthesized and / or isolated as single diastereomers and / or mixtures of diastereomers. It should be understood that this application includes all such enantiomers and diastereomers and mixtures thereof in all proportions.

[1015] Isotopes

[1016] This document describes the compounds of the present invention using structural formulas that do not specifically list the mass numbers or isotopic ratios of the constituent atoms. Therefore, this application is intended to include compounds in which the constituent atoms are present in any proportion of isotopic forms. For example, carbon atoms may be in... 12 C 13 C and 14 C exists in any proportion; hydrogen atoms can exist in any proportion. 1 H, 2 H and 3 H is present in any proportion; and so on. Preferably, the constituent atoms in the compounds of the present invention are present in proportions of their naturally occurring isotopic forms.

[1017] Prodrugs and metabolites

[1018] Compounds of Formula I and its derivatives can be administered as prodrugs, which decompose in the human or animal body to release the compounds of the present invention. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain suitable groups or substituents, and the modifying groups can be attached to these groups or substituents. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at the carboxyl or hydroxyl group of a compound of Formula I, and in vivo cleavable amide derivatives that can be formed at the carboxyl or amino group of a compound of Formula I and its derivatives.

[1019] Therefore, this invention includes compounds of Formula I and its sub-formulas as defined above, when they are obtainable through organic synthesis and in humans or animals through the cleavage of their prodrugs. Thus, this invention includes Formula I compounds produced by organic synthesis, as well as compounds produced in humans or animals through the metabolism of precursor compounds; that is, compounds of Formula I and its sub-formulas can be synthetically produced or metabolically produced compounds.

[1020] Suitable pharmaceutically acceptable prodrugs of Formula I and its subforms are prodrugs based on reasonable medical judgment that are suitable for administration to humans or animals without undesirable pharmacological activity or undue toxicity.

[1021] Various forms of prodrugs have been described, for example in the following literature:

[1022] a) Methods in Enzymology , Vol. 42 , p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

[1023] b)Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);

[1024] c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);

[1025] d)H. Bundgaard, Advanced Drug Delivery Reviews ,8 , 1-38 (1992);

[1026] e)H. Bundgaard, et al., Journal of Pharmaceutical Sciences , 77 , 285(1988);

[1027] f)N. Kakeya, et al., Chem. Pharm. Bull. , 32 , 692 (1984);

[1028] g)T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”,ACSSymposium Series, Volume 14; and

[1029] h)E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[1030] Suitable pharmaceutically acceptable prodrugs of compounds of formula I and its derivatives containing a carboxyl group are, for example, esters that are cleavable in vivo. Cleavable esters of formula I compounds containing a carboxyl group are, for example, pharmaceutically acceptable esters that cleave in the human or animal body to produce a parent acid. Suitable pharmaceutically acceptable esters containing a carboxyl group include C... 1-6 Alkyl esters, such as, but not limited to, methyl, ethyl, and tert-butyl esters, C 1-6 Alkoxymethyl esters, such as, but not limited to, methoxymethyl esters, C 1-6 Alkyloxymethyl esters, such as, but not limited to, neopentyloxymethyl esters, 3-phthalate esters, C 3-8 Cycloalkylcarbonyl-C 1-6 Alkyl esters, such as, but not limited to, cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxacyclopentenyl methyl ester, such as, but not limited to, 5-methyl-2-oxo-1,3-dioxacyclopenten-4-ylmethyl ester and C 1-6 Alkoxycarbonyloxy-C 1-6 Alkyl esters, such as, but not limited to, methoxycarbonyloxymethyl esters and 1-methoxycarbonyloxyethyl esters.

[1031] Suitable pharmaceutically acceptable prodrugs of compounds of formula I and its derivatives containing a hydroxyl group are, for example, esters or ethers that are cleavable in vivo. These cleavable esters or ethers are, for example, pharmaceutically acceptable esters or ethers that cleave in the human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable esterifying groups of the hydroxyl group include inorganic esters, such as, but not limited to, phosphate esters (including cyclic aminophosphates). Other suitable pharmaceutically acceptable esterifying groups of the hydroxyl group include C... 1-10 Alkyl groups, such as but not limited to acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, C 1-10 Alkoxycarbonyl, such as but not limited to ethoxycarbonyl, N,N-(C 1-6 2-Carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinemethyl, piperazine-1-ylmethyl, and 4-(C 1-4 Alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable etherifying groups of the hydroxyl group include α-acyloxyalkyl, such as, but not limited to, acetoxymethyl and neopentyloxymethyl.

[1032] Suitable pharmaceutically acceptable prodrugs of compounds of formula I and its derivatives having a carboxyl group are, for example, amides that are cleavable in vivo, such as amides formed with amines, including but not limited to ammonia. 1-4 Alkylamines, such as, but not limited to, methylamine, (C 1-4 Alkyl)2-amines, such as, but not limited to, dimethylamine, N-ethyl-N-methylamine, or diethylamine, C 1-4 Alkoxy-C 2-4 Alkylamines, such as, but not limited to, 2-methoxyethylamine, phenyl-C 1-4 Alkylamines, such as, but not limited to, benzylamine, and amino acids, such as, but not limited to, glycine or its esters.

[1033] Suitable pharmaceutically acceptable prodrugs of compounds having an amino group of formula I and its derivatives are, for example, their in vivo cleavable amide derivatives. Suitable pharmaceutically acceptable aminoamides include, for example, those with C... 1-10 Amides formed from alkyl acyl groups, wherein the alkyl acyl group is, for example but not limited to, acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinemethyl, piperazine-1-ylmethyl, and 4-(C 1-4 Alkyl)piperazine-1-ylmethyl.

[1034] The in vivo effects of compounds of Formula I and its derivatives can be partially exerted through one or more metabolites formed in the human or animal body after administration of compounds of Formula I and its derivatives. As mentioned above, the in vivo effects of compounds of Formula I and its derivatives can also be exerted through the metabolism of prodrugs (prodrugs).

[1035] Pharmaceutical compositions

[1036] According to another aspect of the invention, a pharmaceutical composition is provided comprising the compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[1037] The compositions of the present invention may be suitable for oral use (e.g., as tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g., as creams, ointments, gels or aqueous or oily solutions or suspensions), for inhalation (e.g., as fine powders or liquid aerosols), for inhalation (e.g., as fine powders), or for parenteral use (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[1038] The compositions of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Therefore, compositions for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[1039] An effective amount of the compound of the present invention used for treatment is sufficient to treat or prevent the proliferative condition mentioned herein, slow its progression, and / or alleviate symptoms associated with the disease.

[1040] The amount of active ingredient combined with one or more excipients to produce a single dosage form must vary depending on the individual being treated and the specific route of administration. For example, formulations intended for oral administration to humans typically contain, for example, 0.5 mg to 1.5 g (more suitably 0.5 to 600 mg, e.g., 1 to 200 mg) of the active ingredient, mixed with an appropriate and convenient amount of excipients, the amount of which can vary from about 5% to about 98% of the total composition weight.

[1041] According to well-known medical principles, the dosage of Formula I compounds used for therapeutic or preventative purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[1042] It should be noted that dosage and dosing regimens can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses administered over a specific period of time (days or hours), i.e., QD (once daily), BID (twice daily), etc. It should also be understood that for any given subject or patient, the specific dosage regimen may need to be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition. For example, the dosage may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Therefore, this application includes dose escalation in patients as determined by a person skilled in the art. Procedures and methods for determining appropriate dosages and dosing regimens are well known in the relevant art and readily identified by a person skilled in the art. Therefore, it will be readily understood and recognized by a person of ordinary skill that the dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.

[1043] When the compounds of the present invention are used for therapeutic or preventative purposes, they are typically administered at a daily dose, for example, ranging from 0.1 mg / kg to 75 mg / kg body weight, and may be divided into doses if necessary. Generally, a lower dose is administered when the administration is via a parenteral route. Thus, for example, for intravenous or intraperitoneal administration, a dose ranging from 0.1 mg / kg to 30 mg / kg body weight is typically used. Similarly, for inhalation administration, a dose ranging from, for example, 0.05 mg / kg to 25 mg / kg body weight is used.

[1044] For the compounds of the present invention, oral administration is particularly suitable. The compounds of the present invention can be formulated into tablets, capsules, or solutions for oral administration. Suitably, the compounds of the present invention are formulated into unit dosage forms (e.g., tablets or capsules) for oral administration. Typically, a unit dosage form will contain about 0.5 mg to 1.5 g of the compound of the present invention.

[1045] Synthesis

[1046] The compounds of the present invention can be prepared by any suitable technique known in the art. Specific methods for forming compounds of formula I as defined herein are shown in the accompanying Examples section.

[1047] In the description of the synthetic methods described herein and in any reference synthetic methods used to prepare the starting materials, it should be understood that those skilled in the art can choose all the proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and operating procedures.

[1048] Those skilled in the field of organic synthesis can understand that the functional groups present on different parts of a molecule must be compatible with the reagents and reaction conditions used.

[1049] It should be understood that during the synthesis of the compounds of this invention using the methods defined herein, or during the synthesis of certain starting materials, it may be necessary to protect certain substituents to prevent them from undergoing undesirable reactions. A skilled chemist will understand when such protection is needed and how to place such protecting groups in the appropriate positions before removing them.

[1050] For examples of protecting groups, see one of the many general textbooks on the subject, such as Theodora Green's 'Protective Groups in Organic Synthesis' (published by John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to a skilled chemist suitable for removing the protecting groups in question, chosen so as to achieve the removal of the protecting groups with minimal interference to groups elsewhere in the molecule.

[1051] Therefore, if the reactants include groups such as amino, carboxyl, or hydroxyl, it may be necessary to protect these groups in some of the reactions mentioned herein.

[1052] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups, such as but not limited to acetyl groups, alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or tert-butyloxycarbonyl groups, arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups, or aromatic acyl groups, such as benzoyl groups. The deprotection conditions for these protecting groups must vary depending on the choice of protecting group. Thus, for example, acyl groups such as alkanoyl, alkoxycarbonyl, or aromatic acyl groups can be removed, for example, by hydrolysis with a suitable base, such as but not limited to alkali metal hydroxides, such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as tert-butyloxycarbonyl groups can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed, for example, by hydrogenation on a catalyst such as carbon-supported palladium, or by treatment with a Lewis acid such as tris(boron trifluoroacetate). Suitable alternative protecting groups for primary amino groups are, for example, phthalyl groups, which can be removed by treatment with an alkylamine, such as dimethylaminopropylamine, or with hydrazine.

[1053] Suitable protecting groups for the hydroxyl group are, for example, acyl groups, alkanoyl groups such as acetyl, aromatic acyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for these protecting groups must vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or aromatic acyl groups can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl can be removed, for example, by hydrogenation on a catalyst such as a carbon-supported palladium.

[1054] Suitable protecting groups for the carboxyl group are, for example, esterification groups, such as methyl or ethyl groups that can be removed by hydrolysis with a base such as sodium hydroxide, or tert-butyl groups that can be removed by treatment with an acid such as an organic acid such as trifluoroacetic acid, or benzyl groups that can be removed by hydrogenation on a catalyst such as a carbon-supported palladium.

[1055] Resins can also be used as protecting groups.

[1056] The method for synthesizing compounds of formula (I) will be based on rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R 100a and R 100b The properties vary depending on the nature of any substituents associated with them. Suitable methods for preparing them are further described in the accompanying Examples section.

[1057] After a compound of formula (I) has been synthesized using any of the methods defined herein, the method may further include one or more additional steps:

[1058] (i) Remove any remaining protecting groups;

[1059] (ii) Converting a compound of formula (I) into another compound of formula (I);

[1060] (iii) pharmaceutically acceptable salts, hydrates, or solvates of compounds of formula I; and / or

[1061] (iv) Formation of a prodrug of a compound of formula I.

[1062] An example of (ii) above is when a compound of formula (I) is synthesized, and then rings A, R1, R... 100 R2, R3, integer a, integer b, X4, X5, X6, X7, R x4 R x5 R x6 R x7 X8, R 100a and R100b One or more groups in the compound can be further reacted to change the properties of the group and provide alternative compounds of formula (I).

[1063] The obtained compound of formula (I) can be separated and purified using techniques known in the art.

[1064] Therapeutic uses and applications

[1065] The compounds of this invention are potent inhibitors of Polθ. Data showing the Polθ inhibition of example compounds are given in the accompanying Examples section.

[1066] Therefore, compounds of formula I can be used to treat and / or prevent diseases and conditions associated with Polθ activity, such as, but not limited to, treating and / or preventing cancer and / or benign tumors.

[1067] On the one hand, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for therapeutic purposes.

[1068] On the other hand, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for treating diseases or conditions related to Polθ activity.

[1069] On the other hand, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for treating diseases or conditions associated with Polθ activity.

[1070] On the other hand, the present invention provides a method for treating a disease or condition related to Polθ activity, the method comprising administering to a subject in need an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[1071] On the other hand, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for treating diseases or conditions associated with abnormal Polθ activity.

[1072] On the other hand, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for treating diseases or conditions associated with abnormal Polθ activity.

[1073] On the other hand, the present invention provides a method for treating a disease or condition associated with abnormal Polθ activity, the method comprising administering to a subject in need an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[1074] On the other hand, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for the treatment of cancer or benign tumors.

[1075] On the other hand, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for treating cancer or benign tumors.

[1076] On the other hand, the present invention provides a method for treating cancer or benign tumors, the method comprising administering to a subject in need an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[1077] Benign tumors can include, for example, hemangiomas, hepatocellular adenomas, cavernous hemangiomas, focal nodular hyperplasia, acoustic neuromas, neurofibromas, bile duct adenomas, bile duct cysts, fibromas, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachoma, pyogenic granulomas, hydatidiform moles, uterine fibroids, thyroid adenomas, adrenocortical adenomas, or pituitary adenomas. Benign tumors may also be endometrial implants or odontogenic keratocystic tumors.

[1078] On the other hand, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for the treatment of cancer.

[1079] On the other hand, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for treating cancer.

[1080] On the other hand, the present invention provides a method for treating cancer, the method comprising administering to a subject in need an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[1081] The compounds of the present invention or pharmaceutically acceptable salts thereof may be used to treat homologous recombination (HR) defective cancers.

[1082] The compounds of the present invention or pharmaceutically acceptable salts thereof may be used to treat cancers characterized by a reduction or absence of homologous recombinant (HR) components.

[1083] Therefore, the compounds of the present invention can be used to treat cancers characterized by reduction or deletion of one or more of ATM, BARD1, PALB2, BRCA1 and BRCA2, deletion of one or more of the ATM, BARD1, PALB2, BRCA1 and BRCA2 genes, or reduced function of the ATM, BARD1, PALB2, BRCA1 and BRCA2 proteins.

[1084] In one specific aspect of the invention, the compounds of the invention or pharmaceutically acceptable salts thereof may be used to treat cancers characterized by reduced or absent BRCA gene expression, BRCA gene deletion, or reduced BRCA protein function.

[1085] In another aspect, the present invention relates to compounds of the present invention or pharmaceutically acceptable salts thereof for treating cancers resistant to PARP inhibitors.

[1086] The compounds of this invention can be used to treat adults. The compounds of this invention can also be used to treat pediatric patients.

[1087] Because of their inhibition of Polθ, the compounds of the present invention can be used to provide a method for depriving cells of their ability to undergo MMEJ. Therefore, these compounds are expected to show potential for treating or preventing proliferative conditions such as cancer. Furthermore, the compounds of the present invention can be used to treat diseases associated with cell accumulation.

[1088] In one embodiment, the compounds of the present invention exhibit suitable lethality in primary and secondary solid tumors (including breast tumors, ovarian tumors, prostate tumors, and pancreatic tumors) with BRCA1 and BRCA2 deficiencies. In another embodiment, the compounds of the present invention exhibit suitable lethality in a variety of primary and secondary solid tumors that cause HRD through mechanisms other than BRCA deficiency, such as those with promoter hypermethylation. In these tumors where no DSB repair pathway can be fully downregulated, the compounds of the present invention can be administered co-administered with another DDR modulator such as a PARP inhibitor, DNA-PK inhibitor, ATR inhibitor, ATM inhibitor, wee1 inhibitor, or CHK1 inhibitor.

[1089] In another embodiment, the compounds of the present invention possess suitable lethality in primary and secondary breast, ovarian, prostate, and pancreatic tumors that retain BRCA1 defects but are resistant to PARP inhibitor treatment after exposure to or without exposure to PARP inhibitor drugs.

[1090] In another embodiment, when administered with a PARP inhibitor treatment regimen, the compounds of the present invention suitably increase the objective response rate (ORR), including the complete response rate (CRR), delay the onset of PARP inhibitor resistance, increase relapse time and disease-free survival (DFS), and increase overall survival (OS) of primary and secondary tumors (breast tumors, ovarian tumors, prostate tumors, and pancreatic tumors) with homologous recombination defects (HRD, BRCA1 / 2 defects, and other HRD mechanisms).

[1091] In another embodiment, the compounds of the present invention are present in a variety of organisms with ATM activity deficiency (ATM). - / - The tumors appropriately exhibit synthetic pathology and / or synthetic lethality, particularly in the case of WT p53. Tumor types will include approximately 10% of all solid tumors, including gastric tumors, lung tumors, breast tumors, and CRC, as well as CLL. This activity can be further enhanced by co-administration with another DDR modulator such as a DNA-PK inhibitor, PARP inhibitor, or ATR inhibitor. Polθ inhibitors will sensitize CLL to classical chemotherapy and chemoimmunotherapy that have already developed resistance. Therefore, according to a further embodiment, the pharmaceutical composition of the present invention also comprises a DNA-PK inhibitor, PARP inhibitor, or ATR inhibitor.

[1092] In another embodiment, the compounds of the present invention suitably exhibit synthetic pathometry and / or synthetic lethality in a variety of tumors lacking the non-homologous end joining (NHEJ-D) DNA double-strand break repair process. Tumor types will include approximately 2-10% of all solid tumors, including prostate tumors, pancreatic tumors, cervical tumors, breast tumors, lung tumors, bladder tumors, and esophageal tumors. This activity can be further enhanced by co-administration with another DDR modulator such as a PARP inhibitor, ATM inhibitor, wee1 inhibitor, CHK inhibitor, or ATR inhibitor. Polθ inhibitors will further sensitize NHEJD cancer cells to chemotherapy and ionizing radiation-based therapies that induce DNA double-strand breaks (DSBs). Therefore, according to a further embodiment, the pharmaceutical compositions of the present invention also comprise a PARP inhibitor, an ATM inhibitor, a wee1 inhibitor, a CHK inhibitor, or an ATR inhibitor.

[1093] In another embodiment, the compounds of the present invention suitably reduce DNA replication stress during chemotherapy in HR-intact tumors such as ovarian tumors, NSCL, and breast tumors overexpressing Polθ. This will increase the objective response rate (ORR) of treatment and increase overall survival (OS). This effect is particularly likely to be used in conjunction with cytarabine (Ara-C) and hydroxyurea for the management of various leukemias and squamous cell carcinomas, including CML.

[1094] In another embodiment, the compounds of the present invention suitably and selectively sensitize solid tumors to radiotherapy (including EBRT and brachytherapy) with little or no sensitization to normal tissues. In graded, curative-oriented cases, this will increase local area control, thereby driving improved survival. This is particularly evident in the treatment of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (SCCH&N), rectal cancer, prostate cancer, and pancreatic cancer. In another embodiment, the compounds of the present invention suitably exhibit synthetic pathophysiology and / or synthetic lethality in PTEN-deficient tumors such as CaP, whether or not administered in combination with a PARP inhibitor. Furthermore, these tumors will exhibit extremely high sensitivity to radiotherapy due to the radiosensitivity induced by PTEN deficiency and Polθ inhibitors.

[1095] In another embodiment, the compounds of the present invention suitably inhibit TLS polymerase activity, thereby sensitizing primary and secondary solid tumors (e.g., breast tumors, lung tumors, ovarian tumors, CRC) to drugs (e.g., cisplatin, mitomycin, and cyclophosphamide) and reducing the acquisition of drug-induced mutations associated with tumor resistance, resulting in prolonged remission and increased TTR.

[1096] In another embodiment, the compounds of the present invention suitably resensitize BCR-ABL-positive CML that has developed imatinib resistance, as well as other solid tumors with elevated ligase Ilia levels, decreased ligase IV levels, and increased dependence on altEJ DSB repair.

[1097] In another embodiment, the compounds of the present invention suitably exhibit synthetic pathoxia and / or synthetic lethality in aromatase inhibitor-resistant ER primary and secondary breast cancer, again showing elevated ligase Ilia levels, decreased ligase IV levels, and increased dependence on altEJ DSB repair.

[1098] According to another aspect of the invention, a compound of formula (I) as defined herein is provided for treating tumors characterized by homologous recombination (HRD) defects.

[1099] It should be understood that the term "homologous recombination defect (HRD)" as used herein refers to any genetic variation that results in the defective or lost function of the resulting homologous recombination gene. Examples of such genetic variations include mutations (e.g., point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosomal abnormalities, copy number variations (CNVs), epigenetics, DNA inversions, reduced expression, and mislocations.

[1100] In one embodiment, the homologous recombination gene is selected from any of the following: ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), PTEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4, LIG1, RPA1, RPA2, BRIP1, and PTEN.

[1101] It should be understood that the term "non-homologous end junction defect (NHEJD)" as used herein refers to any genetic variation that results in defective or lost function of the resulting homologous recombination gene. Examples of such genetic variations include mutations (e.g., point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosomal abnormalities, copy number variations (CNVs), epigenetics, DNA inversions, reduced expression, and mislocations.

[1102] In one embodiment, the non-homologous end joining gene is selected from any one or more of the following: LIG4, NHEJ1, POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6, and DCLRE1C.

[1103] According to another aspect of the invention, a compound of formula (I) as defined herein is provided for treating tumors that overexpress Polθ.

[1104] According to another aspect of the invention, a compound of formula (I) as defined herein is provided for treating tumors having elevated levels of ligase Ilia, decreased levels of ligase IV, and increased dependence on altEJ DSB repair.

[1105] The cancer can be non-metastatic or metastatic, and can be a solid tumor or a hematologic (“liquid”) cancer. For example, the cancer can be selected from:

[1106] (1) Cancer, including, for example, tumors originating from stratified squamous epithelium (squamous cell carcinoma) and tumors occurring within organs or glands (adenocarcinoma). Examples include breast cancer, colon cancer, lung cancer, prostate cancer, ovarian cancer, esophageal cancer (including but not limited to esophageal adenocarcinoma and squamous cell carcinoma), basaloid breast cancer, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), head and neck cancer (including but not limited to squamous cell carcinoma), gastric cancer (including but not limited to gastric adenocarcinoma and gastrointestinal stromal tumor), signet ring cell carcinoma, bladder cancer (including transitional cell carcinoma (a malignant tumor of the bladder)), bronchial cancer, colorectal cancer (including but not limited to colon cancer and rectal cancer), anal cancer, Gastric cancer, lung cancer (including but not limited to small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, and mesothelioma), neuroendocrine tumors (including but not limited to carcinoid tumors of the gastrointestinal tract, breast, and other organs), adrenocortical carcinoma, thyroid cancer, pancreatic cancer (including but not limited to pancreatic ductal adenocarcinoma, pancreatic cancer, acinar cell carcinoma, intraductal papillary mucinous tumor with invasive carcinoma, mucinous cystic tumor with invasive carcinoma, islet cell carcinoma, and neuroendocrine tumors). Tumors, breast cancer (including but not limited to ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, and mucinous carcinoma), ovarian cancer (including but not limited to ovarian epithelial carcinoma or surface epithelial-stromal tumors, including serous tumors, endometrioid tumors, mucinous cystadenocarcinoma, and sex cord-stromal tumors), liver and bile duct cancers (including but not limited to hepatocellular carcinoma, bile duct cancer, and hemangioma), prostate cancer, adenocarcinoma, brain tumors (including but not limited to glioma, glioblastoma, and medulloblastoma), germ cell tumors, sweat gland cancer, sebaceous gland cancer, Papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, renal cell carcinoma (including but not limited to renal cell carcinoma, clear cell carcinoma, and Wilms' tumor), medullary carcinoma, ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, cervical cancer, uterine cancer (including but not limited to endometrial adenocarcinoma, papillary serous carcinoma of the uterus, clear cell carcinoma of the uterus, uterine sarcoma and leiomyosarcoma, mixed Müllerian tumor), testicular cancer, osteoblastic carcinoma, epithelial carcinoma, sarcomatoid carcinoma, nasopharyngeal carcinoma, laryngeal cancer; oral and oropharyngeal squamous cell carcinoma;

[1107] (2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelioma and mesothelioma (coelomic membrane lining); fibrosarcoma (fibrous tissue); angiosarcoma and angioendothelioma (vascular); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primordial embryonic connective tissue); chordoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, Ewing's sarcoma, mesenchymal and mixed mesodermal tumors (mixed connective tissue types) and other soft tissue sarcomas;

[1108] (3) Myeloma and multiple myeloma;

[1109] (4) Hematopoietic system tumors, including: myeloid and granulocytic leukemia (malignant tumors of the myeloid and granulocytic leukocyte series); lymphocytic, lymphocyte and lymphoblastic leukemia (malignant tumors of the lymphocyte and lymphocyte blood cell series); polycythemia vera and polycythemia vera (malignant tumors of various blood cell products but mainly of red blood cells); myelofibrosis.

[1110] (5) Lymphoma, including: Hodgkin lymphoma and non-Hodgkin lymphoma;

[1111] (6) Solid tumors of the nervous system, including medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma and schwannoma;

[1112] (7) Melanoma, uveal melanoma, and retinoblastoma; and

[1113] (8) Mixed types, including, for example, adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma or teratoma.

[1114] Other examples of treatable (or suppressable) cancers (and their benign counterparts) include, but are not limited to, tumors of epithelial origin (various types of adenomas and carcinomas, including adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, and other cancers), such as bladder and urinary tract cancers, breast cancers, gastrointestinal cancers (including esophageal cancer, gastric cancer, small bowel cancer, colon cancer, rectal cancer, and anal cancer), liver cancer (hepatocellular carcinoma), gallbladder and biliary system cancers, exocrine pancreatic cancers, kidney cancers, lung cancers (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma, and mesothelioma), head and neck cancers (e.g., tongue cancer, oral cavity cancer, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, tonsil cancer, salivary gland cancer, nasal cavity cancer, and paranasal sinus cancer), ovarian cancer, fallopian tube cancer, peritoneal cancer, vaginal cancer, vulvar cancer, penile cancer, cervical cancer, myometrial cancer, and endometrial cancer. Thyroid cancer (e.g., follicular thyroid carcinoma), adrenal cancer, prostate cancer, skin and adnexal cancers (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, nevus dysplasia); hematologic malignancies (i.e., leukemia, lymphoma) and pre-exacerbating hematologic disorders and borderline malignancies, including hematologic malignancies and lymphoid spectrum-related conditions (e.g., acute lymphoblastic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, MALT lymphoma, T-cell lymphoma and leukemia, natural killer [NK] cell lymphoma, Hodgkin's lymphoma, hairy cell leukemia, monoclonal gammopathy of undetermined significance). Gammopathy of uncertain significance), plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorders; as well as hematologic malignancies and myeloid-related conditions (e.g., acute myeloid leukemia [AML], chronic myeloid leukemia [CML], chronic myelomonocytic leukemia [CMML], eosinophilic syndrome, myeloproliferative disorders such as polycythemia vera, idiopathic thrombocythemia and primary myelofibrosis, myelodysplastic syndromes, myelodysplastic syndromes and promyelocytic leukemia); mesenchymal tumors, such as soft tissue sarcomas, bone or chondrosarcomas, such as osteosarcoma, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcoma, epithelioid sarcoma, etc. Gastrointestinal stromal tumors, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; tumors of the central or peripheral nervous system (e.g., astrocytomas, gliomas and glioblastomas, meningiomas, ependymomas, pineal tumors, and schwannomas); endocrine tumors (e.g., pituitary tumors, adrenal tumors, islet cell tumors, parathyroid tumors, carcinoid tumors, and medullary thyroid carcinoma); tumors of the eye and adnexa (e.g., retinoblastomas);Germ cell and trophoblastic tumors (e.g., teratomas, seminomas, dysgerminomas, hydatidiform moles, and choriocarcinomas); pediatric and embryonic tumors (e.g., medulloblastomas, neuroblastomas, nephroblastomas, and primitive neuroectodermal tumors); or congenital syndromes or other syndromes that predispose a patient to malignancy (e.g., xeroderma pigmentosum).

[1115] Specific examples of cancers that can be targeted by the compounds of this invention include, but are not limited to, lymphoma, rhabdomyosarcoma, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, prostate cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblastic carcinoma, central nervous system cancer, urinary tract cancer, upper respiratory and digestive tract cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer. More specifically, the cancers may be one or more of the following: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, and / or colorectal cancer.

[1116] Many diseases are characterized by persistent and uncontrolled angiogenesis. Chronic proliferative diseases are often accompanied by deep angiogenesis, which can lead to or maintain an inflammatory and / or proliferative state, or cause tissue destruction through invasive proliferation of blood vessels. Tumor growth and metastasis have been found to depend on angiogenesis. Therefore, the compounds of the present invention can be used to prevent and disrupt the initiation of tumor angiogenesis. In particular, the compounds of the present invention can be used to treat metastatic and metastatic cancers.

[1117] Metastatic or metastatic disease refers to the spread of disease from one organ or site to another non-adjacent organ or site. Cancers that can be treated with the compounds of this invention include primary tumors (i.e., cancer cells at the site of origin), locally invasive tumors (cancer cells that penetrate and infiltrate the surrounding normal tissue of a local area), and metastatic (or secondary) tumors, i.e., tumors formed by malignant cells that circulate to other parts and tissues of the body via the bloodstream (hematogenous spread), lymphatic vessels, or through body cavities (vacuole metastasis).

[1118] Specific cancers include hepatocellular carcinoma, melanoma, esophageal cancer, kidney cancer, colon cancer, colorectal cancer, lung cancer (such as mesothelioma or lung adenocarcinoma), breast cancer, bladder cancer, gastrointestinal cancer, ovarian cancer, and prostate cancer.

[1119] The compounds can also be used to treat tumor growth, pathogenesis, and resistance to chemotherapy and radiotherapy by sensitizing cells to chemotherapy, and as anti-metastatic agents.

[1120] Routes of administration

[1121] The compounds of the present invention or pharmaceutical compositions comprising these compounds may be administered to subjects via any convenient route of administration, whether systemic / peripheral or local (i.e., at the site of desired action).

[1122] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (e.g., by patches, plasters, etc.); transmucosal (e.g., by patches, plasters, etc.); intranasal (e.g., by nasal sprays); ocular (e.g., by eye drops, eye ointments, etc.); pulmonary (e.g., by inhalation or blowing therapy, such as by aerosols, such as by nose or mouth); rectal (e.g., by suppositories or enemas); vaginal (e.g., by vaginal suppositories); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; and by implantation of a reservoir or reservoir formulation, such as subcutaneous or intramuscular implantation.

[1123] The compounds of this invention are particularly suitable for oral administration.

[1124] Combination therapy

[1125] The compounds of the present invention as defined above, and their salts and solvates, may be used as a single therapy, or may include one or more other therapeutic agents, such as antitumor agents, in addition to the compounds of the present invention.

[1126] In the context of cancer treatment, in addition to the compounds of this invention, the therapy may additionally include conventional surgery, radiotherapy, and / or chemotherapy. Such chemotherapy may include one or more antitumor agents from the following classes:

[1127] - Other antiproliferative / antitumor drugs and combinations thereof used in medical oncology, such as, but not limited to, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine and folic acid antagonists, such as, but not limited to, fluoropyrimidines, such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); and antitumor antibiotics (e.g., anthracyclines). Drugs such as doxorubicin, bleomycin, doxorubicin, doxorubicin, epirubicin, idarubicin, mitomycin-C, styromycin, and styromycin; antimitotic agents (such as vinca alkaloids, such as vincristine, vinblastine, vinorelbine, and vinorelbine, as well as taxanes, such as paclitaxel and tisole, and multi-kinase inhibitors); and topoisomerase inhibitors (such as epipodophyllotoxin, such as etoposide and teniposide, acridine, topotecan, and camptothecin);

[1128] - Cell growth inhibitors, such as, but not limited to, anti-estrogenic drugs (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), anti-androgenic drugs (e.g., bicalutamide, flutamide, nilumet, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors, such as, but not limited to, finasteride;

[1129] - Anti-invasive agents [e.g., c-Src kinase family inhibitors, such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazolyl-5-carboxamide (dasatinib; BMS-354825; J. Med. Chem. , 2004, 47 [6658-6661) and besutinib (SKI-606) and metalloproteinase inhibitors such as marimastat, urokinase plasminogen activator receptor function inhibitors or heparanase antibodies];

[1130] - Inhibitors of growth factor function: Inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin™], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225], and Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54)). Any growth factor or growth factor receptor antibody disclosed in pp. 11-29); such inhibitors also include tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as, but not limited to, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI). 1033), erbB2 tyrosine kinase inhibitors, such as but not limited to lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as but not limited to imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as but not limited to farnesyltransferase inhibitors, such as sorafenib (BAY)). 43-9006), telbifabyl (R115777) and lonafabyl (SCH66336), cell signaling inhibitors via MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (e.g. AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors, such as, but not limited to, CDK2 and / or CDK4 inhibitors;

[1131] - Anti-angiogenic agents, such as, but not limited to, those drugs that inhibit the action of vascular endothelial growth factor (VEGF), [e.g., the anti-VEGF antibody bevacizumab (Avastin™) and, for example, VEGF receptor tyrosine kinase inhibitors, such as, but not limited to, vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034), and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidone-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00 / 47212), such as, but not limited to, international patent applications WO97 / 22596, WO97 / 30035, WO The compounds disclosed in WO 97 / 32856 and WO 98 / 13354, as well as compounds that act through other mechanisms (e.g., linomide, integrin αvβ3 function inhibitors, and angiostatin);

[1132] - Vascular damaging agents, such as, but not limited to, Combretastatin A4 and compounds disclosed in international patent applications WO 99 / 02166, WO00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;

[1133] - Endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan;

[1134] - Antisense therapies, such as those targeting the targets listed above, such as, but not limited to, ISIS 2503, an anti-ras antisense therapy;

[1135] - Gene therapy approaches, including, for example, methods of replacing abnormal genes, such as, but not limited to, abnormal p53 or abnormal BRCA1 or BRCA2; GDEPT (gene-directed enzyme prodrug therapy) approaches, such as, but not limited to, methods using cytosine deaminase, thymidine kinase, or bacterial nitroreductase; and methods of increasing patient tolerance to chemotherapy or radiotherapy, such as gene therapy for multidrug resistance; and

[1136] - Immunotherapy methods, including, for example, in vitro and in vivo methods, to increase the immunogenicity of a patient's tumor cells, such as, but not limited to, transfection with cytokines such as interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor, methods to reduce T cell incompetence, methods using transfected immune cells (e.g., but not limited to, cytokine-transfected dendritic cells), methods using cytokine-transfected tumor cell lines, and methods using anti-idiotype antibodies.

[1137] In one specific implementation, in addition to the compounds of the present invention, the antiproliferative treatment defined above may include conventional surgery, radiotherapy, or chemotherapy.

[1138] In another embodiment, in addition to the compounds of the present invention, the antiproliferative treatment defined above may include standard chemotherapy for the relevant cancer and / or therapy with DNA damage repair inhibitors (e.g., PARP, ATM, ATR, WEE1, CHK1, USP1 and DNAPK inhibitors).

[1139] In another embodiment, in addition to the compounds of the present invention, the antiproliferative treatment defined above may include therapy with PARP inhibitors.

[1140] This combination therapy can be achieved by administering the individual therapeutic components simultaneously, sequentially, or separately. This combination product uses compounds of the invention within the dosage range described above, and other pharmaceutically active agents within their approved dosage range.

[1141] According to this aspect of the invention, a composition for treating cancer (e.g., cancer involving solid tumors) is provided, comprising the compound of the invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another antitumor agent.

[1142] According to this aspect of the invention, there is provided a composition for treating proliferative conditions such as, but not limited to, cancer; proliferative diseases such as, but not limited to, cancer (e.g., cancer involving solid tumors), comprising the compound of the invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any of the antitumor agents listed above.

[1143] In another aspect of the invention, compounds of the invention or pharmaceutically acceptable salts, hydrates or solvates thereof are provided for use in combination with another antitumor agent for the treatment of cancer, said other antitumor agent optionally selected from one of those listed above.

[1144] In this document, when the term "combination" is used, it should be understood to mean simultaneous, separate, or sequential application. In one aspect of the invention, "combination" means simultaneous application. In another aspect of the invention, "combination" means separate application. In yet another aspect of the invention, "combination" means sequential application. When applied sequentially or separately, the delayed application of the second component should not result in a loss of the beneficial effects of the combination. In one embodiment, the composition refers to a combined product.

[1145] According to another aspect of the invention, a pharmaceutical composition is provided comprising a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with an antitumor agent (optionally selected from one listed above), and a pharmaceutically acceptable diluent or carrier.

[1146] Biological activity

[1147] The bioassays described in the Examples section (Bioassay 1) can be used to measure the pharmacological effects of the compounds of the present invention.

[1148] Although, as expected, the pharmacological properties of compounds of Formula I vary with structural changes, the compounds of the present invention were found to be active in the assays described in Bioassay 1. Typically, the compounds of the present invention show an IC50 of 5000 nM or lower in the assays described in Bioassay 1. 50 The preferred compounds of this invention exhibit IC50 of 100 nM or lower. 50 The most preferred compound of this invention exhibits an IC50 concentration of 30 nM or lower. 50 .

[1149] Other applications

[1150] The compounds of this invention are also potentially useful agents for improving the efficiency and robustness of CRISPR gene editing in vitro and in vivo.

[1151] In this regard, homologous recombination (HR) is fundamental to ensuring the correct modification of DNA (insertion of DNA into the genome, base mutations, etc.). Consistent with the hypothesis of TMEJ competing with HR to excise DNA breaks (Mateos-Gomez PA et al., (2017), Nat. Struct. Mol. Biol. (2017) 24(12):1116-1123), it has been shown that the absence of Polθ leads to an increase in HR of CRISPR-induced breaks and improves the fidelity and frequency of genome modifications (Mara K. et al., NewPhyto. (2019); 222(3):1380-1391; Zelenski AN et al., Nat. Commun., (2017); 8(1):66). Therefore, Polθ inhibitors can be used to improve the efficiency and robustness of CRISPR genome editing in vitro and potentially in vivo (Schimmel J. et al., Cell Rep. (2023) 42: 112019).

[1152] Therefore, the effect of Polθ deletion in enhancing the efficacy of CRISPR-mediated gene editing is described in WO 2017 / 062754. Consequently, the compounds of the present invention may be used to enhance the efficacy of CRISPR-based editing methods and / or CRISPR-based editing therapies. Furthermore, compound-mediated Polθ inhibition may reduce the frequency of random integration events, thereby providing a pathway to address any safety concerns associated with CRISPR-mediated technologies. Therefore, according to another aspect of the invention, the use of compounds of formula (I) as defined herein in CRISPR-based editing methods and / or CRISPR-based editing therapies, such as enhancing the efficacy of CRISPR-based editing methods and / or CRISPR-based editing therapies, is provided.

[1153] Therefore, on the other hand, the present invention provides the use of the compounds of the present invention (i.e., compounds of formula I or any of its sub-forms) or their salts, hydrates or solvates for in vitro or in vivo CRISPR gene editing.

[1154] On the other hand, the present invention provides the use of the compounds of the present invention (i.e., compounds of formula I or any of its subforms) or their salts, hydrates or solvates for increasing the efficiency of CRISPR gene editing in vitro or in vivo.

[1155] On the other hand, the present invention provides compounds of the present invention (i.e., compounds of formula I or any of its subforms) for in vivo CRISPR gene editing, or their salts, hydrates or solvates.

[1156] On the other hand, the present invention provides compounds of the present invention (i.e., compounds of formula I or any of its sub-forms) or their salts, hydrates or solvates for increasing the efficiency of CRISPR gene editing in vivo.

[1157] Example - Part A

[1158] The invention will now be described with reference to specific embodiments illustrated in the following examples, but is not limited thereto. Compounds are named using conventional IUPAC nomenclature or by the chemical supplier.

[1159] The following synthetic procedures are provided to illustrate the methods used; for a given preparation or step, the precursor used does not necessarily have to be derived from a single batch synthesized according to the steps described in the given description.

[1160] General

[1161] All solvents and chemical reagents were obtained from commercial sources and were ready for use without further purification or drying. NMR spectra were recorded on Bruker Avance III HD 400 MHz, Bruker NEO 400 MHz, Bruker Avance IIIHD 500 MHz, Bruker Avance NEO 500 MHz, or Bruker Avance III HD 600 MHz spectrometers. Chemical shifts are given in ppm using residual undeuterated solvents as an internal reference.

[1162] The following method was used to record LCMS spectra on a Waters Aquity UPLC:

[1163] Method A: Waters UPLC® BEH at -40°C TM A C18 2.1 x 50 mm 1.7 µm column was used for elution with 0.1% formic acid in acetonitrile and 0.1% formic acid in aqueous solution, using a gradient of 5-100%, for 1.35 min at a flow rate of 0.9 mL / min.

[1164] Method B: At -40℃, a Phenomenex Kinetix-XB C18 2.1 x 100 mm, 1.7 µm column was used for elution with 0.1% formic acid in acetonitrile and 0.1% formic acid in aqueous solution, using a gradient of 5-100%, for 5.8 min at a flow rate of 0.6 mL / min.

[1165] Method C, Waters UPLC® BEH at -55℃ TMC18 2.1 x 50 mm 1.7 µm column, eluted with 2 mM ammonium bicarbonate aqueous solution buffered to pH 10 and acetonitrile, using a gradient of 1-100%, for 1.10 min at a flow rate of 1 mL / min;

[1166] Method D, Waters UPLC® BEH at -55℃ TM C18 2.1 x 100 mm 1.7 µm column, eluted with 2 mM ammonium bicarbonate aqueous solution buffered to pH 10 and acetonitrile, using a gradient of 5-100%, for 5.30 min at a flow rate of 0.6 mL / min;

[1167] Method E: At -55℃, a CSH C18 2.1 x 50 mm, 1.7 µm column was used for elution with 0.035% TFA in acetonitrile and 0.05% TFA in aqueous solution, using a gradient of 2%-98%, for 1.5 min at a flow rate of 0.8 mL / min.

[1168] Method F: At -55℃, a Waters CSH C18 2.1 x 50 mm, 1.7 µm column was used for elution with 0.035% TFA in acetonitrile and 0.05% TFA in aqueous solution, using a gradient of 2%-98%, for 2.4 min at a flow rate of 0.8 mL / min.

[1169] Method G: Elution was performed at -55℃ using a CSH C18 2.1 x 50 mm, 1.7 µm column, eluting with a gradient of 2%–98% using acetonitrile solution of 0.02% formic acid and aqueous solution of 0.02% formic acid, for 4.5 min at a flow rate of 1 mL / min; or

[1170] Method H: At 55 °C, a CSH C18 2.1 x 50 mm, 1.7 µm column was used for elution with 0.02% formic acid in acetonitrile and 0.02% formic acid in aqueous solution, using a gradient of 2%–98%, for 2.4 min at a flow rate of 0.8 mL / min.

[1171] Mass spectra were obtained using electrospray ionization in positive or negative modes with a Waters SQD, SQD2, or QDA detector. LCMS purity was determined at 215, 254, or 280 nm using AUC monitoring.

[1172] Preparative HPLC was performed using any of the following methods:

[1173] Method A - At room temperature, using a Waters Sunfire C18 30 mm × 100 mm, 5 μm column, incubation was performed for 1.9 min with a solution of 30% 0.1% formic acid in acetonitrile and 70% 0.1% formic acid in aqueous solution, followed by a gradient of 30-95% 0.1% formic acid in acetonitrile for 9.6 min at a flow rate of 40 mL / min;

[1174] Method B - At room temperature, using a Waters XBridge C18 column (30 mm × 100 mm, 5 μm), incubate with an aqueous solution of 30% acetonitrile and 70% 0.2% ammonium hydroxide for 2 min, followed by an acetonitrile gradient of 30-95% for 9.5 min at a flow rate of 40 mL / min; or

[1175] Method C - Waters Sunfire™ C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), injection volume 1500 μL, flow rate 40 mL / min, 10% B for 1.90 min, followed by a 10–95% B gradient for 14.10 min, hold for 2.0 min, where A = 0.1% aqueous formic acid and B = 0.1% acetonitrile formic acid.

[1176] The UV spectrum was recorded at 215 nm using a Gilson detector.

[1177] List of abbreviations

[1178] RT room temperature

[1179] DTBPF di-tert-butylphosphine ferrocene

[1180] THF tetrahydrofuran

[1181] TCFH Chloro-N,N,N′,N′-Tetramethylformamidin hexafluorophosphate

[1182] DCM dichloromethane

[1183] DIPEAN, N-diisopropylethylamine

[1184] DMF dimethylformamide

[1185] DCE dichloroethane

[1186] DPPF diphenylphosphine ferrocene

[1187] Sat. saturation

[1188] Equiv. equivalent

[1189] SPhos2-Bicyclohexylphosphino-2′,6′-dimethoxybiphenyl

[1190] Pd2(dba)3tris(dibenzylacetone)dipalladium(0)

[1191] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene

[1192] NMIN-methylimidazole

[1193] NBSN-bromosuccinimide

[1194] DPEPhos (oxydi-2,1-phenylene)bis(diphenylphosphine)

[1195] THF tetrahydrofuran

[1196] DMAPN, N-dimethylaminopyridine

[1197] Rt retention time

[1198] General schemes

[1199] Note: Procedure = program, OR = or, the same applies below.

[1200] In the above scheme, X 100 It is a halide; A1 is N or C-Me; when A1 is C-Me, A2 is N, or when A is N, A2 is CH; group R x5a and R x6a They are different groups R formed by program D respectively. x5 and R x6 The remaining groups are as defined above.

[1201] General procedure A for Suzuki coupling

[1202] To the desired aryl halide (1 equivalent) in a round-bottom flask equipped with a magnetic stir bar, add the corresponding boric acid (1.5 equivalents), dipotassium carbonate (3.7 equivalents), and palladium catalyst (10 mol%). The mixture was purged with nitrogen, stirred at 90 °C for 18 h using a condenser. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The solution was then analyzed via Biotage Isolera. TM Automated chromatography was used to purify the crude product using a gradient of ethyl acetate in heptane to obtain the desired biaryl product.

[1203] Intermediate 1:

[1204] 4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3-carboxylic acid methyl ester

[1205]

[1206] To a solution of methyl 4-chloro-6-methylpyridin-3-carboxylic acid (1.20 g, 6.47 mmol) in 1,4-dioxane (21 mL) and water (7 mL) equipped with a magnetic stir bar, 2-chloro-5-methoxy-4-pyridinyl)boronic acid (1.60 g, 8.54 mmol), dipotassium carbonate (3.30 g, 23.9 mmol), and palladium dichloride (DTBPF) (360 mg, 0.55 mmol) were added. The mixture was purged with nitrogen, stirred at 90 °C for 18 h using a condenser. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The organic extracts were combined, washed with brine, dried (Na₂SO₄), and the solvent was removed under reduced pressure. The solution was then analyzed by Biotage Isolera. TM The crude product was purified by automated chromatography (Sfar Duo, 100 g) using a gradient of 0-100% ethyl acetate in heptane. The fraction containing the product was evaporated under reduced pressure to give the title compound (5.03 g, 91% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO – d6) δ 8.88 (s, 1H), 8.23 ​​(s, 1H), 7.50 (s, 1H), 7.38 (s, 1H), 3.78 (s, 3H), 3.68 (s, 3H), 2.58(s, 3H). LCMS (Method B); RT 2.58 min (100%), m / z 293.1 / 295.1 (M+H) + .

[1207] Using the general procedure A detailed above, intermediates 2 and 3 in Table 1 below are synthesized in the same way.

[1208] Table 1 – Intermediates 2 and 3 synthesized using general procedure A

[1209] Intermediate Yield LCMS purity (%) LCMS RT (min) m / z LCMS method 1H NMR Intermediate 2 3-(2-methoxyphenyl)pyridine-4-carboxylic acid methyl ester 65 90 0.76 244.2 A 1 H NMR (500 MHz, DMSO - d6) δ 8.70 (d, J = 4.9 Hz, 1H), 8.59 (s, 1H), 7.64 (dd, J = 4.9, 0.8 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.33 (dd, J = 7.4, 1.7 Hz, 1H), 7.09 - 7.04 (m, 2H), 3.66 (d, J = 2.7 Hz, 6H). <!-- 64 -->]]> ​ Intermediate 3 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester 91 100 2.58 293.1 / 295.1 B 1 H NMR (400 MHz, DMSO - d6) δ 8.88 (s, 1H), 8.23 (s, 1H), 7.50 (s, 1H), 7.38 (s, 1H), 3.78 (s, 3H), 3.68 (s, 3H), 2.58 (s, 3H)]]> ​

[1210] General procedure B for ester hydrolysis

[1211] A solution of methyl ester (1 equivalent) in THF (0.2 mmol / mL) was added to a solution of 1 M lithium hydroxide aqueous solution (2 equivalents), and the mixture was stirred for 18 h. The mixture was acidified to pH 3 with 1 M HCl aqueous solution and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure. The resulting solid was dried overnight in a vacuum oven at 40 °C to obtain the desired carboxylic acid.

[1212] Intermediate 4

[1213] 4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3-carboxylic acid

[1214]

[1215] To a solution of methyl 4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3-carboxylic acid (5.03 g, 17.2 mmol) in THF (98 mL), 1 M lithium hydroxide aqueous solution (35 mL, 35.0 mmol) was added, and the mixture was stirred for 18 h. The mixture was acidified to pH 3 with 1 M HCl aqueous solution and extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were dried (Na₂SO₄) and concentrated under reduced pressure. The resulting solid was dried overnight in a vacuum oven at 40 °C to give the title compound (3.30 g, 69% yield) as a white solid. 1 H NMR (400 MHz, DMSO - d6) δ 13.06 (s,1H), 8.89 (s, 1H), 8.21 (s, 1H), 7.44 (s, 1H), 7.30 (s, 1H), 3.79 (s, 3H), 2.56 (s, 3H). LCMS (Method B); RT 1.63 min (100%), m / z 279.1 / 281.1 (M+H) + .

[1216] Using the general procedure B detailed above, intermediates 5 and 6 in Table 2 below are synthesized in the same way.

[1217] Table 2 - Intermediates 2 and 3 synthesized using general procedure A

[1218] Intermediate Yield LCMS purity (%) LCMS RT (min) m / z LCMS method 1H NMR Intermediate 53 - (2-methoxyphenyl)pyridine-4-carboxylic acid 70 95 0.4 230.2 A 1 H NMR (400 MHz, DMSO - d6) δ 8.66 (d, J = 5.0 Hz, 1H), 8.53 (d, J = 0.7 Hz, 1H), 7.63 (dd, J = 5.0, 0.7 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.28 (dd, J = 7.7, 1.7 Hz, 1H), 7.07 - 7.03 (m, 2H), 3.67 (s, 3H). ​ Intermediate 62 - Chloro-5'-methoxy-6-methyl- [4,4'-bipyridinyl]-3-carboxylic acid 69 100 1.63 279.1 / 281.1 B 1 H NMR (400 MHz, DMSO - d6) δ 13.06 (s, 1H), 8.89 (s, 1H), 8.21 (s, 1H), 7.44 (s, 1H), 7.30 (s, 1H), 3.79 (s, 3H), 2.56 (s, 3H)]]> ​

[1219] General procedure C for amide coupling

[1220] A solution of TCFH (1.1 equivalents) in acetonitrile was added to a solution of carboxylic acid (1.1 equivalents), amine (1 equivalent), and 1-methylimidazole (5.1 equivalents) in acetonitrile. The mixture was stirred at room temperature for 18 h.

[1221] When the product precipitates from the solution, it is filtered, washed with diethyl ether, and dried in a vacuum oven at 40°C to obtain the desired amide. When no precipitate forms, the solution is diluted with ethyl acetate and washed with a saturated aqueous solution of NaHCO3. The organic extracts are combined, dried (using Na2SO4), and concentrated under reduced pressure. The solution is then analyzed via Biotage Isolera. TM The crude product was purified by automated chromatography using a gradient of methanol in methyl acetate or by preparative HPLC method A to obtain the desired amide.

[1222] Example 1 - N-(6-chloro-1,3-benzothiazol-2-yl)-4-(2-chloro-5-methoxy-4-pyridyl)-6- methyl-pyridine-3-carboxamide Example

[1223]

[1224] To a solution of 4-(2-chloro-5-methoxy-4-pyridyl)-6-methylpyridine-3-carboxylic acid (50 mg, 0.18 mmol) in acetonitrile (1 mL), 6-chloro-1,3-benzothiazol-2-amine (36 mg, 0.20 mmol) and 1-methylimidazole (73 μL, 0.91 mmol) were added, followed by rinsing with nitrogen. A solution of TCFH (53 mg, 0.20 mmol) in acetonitrile (1 mL) was added to the above solution, and the reaction mixture was stirred at room temperature for 18 h. The product was precipitated from the reaction mixture and filtered. The filter cake was washed successively with acetonitrile and diethyl ether, and then dried in a vacuum oven at 40 °C for 3 h to give the title compound (53 mg, 66% yield) as a colorless powder. 1 H NMR (500 MHz, DMSO – d6) δ 13.04 (s, 1H), 8.85 (s, 1H), 8.16(s, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.58 (s, 1H), 7.50 – 7.44 (m, 2H), 3.59 (s, 3H), 2.60 (s, 3H). LCMS (Method B); RT 3.60 min(99%), m / z 445.0 / 446.9 (M+H) +

[1225] The same general procedure C described above is used to synthesize Examples 2 to 18 in Table 3 below.

[1226] Table 3 - Examples 2 to 18 synthesized using general procedure C

[1227] Yield LCMS purity (%) LCMS RT (min) m / z LCMS method 1H NMR General procedure D for SNAr reaction Example 22 -Chloro-N-(6-methanesulfonyl-l,3-benzothiazol-2-yl)-5'-methoxy-6- methyl-[4,4'-bipyridine]-3-carboxamide 12 100 2.73 489.2 / 491.2 B <![CDATA[ 1 H NMR (500MHz, DMSO –d6) δ 13.26(s, 1H), 8.87(s, 1H), 8.65(s, 1H), 8.16(s, 1H), 7.99– 7.95 (m,2H), 7.60 (s,1H), 7.48 (s,1H), 3.58 (s,3H), 3.25 (s,3H), 2.61 (s,3H). <!-- 67 -->]]> Example 32 -Chloro-N-(6-cyano-l,3-benzothiazol-2-yl)-5'-methoxy-6-methyl- [4,4'-bipyridine]-3-carboxamide 15 100 3.1 436.2 / 438.2 B 1 H NMR (500MHz, DMSO - d6) δ 13.28 (s, 1H), 8.87 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.5, 1.8 Hz, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 3.58 (s, 3H), 2.61 (s, 3H).]] ​ Example 42 -chloro-N-(6-iodo-l,3-benzothiazol-2-yl)-5'-methoxy-6-methyl- [4,4'-bipyridine]-3-carboxamide 72 100 3.79 535.1 / 537.1 B <![CDATA[ 1 H NMR (500MHz, DMSO –d6) δ 13.02(s, 1H), 8.85(s, 1H), 8.39(d, J = 1.8Hz, 1H), 8.16(s, 1H), 7.74(dd, J = 8.4,1.8 Hz, 1H),7.59 – 7.55(m, 2H), 7.46(s, 1H), 3.59(s, 3H), 2.60(s, 3H)。 <!-- 68 -->]]> Example 5 N-(6-bromo-l,3-benzothiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl- [4,4'-bipyridine]-3-carboxamide 65 98 3.73 489.1 / 491.1 B 1 H NMR (400MHz, CDCl3) δ11.63 (s,1H), 8.77 (s,1H), 8.04 (s,1H), 7.94 (d,J = 2.0 Hz,1H), 7.29(dd, J = 8.6,2.0 Hz, 1H),7.13 (s, 1H),7.05 (s, 1H),6.80 (d, J =8.7 Hz, 1H),3.70 (s, 3H),2.64 (s, 3H)]]> ​ Example 62 -chloro-N-{5-chloro-[l,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6- methyl-[4,4'-bipyridinyl]-3-carboxamide 22 95 3.08 447.0 / 449.0 B 1 H NMR (400MHz, DMSO –d6) δ 13.50(s, 1H), 9.12(s, 1H), 8.88(s, 1H), 8.17(s, 1H), 7.59(s, 1H), 7.47(s, 1H), 3.61(s, 3H), 2.61(s, 3H).]]> ​ Example 72 -chloro-N-{5-chloro-[l,3]thiazolo[5,4-b]pyridin-2-yl}-5'-methoxy-6-methyl- [4,4'-bipyridinyl]-3-carboxamide 4 85 3.29 446.0 / 448.0 B <![CDATA[ 1 H NMR (400MHz, DMSO –d6) δ 13.21(s, 1H), 8.87(s, 1H), 8.20– 8.15 (m,2H), 7.60 –7.55 (m, 2H),7.46 (s, 1H),3.61 (s, 3H),2.60 (s, 3H)。 <!-- 69 -->]]> Example 83 - (2-methoxyphenyl) -N- { [1,3] thiazolo [5,4-d] pyrimidin-2-yl} pyridine-4- carboxamide 11 100 2.41 364 B 1 H NMR (400MHz, DMSO -d6) δ 13.33 (s, 1H), 9.20 (s, 1H), 9.03 (s, 1H), 8.76 (d, J = 4.9 Hz, 1H), 8.66 (s, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.09 (t, J = 6.9 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 3.51 (s, 3H). ​ Example 9 N-(6-bromo-l,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4- carboxamide 16 100 3.7 440.0 / 442.1 B 1 H NMR (400MHz, DMSO –d6) δ 8.72(s, 1H), 8.62(s, 1H), 8.23(s, 1H), 7.68(d, J = 5.1Hz, 2H), 7.57(s, 1H), 7.38(s, 2H), 7.10– 7.05 (m,1H), 6.98 (d,J = 8.3 Hz,1H), 3.49 (s,3H). <!-- 70 -->]]> ​ Example 103 - (2-methoxyphenyl) -N- { [1,3] thiazolo [4,5-c] pyridin-2-yl} pyridine-4- carboxamide 6 99 1.73 363.1 B 1 H NMR (400MHz, DMSO –d6) δ 9.00(s, 1H), 8.76– 8.70 (m,1H), 8.62 (s,1H), 8.41 –8.35 (m, 1H),8.02 (s, 1H),7.72 – 7.67(m, 1H), 7.42– 7.33 (m,2H), 7.10 –7.03 (m, 1H),6.99 – 6.94(m, 1H), 3.48(s, 3H).]]> ​ Example 113 - (2-methoxyphenyl) -N- { [1,3] thiazolo [4, 5-b] pyridin-2-yl} pyridine-4- carboxamide 25 98 2.49 363.1 B 1 H NMR (400MHz, DMSO - d6) δ 13.14 (s, 1H), 8.78 - 8.72 (m, 1H), 8.65 (s, 1H), 8.60 - 8.54 (m, 1H), 8.46 - 8.41 (m, 1H), 7.70 (d, J = 4.9 Hz, 1H), 7.45 - 7.35 (m, 2H), 7.36 - 7.29 (m, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 3.50 (s, 3H). <!-- 71 -->]]> ​ Example 123 - (2-methoxyphenyl) -N- [5- (trifluoromethyl) -1, 3- benzothiazol-2-yl] pyridine-4-carboxamide 17 100 3.72 430.2 B 1 H NMR (500MHz, DMSO –d6) δ 13.12(s, 1H), 8.75(d, J = 5.0Hz, 1H), 8.65(s, 1H), 8.24(d, J = 8.2Hz, 1H), 8.09(s, 1H), 7.70(d, J = 4.9Hz, 1H), 7.65(d, J = 10.4Hz, 1H), 7.43– 7.35 (m,2H), 7.08 (t,J = 6.9 Hz,1H), 6.97 (d,J = 8.4 Hz,1H), 3.48 (s,3H). <!-- 72 -->]]> ​ Example 13 N-(5-chloro-l,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4- carboxamide 18 100 3.58 396.0 / 397.9 B 1 H NMR (400MHz, DMSO –d6) δ 13.00(s, 1H), 8.74(d, J = 4.9Hz, 1H), 8.64(s, 1H), 8.01(d, J = 8.5Hz, 1H), 7.84(d, J = 2.0Hz, 1H), 7.68(d, J = 5.0Hz, 1H), 7.43– 7.34 (m,3H), 7.08 (t,J = 6.9 Hz,1H), 6.97 (d,J = 8.3 Hz,1H), 3.48 (s,3H). <!-- 73 -->]]> ​ Example 143 - (2-methoxyphenyl) -N- { [1,3] thiazolo [5, 4-b] pyridin-2-yl} pyridine-4- carboxamide 10 100 2.57 363.1 B 1 H NMR (500MHz, DMSO –d6) δ 13.00(s, 1H), 8.75(d, J = 5.0Hz, 1H), 8.65(s, 1H), 8.49(dd, J = 4.7,1.5 Hz, 1H),8.16 – 8.12(m, 1H), 7.69(d, J = 5.0Hz, 1H), 7.51(dd, J = 8.2,4.7 Hz, 1H),7.43 – 7.35(m, 2H), 7.11– 7.07 (m,1H), 6.98(dd, J = 8.4,1.0 Hz, 1H),3.51 (s, 3H). <!-- 74 -->]]> ​ Example 15 N-(l,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide 30 100 3.2 360.2 B 1 H NMR (500MHz, DMSO –d6) δ 8.75 –8.66 (m, 1H),8.65 – 8.56(m, 1H), 7.98– 7.88 (m,1H), 7.77 –7.70 (m, 1H),7.68 (d, J =4.9 Hz, 1H),7.45 – 7.32(m, 3H), 7.32– 7.24 (m,1H), 7.09 –7.03 (m, 1H),6.98 (d, J =8.1 Hz, 1H),3.51 (s, 3H). <!-- 75 -->]]> ​ Example 16 N-(5-cyano-l,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4- carboxamide 53 100 3.16 387.1 B 1 H NMR (500MHz, DMSO –d6) δ 13.13(s, 1H), 8.75(d, J = 4.9Hz, 1H), 8.65(s, 1H), 8.29(d, J = 1.5Hz, 1H), 8.22(d, J = 8.2Hz, 1H), 7.71(dd, J = 8.2,1.5 Hz, 1H),7.69 (d, J =5.0 Hz, 1H),7.41 (dd, J =7.5, 1.7 Hz,1H), 7.40 –7.36 (m, 1H),7.08 (td, J =7.5, 1.0 Hz,1H), 6.97 (d,J = 7.9 Hz,1H), 3.48 (s,3H). <!-- 76 -->]]> ​ Example 172'-Chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-1,3- benzothiazol-2-yl]-[4,4'-bipyridin]-3-carboxamide 56 100 2.88 496.1 / 498.1 B 1 H H NMR (500MHz, DMSO –d6) δ 8.83(s, 1H), 8.16(s, 1H), 7.61(d, J = 8.9Hz, 1H), 7.56(s, 1H), 7.46(d, J = 2.5Hz, 1H), 7.44(s, 1H), 7.15(dd, J = 8.9,2.5 Hz, 1H),3.78 – 3.73(m, 4H), 3.60(s, 3H), 3.16– 3.10 (m,4H), 2.59 (s,3H)]]> ​ Example 182'-chloro-5'-methoxy-6-methyl-N-(6-nitro-l,3-benzothiazol-2-yl)- [4,4'-bipyridine]-3-carboxamide 56 38 0.91 456.1 / 458.0 A 1 H NMR (400MHz, DMSO - d6) δ 13.38 (s, 1H), 9.06 (s, 1H), 8.88 (s, 1H), 8.32 - 8.29 (m, 1H), 8.17 (s, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 3.59 (s, 3H), 2.61 (s, 3H). ​

[1228] Example 19 - 4-(2-chloro-5-methoxy-4-pyridyl)-N-[5-[(3R)-3-hydroxypyrrolidin-1-yl]thiazolo[5,4- d]pyrimidin-2-yl]-6-methyl-pyridine-3-carboxamide

[1229] Add the desired amine (5 equivalents) to a solution of the required chloro-thiazopyrimidine (1 equivalent, prepared using general procedure C) in DMF, ethanol, ethanol / DCE 1:1, or n-butanol. Heat the reaction mixture to 80 or 100 °C and monitor the reaction by LCMS until completion. If necessary, add additional amine (5 equivalents). After the reaction is complete, concentrate the reaction mixture under reduced pressure and purify the crude product by preparative HPLC using method A or method B.

[1230] Example Yield

[1231]

[1232] To a solution of 4-(2-chloro-5-methoxy-4-pyridinyl)-N-(5-chlorothiazo[5,4-d]pyrimidin-2-yl)-6-methyl-pyridine-3-carboxamide (30.0 mg, 0.07 mmol) in a mixture of ethanol (0.5 mL) and DCE (0.5 mL), (3R)-pyrrolidine-3-ol (30 mg, 0.34 mmol) was added, and the reaction mixture was stirred at 80 °C for 24 h. An additional 5 equivalents of (3R)-pyrrolidine-3-ol were added, and heating continued for 8 h. An additional 5 equivalents of (3R)-pyrrolidine-3-ol were added, and heating continued for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile / water (1:1, 1 mL) and purified by preparative HPLC method A. The fraction containing the product was concentrated and lyophilized to give the title compound (7.0 mg, 21% yield) as a yellow powder. 1 H NMR (500 MHz, DMSO – d6) δ 8.84 (s, 1H), 8.71 (s, 1H), 8.16 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 4.96 (d, J = 3.5 Hz, 1H), 4.41 – 4.36 (m, 1H), 3.63 – 3.54 (m, 6H), 3.49 – 3.46 (m, 1H), 2.59 (s, 3H), 2.05 – 1.98 (m, 1H), 1.92 – 1.86 (m, 1H). LCMS (Method B); RT 2.41 min (100%), m / z 498.1 / 500.1 (M+H) +

[1233] The embodiments 20 to 35 in Table 4 below are synthesized using the general procedure D detailed above.

[1234] Table 4 - Examples 20 to 35 synthesized using general procedure D

[1235] LCMS purity (%) LCMS RT (min) m / z LCMS method 1H NMR Footnotes in Table 4 above Reaction solvent Example 20 1 2'-chloro-5'-methoxy-6-methyl-N-[5-(piperidin-l-yl)-[l,3]thiazolo[5,4- d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide ]]> 9 100 3.86 496.5 / 498.5 B 1 H NMR (400 MHz, DMSO– d6) δ 12.86 (s,1H), 8.83 (s, 1H),8.72 (s, 1H), 8.17(s, 1H), 7.56 (s,1H), 7.44 (s, 1H),3.82 – 3.72 (m, 4H),3.62 (s, 3H), 2.59(s, 3H), 1.68 – 1.58(m, 2H), 1.58 – 1.48(m, 4H).]]> ​ Example 21 2 2'-chloro-N-[5-(4,4-difluoropiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide ]]> 35 100 3.7 532.1 / 534.1 B 1 H NMR (500 MHz, DMSO– d6) δ 12.93 (s,1H), 8.84 (s, 1H),8.79 (s, 1H), 8.17(s, 1H), 7.56 (s,1H), 7.45 (s, 1H),3.99 – 3.87 (m, 4H),3.63 (s, 3H), 2.60(s, 3H), 2.07 – 1.97(m, 4H). <!-- 78 -->]]> ​ Example 22 3 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[l,3]thiazolo[5,4- d]pyrimidin-2-yl]-[4,4'-bipyridin]-3-carboxamide ]]> 28 97 3.03 498.1 / 500.1 B 1 H NMR (500 MHz, DMSO– d6) δ 12.93 (s,1H), 8.83 (s, 1H),8.79 (s, 1H), 8.17(s, 1H), 7.57 (s,1H), 7.45 (s, 1H),3.74 – 3.66 (m, 8H),3.62 (s, 3H), 2.60(s, 3H).]]> ​ Example 23 4 2'-chloro-N-{5-[(3S)-3-hydroxypyrrolidin-1-yl]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide ]]> 22 90 2.4 498.1 / 500.1 B 1 H NMR (500 MHz, DMSO– d6) δ 8.83 (s, 1H), 8.72 (s, 1H), 8.16 (s, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 4.96 (d, J = 3.5 Hz, 1H), 4.41 - 4.36 (m, 1H), 3.65 - 3.53 (m, 6H), 3.50 - 3.45 (m, 1H), 2.59 (s, 3H), 2.05 - 1.98 (m, 1H), 1.93 - 1.87 (m, 1H). ​ Example 24 5 2'-chloro-5'-methoxy-6-methyl-N-[5-(pyrrolidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]- [4,4'-bipyridine]-3-carboxamide ]]> 31 100 3.21 482.2 / 484.2 B 1 H NMR (500 MHz, DMSO– d6) δ 12.84 (s,1H), 8.82 (s, 1H),8.75 (s, 1H), 8.17(s, 1H), 7.57 (s,1H), 7.46 (s, 1H),3.63 (s, 3H), 3.55 –3.49 (m, 4H), 2.60(s, 3H), 1.98 – 1.91(m, 4H).]]> ​ Example 25 6 2'-chloro-N-[5-(3,3-difluoropyrrolidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide ]]> 42 98 3.33 518.2 / 520.2 B 1 H NMR (400 MHz, DMSO– d6) δ 12.93 (s,1H), 8.83 (m, 2H),8.17 (s, 1H), 7.57(s, 1H), 7.46 (s,1H), 3.95 (t, J =13.1 Hz, 2H), 3.77(t, J = 7.4 Hz, 2H),3.62 (s, 3H), 2.60(m, 5H). <!-- 79 -->]]> ​ Example 26 7 2'-chloro-N-{5-[(3R)-3-hydroxypyrrolidin-1-yl]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide ]]> 21 100 2.41 498.1 / 500.1 B 1 H NMR (500 MHz, DMSO– d6) δ 8.84 (s, 1H), 8.71 (s, 1H), 8.16 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 4.96 (d, J = 3.5 Hz, 1H), 4.41 - 4.36 (m, 1H), 3.63 - 3.54 (m, 6H), 3.49 - 3.46 (m, 1H), 2.59 (s, 3H), 2.05 - 1.98 (m, 1H), 1.92 - 1.86 (m, 1H). ​ Example 27 8 2'-chloro-N-[5-(1,1-dioxo-1 lambda 6 - thiomorpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl- [4,4'-bipyridin]-3-formamide ]]> 9 100 2.78 546.1 / 548.0 B 1 H NMR (400 MHz, DMSO– d6) δ 12.98 (s,1H), 8.87 (s, 1H),8.16 (s, 1H), 7.56 –7.37 (m, 3H), 4.23(s, 4H), 3.61 (s,3H), 3.17 (s, 4H),2.59 (s, 3H).]]> ​ Example 28 9 2'-chloro-5'-methoxy-6-methyl-N-[5-(4-methylpiperazin-1-yl)-[1,3]thiazolo[5,4- d]pyrimidin-2-yl]-[4,4'-bipyridin]-3-carboxamide ]]> 42 100 1.76 511 / 513.1 B 1 H NMR (500 MHz, DMSO– d6) δ 8.84 (s, 1H), 8.76 (s, 1H), 8.17 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 3.79 - 3.73 (m, 4H), 3.63 (s, 3H), 2.60 (s, 3H), 2.44 - 2.39 (m, 4H), 2.24 (s, 3H).]] ​ Example 29 10 2'-chloro-5'-methoxy-6-methyl-N-(5-{2-oxa-6-azaspiro[3.3]heptan-6-yl}- [1,3]thiazolo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridin]-3-carboxamide ]]> 21 100 2.55 510.1 / 512.1 B <![CDATA[ 1 H NMR (500 MHz, DMSO– d6) δ 12.92 (s,1H), 8.83 (s, 1H),8.75 (s, 1H), 8.16(s, 1H), 7.56 (s,1H), 7.44 (s, 1H),4.73 (s, 4H), 4.24(s, 4H), 3.61 (s,3H), 2.59 (s, 3H)。 <!-- 80 -->]]> Example 30 11 2'-chloro-5'-methoxy-N-{5-[(2-methoxyethyl)amino]-[l,3]thiazolo[5,4- d]pyrimidin-2-yl}-6-methyl-[4,4'-bipyridin]-3-carboxamide ]]> 38 100 2.69 486.0 / 488.1 B 1 H NMR (400 MHz, DMSO– d6) δ 12.86 (s,1H), 8.85 (s, 1H),8.66 (s, 1H), 8.17(s, 1H), 7.55 (s,1H), 7.43 (s, 1H),7.28 (s, 1H), 3.63(s, 3H), 3.50 – 3.45(m, 4H), 3.27 (s,3H), 2.60 (s, 3H).]]> ​ Example 31 12 2'-chloro-N-[5-(3-hydroxyazetidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide ]]> 7 100 2.27 484.1 / 486.0 B 1 H NMR (500 MHz, DMSO– d6) δ 12.87 (s,1H), 8.88 (s, 1H),8.64 (s, 1H), 8.15(s, 1H), 7.50 (s,1H), 7.37 (s, 1H),5.67 (d, J = 6.7 Hz,1H), 4.59 – 4.52 (m,1H), 4.28 – 4.21 (m,2H), 3.82 – 3.76 (m,2H), 3.62 (s, 3H),2.58 (s, 3H).]]> ​ Example 32 13 2'-chloro-5'-methoxy-N-[5-(3-methoxypyrrolidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridin]-3-carboxamide ]]> 32 99 2.93 512.1 / 514.1 B 1 H NMR (500 MHz, DMSO– d6) δ 12.87 (s,1H), 8.83 (s, 1H),8.76 (s, 1H), 8.18(s, 1H), 7.57 (s,1H), 7.46 (s, 1H),4.08 (s, 1H), 3.69 –3.57 (m, 6H), 3.49(q, J = 8.7 Hz, 1H),3.27 (s, 3H), 2.60(s, 3H), 2.10 – 2.04(m, 2H) <!-- 81 -->]]> ​ Example 33 14 2'-chloro-N-[5-(4-hydroxypiperidin-l-yl)-[l,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide ]]> 28 100 2.66 512.1 / 514.1 B 1 H NMR (400 MHz, DMSO– d6) δ 12.87 (s,1H), 8.83 (s, 1H),8.72 (s, 1H), 8.16(s, 1H), 7.55 (s,1H), 7.44 (s, 1H),4.73 (d, J = 4.3 Hz,1H), 4.33 – 4.22 (m,2H), 3.74 (dq, J =8.5, 4.1 Hz, 1H),3.62 (s, 3H), 2.59(s, 3H), 1.83 – 1.74(m, 2H), 1.40 – 1.29(m, 2H).]] ​ Example 34 15 2'-chloro-5'-methoxy-6-methyl-N-{5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]- [1,3]thiazolo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide ]]> 24 100 2.74 510.1 / 512.1 B 1 H NMR (400 MHz, DMSO– d6) δ 12.88 (s,1H), 8.84 (s, 1H),8.74 (s, 1H), 8.17(s, 1H), 7.55 (s,1H), 7.44 (s, 1H),4.96 (s, 1H), 4.67(s, 1H), 3.81 (d, J =5.8 Hz, 1H), 3.68 (d,J = 7.3 Hz, 1H), 3.62(s, 3H), 3.52 (d, J =9.3 Hz, 1H), 3.42 (d,J = 11.4 Hz, 1H),2.59 (s, 3H), 1.94(d, J = 7.3 Hz, 1H),1.87 (d, J = 9.5 Hz,1H)]) ​ Example 35 16 2'-chloro-N-[5-(3-cyanopiperidin-l-yl)-[l,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide ]]> 18 100 3.27 521.1 / 523.1 B 1 H NMR (400 MHz, DMSO– d6) δ 12.93 (s,1H), 8.84 (s, 1H),8.78 (s, 1H), 8.16(s, 1H), 7.56 (s,1H), 7.45 (s, 1H),4.24 – 4.17 (m, 1H),4.02 – 3.94 (m, 1H),3.90 – 3.84 (m, 1H),3.68 – 3.63 (m, 1H),3.62 (s, 3H), 3.14 –3.08 (m, 1H), 2.59(s, 3H), 1.99 – 1.88(m, 2H), 1.72 – 1.55(m, 2H).]] ​

[1236] Table 5 - Reaction solvents and temperatures used in the preparation examples in Table 4 above.

[1237] DMF Ethanol / DCE reaction temperature o C 1 Ethanol / DCE 80 2 Ethanol / DCE 80 3 Ethanol / DCE 80 4 Ethanol / DCE 80 5 Ethanol / DCE 80 6 Ethanol / DCE 80 7 Ethanol / DCE 80 8 Ethanol / DCE 80 9 n-Butanol 80 10 Ethanol 80 11 Ethanol 100 12 DMF 80 13 Ethanol 80 14 Ethanol / DCE 80 15 Step A - N-(6-amino-1,3-benzothiazol-2-yl)-4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl- pyridine-3-carboxamide (Example 36A) 80 16 Step B 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxopiperidin-1-yl)-1,3-benzothiazol-2-yl]- [4,4'-bipyridine]-3-carboxamide (Example 36B) 80

[1238] Examples 36A and 36B - Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxopiperidin-1-yl)-1,3-benzothiazolyl-2-yl]-[4,4'-bipyridine]-3-carboxamide

[1239]

[1240] Note: Step = steps, the same below.

[1241] Example 37 - Synthesis of 2'-chloro-N-[5-(5,6-dihydro-2H-pyran-3-yl)-[1,3]thiazolo[5,4- b]pyrimidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide Step A

[1242]

[1243] A stirred solution of 4-(2-chloro-5-methoxy-4-pyridinyl)-6-methyl-N-(6-nitro-1,3-benzothiazo-2-yl)pyridin-3-carboxamide (1.1 g, 2.41 mmol, prepared using general procedure C) in ethanol (11 mL) and water (4.4 mL) was purged with nitrogen for 5 min, followed by the addition of iron powder (0.9 g, 16.1 mmol) and solid ammonium chloride (1.2 g, 22.4 mmol). The reaction mixture was stirred at 60 °C for 30 min, then filtered through a diatomaceous earth mat, washed with ethyl acetate (20 mL), and the resulting filtrate was washed with water (15 mL). The organic layer was separated, dried (Na₂SO₄), and concentrated under reduced pressure. The solution was then analyzed by Biotage Isolera. TM Automated chromatography (Sfar Duo 10 g) was used to purify the residue using a gradient of 0-10% methanol in DCM to give the title compound (454 mg, 44% yield) as a yellow-brown solid. 1H NMR (400 MHz, DMSO – d6) δ 12.59 (s,1H), 8.82 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.46 – 7.41 (m, 2H), 7.00 (d,J = 2.2 Hz, 1H), 6.73 (dd, J = 8.6, 2.3 Hz, 1H), 5.17 (s, 2H), 3.62 (s, 3H), 2.60 (s, 3H). LCMS (Method B); RT 1.93 min (99%), m / z 424.5 / 426.5 (M+H) +

[1244] tert-Butyl N-(5-chlorothiazolo[5,4-b]pyrimidin-2-yl)carbamate ​

[1245]

[1246] A solution of 5-bromopentanoyl chloride (11 μL, 0.08 mmol) in THF (0.6 mL) was added dropwise to an ice-cold stirred solution of N-(6-amino-1,3-benzothiazo-2-yl)-4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3-carboxamide (30.0 mg, 0.07 mmol) and DIPEA (12 μL, 0.07 mmol) in THF (0.6 mL), and the reaction mixture was stirred for 15 min. The mixture was then treated fractionally with potassium tert-butoxide (30.0 mg, 0.27 mmol). Stirring was continued for 30 min. The mixture was treated with water (5 mL) and brine (5 mL), and extracted with ethyl acetate (2 × 15 mL). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by preparative HPLC method A. Vacuum evaporation containing product fractions and freeze-drying yielded the title compound (6.8 mg, 19% yield) as a white powder. 1H NMR (500 MHz, DMSO –d6) δ 12.97 (s, 1H), 8.87 (s, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.75 (d, J =8.6 Hz, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 7.34 (dd, J = 8.5, 2.1 Hz, 1H), 3.64(t, J = 5.7 Hz, 2H), 3.60 (s, 3H), 2.61 (s, 3H), 2.41 (t, J = 6.3 Hz, 2H),1.92 – 1.83 (m, 4H). LCMS (Method B); RT 2.79 min (100%), m / z 508.2 / 510.1 (M+H) + .

[1247] ​ ​

[1248]

[1249] ​ ​

[1250]

[1251] At room temperature, N,N-dimethylpyridine-4-amine (6.17 mg, 0.05 mmol) was added to a solution of 5-chlorothiazo[5,4-b]pyridine-2-amine (100 mg, 0.54 mmol) in DCE (2.5 mL) and DIPEA (0.20 mL, 1.15 mmol). Di-tert-butyl dicarbonate (124 mg, 0.57 mmol) was added to the above solution, and the resulting mixture was stirred at room temperature for 4 h. An additional 0.5 equivalent of N,N-dimethylpyridine-4-amine and di-tert-butyl dicarbonate were added, and stirring was continued for 18 h. The mixture was diluted with DCM and washed with a water and saline solution (10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The extract was then analyzed by Biotage Isolera. TM The crude product was purified by automated chromatography (10 g, Sfar Duo) and eluted with a heptane solution of 0-50% ethyl acetate to give the title compound (137 mg, 89% yield) as a colorless powder. 1H NMR (500 MHz, DMSO – d6) δ 12.09 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 1.52 (s, 9H). LCMS (Method A); 0.97 min (100%), m / z 230.0 / 232.0 (M- t Bu+H) + .

[1252] Step B N-[5-(3,6-dihydro-2H-pyran-5-yl)thiazolo[5,4-b]pyridin-2-yl]carbamic acid tert-butyl ester Step B N-[5-(3,6-dihydro-2H-pyran-5-yl)thiazolo[5,4-b]pyridin-2-yl]carbamic acid tert-butyl ester

[1253]

[1254] To a solution of N-(5-chlorothiazo[5,4-b]pyridin-2-yl)carbamate tert-butyl ester (130 mg, 0.46 mmol) in 1,4-dioxane (1.8 mL) and water (0.45 mL) in a pressure flask, 2-(3,6-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (115 mg, 0.55 mmol) and dipotassium carbonate (157 mg, 1.14 mmol) were added. The mixture was degassed under nitrogen, and then palladium dichloride DTBPF (30 mg, 0.05 mmol) was added. The mixture was stirred at 90 °C for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL). The solution was washed with water and saline solution (10 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The solution was then analyzed by Biotage Isolera. TM The crude product was purified by automated chromatography (25 g, Sfar Duo) and eluted with a heptane solution of 0-50% ethyl acetate to give the title compound (92 mg, 58% yield) as a colorless powder. 1 H NMR (500 MHz, DMSO – d6) δ 11.91 (s, 1H), 7.97 (d, J =8.6 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 6.82 – 6.78 (m, 1H), 4.58 – 4.54 (m,2H), 3.75 (t, J = 5.5 Hz, 2H), 2.33 – 2.29 (m, 2H), 1.52 (s, 9H). LCMS (Method A); RT 0.96 min (96%), m / z 334.1 (M+H) + .

[1255] Step C 5-(3,6-dihydro-2H-pyran-5-yl)thiazolo[5,4-b]pyridin-2-amine

[1256]

[1257] A solution of 4 M hydrogen chloride (0.22 mL, 0.86 mmol) in 1,4-dioxane was added to a solution of N-[5-(3,6-dihydro-2H-pyran-5-yl)thiazo[5,4-b]pyridin-2-yl]carbamate tert-butyl ester (20.0 mg, 0.06 mmol) in acetonitrile (0.25 mL), and the mixture was stirred at room temperature for 18 h.

[1258] The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 1:1 DCM / methanol (0.5 mL). A solution of 1,4-dioxane (0.22 mL, 0.86 mmol) containing 4 M hydrogen chloride was added.

[1259] The mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure, the resulting solid was dissolved in methanol, and loaded onto a 1 g SCX ion exchange column. The column was washed with methanol (5 mL) followed by a 2 M ammonia methanol solution (5 mL). The ammonia filtrate was concentrated under reduced pressure to give a colorless powder (12 mg, 80% yield) that was ready for immediate use without further purification. LCMS (Method A) RT 0.60 min (87%), m / z 234.5 (M+H) + .

[1260] Step D 4-(2-chloro-5-methoxy-4-pyridyl)-N-[5-(3,6-dihydro-2H-pyran-5-yl)thiazolo[5,4- b]pyridin-2-yl]-6-methyl-pyridine-3-carboxamide Step D 4-(2-chloro-5-methoxy-4-pyridyl)-N-[5-(3,6-dihydro-2H-pyran-5-yl)thiazolo[5,4- b]pyridin-2-yl]-6-methyl-pyridine-3-carboxamide

[1261]

[1262] The title compound (3.5 mg, 15% yield) was prepared using the general procedure C detailed above, and was obtained as a colorless powder. 1H NMR (500 MHz, DMSO – d6) δ 13.05 (s, 1H), 8.85 (s, 1H), 8.16 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.58 (s, 1H), 7.47 (s,1H), 6.87 – 6.80 (m, 1H), 4.58 (d, J = 2.3 Hz, 2H), 3.75 (t, J = 5.5 Hz, 2H), 3.61 (s, 3H), 2.60 (s, 3H), 2.34 – 2.31 (m, 2H). LCMS (Method B) RT 3.22 min(100%) m / z 494.1 / 496.1 (M+H) + .

[1263] Example 38 - Synthesis of 2'-chloro-N-[6-(5-chloropyridin-2-yl)-1,3-benzothiazol-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide Step A N-(6-bromo-1,3-benzothiazol-2-yl)carbamic acid tert-butyl ester

[1264]

[1265] Step B N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]carbamic acid tert-butyl ester

[1266]

[1267] Prepared in a similar manner to the N-(5-chlorothiazo[5,4-b]pyridin-2-yl)carbamate described above, the title compound (665 mg, 58% yield) was obtained as a light orange solid. 1 H NMR (400 MHz, DMSO – d6) δ 8.18 (d,J = 2.0 Hz, 1H), 7.60 (d,J = 8.5 Hz, 1H), 7.52 (dd,J = 8.5, 2.0 Hz, 1H), 1.51 (s, 9H). LCMS (Method B) RT 4.09 min (74%), m / z 329.0 / 331.0 (M+H) + .

[1268] Step C N-[6-(5-chloro-2-pyridyl)-1,3-benzothiazol-2-yl]carbamic acid tert-butyl ester Step D 6-(5-chloro-2-pyridyl)-1,3-benzothiazol-2-amine; dihydrochloride

[1269]

[1270] To a solution of N-(6-bromo-1,3-benzothiazo-2-yl)carbamate tert-butyl ester (150 mg, 0.46 mmol) in 1,4-dioxane (2.5 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxoboronacecyclopentane (231 mg, 0.91 mmol) and potassium acetate (223 mg, 2.28 mmol) were added. The mixture was degassed under nitrogen, and then palladium dichloride DPPF (33 mg, 0.05 mmol) was added. The mixture was stirred at 90 °C for 3 h. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The diatomaceous earth pad was washed with ethyl acetate and then filtered through a Biotage Isolera. TM The filtrate was purified by automated chromatography (25 g, Sfar duo) and eluted with 0-50% ethyl acetate in heptane to give the title compound (210 mg, 86% yield) as a pale yellow glassy substance that begins to crystallize when left to stand at room temperature. 1 H NMR (400 MHz, DMSO –d6) δ 11.85 (br s, 1H), 8.22 (s, 1H), 7.68 – 7.63 (m, 2H), 1.51 (s, 9H), 1.31 (s, 12H). LCMS (Method A); RT 1.16 min (100%), m / z 377.2 (M+H) + .

[1271] Step E 4-(2-chloro-5-methoxy-4-pyridyl)-N-[6-(5-chloro-2-pyridyl)-1,3-benzothiazol-2-yl]-6- methyl-pyridine-3-carboxamide

[1272]

[1273] To a solution of N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3-benzothiazo-2-yl]tert-butyl carbamate (210 mg, 0.39 mmol) in 1,4-dioxane (1.6 mL) and water (0.4 mL) in a pressure flask, 2-bromo-5-chloropyridine (98 mg, 0.51 mmol) and dipotassium carbonate (135 mg, 0.98 mmol) were added. The mixture was degassed under nitrogen, and then palladium dichloride (DTBPF) (26 mg, 0.04 mmol) was added. The mixture was stirred at 90 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with water and brine (10 mL). After separation of the organic layer, precipitation began. The solution was cooled in an ice bath for 30 min, and then the precipitate was filtered. The filter cake was washed with diethyl ether and dried under a nitrogen stream. LCMS confirmed that the solid was a pure product (45 mg). The filtrate was concentrated under reduced pressure and analyzed by Biotage Isolera. TM Purification was performed by automated chromatography (25 g, Sfar Duo), eluting with a heptane solution of 0-100% ethyl acetate to give a second batch of product. The two batches were mixed to give the title compound (109 mg, 77% yield) as a beige powder. 1 H NMR (500 MHz, DMSO– d6) δ 11.88 (br s, 1H), 8.70 (d, J = 2.5 Hz, 1H), 8.67 (d, J = 1.9 Hz, 1H), 8.13 (dd, J = 8.5, 1.9 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.01 (dd, J = 8.6,2.5 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 1.52 (s, 9H). LCMS (Method A); RT 1.15min, m / z 362.364.0 (M+H) + .

[1274] Example 39 - Synthesis of N-[6-(5-chloropyridin-2-yl)-1,3-benzothiazol-2-yl]-3-(2- methoxyphenyl)pyridine-4-carboxamide

[1275] At 0 °C, a solution of 1,4-dioxane containing 4 M hydrogen chloride (1.1 mL, 4.52 mmol) was added dropwise to a suspension of N-[6-(5-chloro-2-pyridyl)-1,3-benzothiazol-2-yl]carbamate (109 mg, 0.3 mmol) in 1,4-dioxane (0.5 mL). After the addition was complete, the mixture was heated to room temperature and stirred for 18 h. The starting material had precipitated from the solution. 1 mL of acetonitrile was added to aid dissolution, and the mixture was concentrated under reduced pressure by stirring for another 24 h. The residue was dried over an azeotropic solution of diethyl ether to give the title compound (109 mg, quantitative yield) as a colorless powder, which was used immediately without further purification. LCMS (Method A); RT 0.75 min (100%) m / z 262.1 / 264.1 (M+H) + .

[1276] Example 40 - Synthesis of 2'-chloro-N-[6-(3-hydroxyoxolan-3-yl)-1,3-benzothiazol-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide Example 41 - Synthesis of 2'-chloro-N-(6-methanesulfonamido-1,3-benzothiazol-2-yl)-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide

[1277]

[1278] The title compound (83 mg, 54% yield) was prepared using the general procedure C detailed above, and was obtained as a colorless powder. 1 H NMR (500 MHz, DMSO – d6) δ 13.08 (s, 1H), 8.87 (s, 1H), 8.73 – 8.70 (m,2H), 8.20 (dd, J = 8.5, 1.9 Hz, 1H), 8.17 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.03 (dd, J = 8.6, 2.5 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.47(s, 1H), 3.61 (s, 3H), 2.61 (s, 3H). LCMS (Method B); RT 3.92 min (100%) m / z 522 / 524 (M+H) + .

[1279] Examples 42 to 44 Table 6

[1280]

[1281] Synthesized from 6-(5-chloropyridin-2-yl)-1,3-benzothiazol-2-amine hydrochloride using standard procedure C, prepared in a manner similar to that described above, yielding the title compound (40 mg, 19% yield) as a colorless powder.1 H NMR (500 MHz, DMSO– d6) δ 12.96 (br s, 1H), 8.5-8.9 (m, 4H), 8.19 (dd, 1H, J=1.8, 8.6 Hz), 8.0-8.1 (m, 1H), 8.02 (dd, 1H, J=2.6, 8.6 Hz), 7.85 (d, 1H, J=8.5 Hz), 7.69 (d,1H, J=4.8 Hz), 7.3-7.4 (m, 2H), 7.0-7.1 (m, 1H), 6.9-7.0 (m, 1H), 3.4-3.6 (m,3H). LCMS (Method B) RT 2.72 min (87%), m / z 473.1 / 475.1 (M+H) + .

[1282] Example Yield

[1283]

[1284] At -78 °C, a hexane solution of 1.6 M butyllithium (50 µL, 0.08 mmol) was added dropwise to a solution of N-(6-bromo-1,3-benzothiazol-2-yl)-4-(2-chloro-5-methoxy-4-pyridinyl)-6-methyl-pyridine-3-carboxamide (16 mg, 0.03 mmol, prepared using the general procedure C detailed above) in THF (0.5 mL). The reaction mixture was stirred at -78 °C for another 15 min. Then, dihydrofuran-3(2H)-one (4.0 mg, 0.05 mmol) was added dropwise to the reaction mixture as a solution in THF (0.2 mL), and the mixture was stirred at -78 °C for 2 h. A saturated aqueous solution of ammonium chloride (10 mL) was added, and the mixture was extracted with diethyl ether (2 × 10 mL) and ethyl acetate (1 × 10 mL) due to the poor solubility of the product. Combine the organic extracts, dry (Na2SO4), filter, and evaporate under reduced pressure. Pass through Biotage Isolera. TM The crude product was purified by automated chromatography (Sfar Duo, 10 g) using a gradient elution from 0-100% ethyl acetate in heptane to 10% methanol in ethyl acetate. The fraction containing the product was concentrated under reduced pressure and further purified by preparative HPLC method A to give the title compound (1.6 mg, 8% yield) as a white powder. 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.05 (s, 1H), 7.85 – 7.81 (m,1H), 7.46 – 7.39 (m, 1H), 7.36 – 7.32 (m, 2H), 7.21 (d, J = 3.0 Hz, 2H), 4.08– 3.91 (m, 2H), 3.76 – 3.72 (m, 4H), 3.66 (d, J = 9.2 Hz, 1H), 2.06 – 1.98(m, 2H). LCMS (Method B); RT 2.91 min (86%), m / z 497.2 / 499.2 (M+H) + .

[1285] LCMS purity (%) LCMS RT (min)

[1286]

[1287] At 0 °C, methanesulfonyl chloride (6 μL, 0.08 mmol) was added to a solution of N-(6-amino-1,3-benzothiazo-2-yl)-4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3-carboxamide (30.0 mg, 0.07 mmol) and DIPEA (15 μL, 0.08 mmol) prepared in DCM (0.5 mL). After the addition was complete, the reaction mixture was heated to room temperature and stirred for 4 h. An additional 1.2 equivalents of DIPEA and methanesulfonyl chloride were added, and the reaction was continued at room temperature for 2 h. The mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic extract was dried (Na2SO4) and concentrated to give a crude product as a yellow glassy substance. The crude product was purified by preparative HPLC method A to give the title compound (10 mg, 28% yield) as a colorless powder. 1H NMR (500 MHz, DMSO – d6) δ 12.90 (s, 1H), 9.77 (s, 1H), 8.84 (s, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.57 (s,1H), 7.45 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 3.60 (s, 3H), 2.99 (s, 3H), 2.60(s, 3H). LCMS (Method B); RT 2.63 min (100%) m / z 504.0 / 506.0 (M+H) + .

[1288] m / z

[1289] The embodiments 42 to 44 listed in Table 6 below are synthesized using the aforementioned general procedure C.

[1290] LCMS Method

[1291] 1H NMR Examples 45 to 53 Table 7 Example Yield LCMS purity (%) LCMS RT (min) Example 42 2'-chloro-5'-methoxy-6-methyl-N-{[l,3]thiazolo[5,4-d]pyrimidin-2-yl}- [4,4'-bipyridine]-3-carboxamide 6 100 2.46 413.0 / 415.0 B <![CDATA[ 1 H NMR (500MHz, DMSO-d6) δ 13.38(s, 1H),9.15 – 8.89(m, 3H),8.15 (s,1H), 7.53(s, 1H),7.40 (s,1H), 3.61(s, 3H),2.59 (s,3H)。 <!-- 89 -->]]> Example 43 2'-chloro-5'-methoxy-6-methyl-N-[6-(methylthio)-l,3-benzothiazol-2-yl]- [4,4'-bipyridine]-3-carboxamide 14 100 3.47 457.0 / 459.0 B 1 H NMR (400MHz, DMSO-d6) δ 12.93(s, 1H),8.84 (s,1H), 8.16(s, 1H),7.91 (d, J =2.0 Hz, 1H),7.69 (d, J =8.5 Hz, 1H),7.57 (s,1H), 7.46(s, 1H),7.36 (dd, J= 8.6, 1.9Hz, 1H),3.59 (s,3H), 2.60(s, 3H),2.53 (s,3H). <!-- 90 -->]]> ​ Example 44 2'-chloro-5'-methoxy-6-methyl-N-{[l,3]thiazolo[5,4-c]pyridin-2-yl}-[4,4'- bipyridine]-3-carboxamide 24 100 1.11 412.0 / 414.0 D 1 H NMR (500MHz, DMSO-d6) δ 13.09(s, 1H),8.87 (s,1H), 8.49(dd, J =4.7, 1.5 Hz,1H), 8.17(s, 1H),8.14 (d, J =8.2 Hz, 1H),7.59 (s,1H), 7.51(dd, J =8.2, 4.7 Hz,1H), 7.47(s, 1H),3.62 (s,3H), 2.61(s, 3H).]]> ​

[1292] m / z

[1293] Using the aforementioned general procedure D, synthesize Examples 45 to 53 and Intermediates 7 and 8 as shown in Table 7 below, with the conditions described in the footnotes of Table 8.

[1294] LCMS Method

[1295] 1H NMR Footnotes x in the tables above Reaction solvent Ethanol n-Butanol Ethanol / DCE n-Butanol <![CDATA[ Example 45 3 N-[5-(4-acetylpiperazin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-2'-chloro-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide 35 100 2.66 539.1 / 541.1 B 1 H NMR (400MHz, DMSO-d6) δ 12.82(s, 1H),8.83 (s,1H), 8.79(s, 1H),8.17 (s,1H), 7.57(s, 1H),7.45 (s,1H), 3.85 –3.77 (m,2H), 3.77 –3.71 (m,2H), 3.62(s, 3H),3.57 – 3.50(m, 4H),2.60 (s,3H), 2.05(s, 3H). <!-- 92 -->]]> ​ Example 46 2 2'-chloro-N-{5-[(2-hydroxyethyl)amino]-[l,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide ​ 6 97 2.24 472.1 / 474.1 B <![CDATA[ 1 ¹H NMR (400MHz, DMSO-d6) δ 8.87 (s, 1H), 8.58 (s, 1H), 8.15 (s, 1H), 7.50 (s, 1H), 7.37 (s, 1H), 7.11 – 7.03 (m, 1H), 4.67 (s, 1H), 3.63 (s, 3H), 3.52 (t, J = 6.3 Hz, 2H), 2.58 (s, 3H). One methylene group was obscured by a water peak, and one exchangeable proton was not observed.<!-- 93 --> ]]> <![CDATA[ Example 47 4 2'-chloro-5'-methoxy-N-[5-(3-methoxyazetidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridin]-3-formamide 46 99 2.74 498.1 / 500.1 B 1 H NMR (400MHz, DMSO-d6) δ 12.92(s, 1H),8.86 (s,1H), 8.72(s, 1H),8.17 (s,1H), 7.54(s, 1H),7.42 (s,1H), 4.35 –4.29 (m,1H), 4.26(dd, J =8.6, 6.5 Hz,2H), 3.89(dd, J =10.1, 3.7Hz, 2H),3.63 (s,3H), 3.26(s, 3H),2.59 (s,3H). <!-- 94 -->]]> ​ Example 48 2 2'-chloro-N-{5-[(4-hydroxycyclohexyl)amino]-[l,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide ​ 13 100 2.42 526.1 / 528.1 B 1 H NMR (500MHz, DMSO-d6) δ 12.80(s, 1H),8.84 (s,1H), 8.60(s, 1H),8.21 – 8.06(m, 1H),7.51 (s,1H), 7.39(s, 1H),7.22 – 6.96(m, 1H),4.52 (d, J =4.4 Hz, 1H),3.72 – 3.38(m, 5H),2.57 (s,3H), 1.95 –1.76 (m,4H), 1.32 –1.16 (m,4H). <!-- 95 -->]]> ​ Example 49 2 racemic-2'-chloro-N-(5-{[(1R,3S)-3-hydroxycyclopentyl]amino}-[1,3]thiazolo[5,4- d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide ​ 18 100 2.50 512.1 / 514.1 B 1 H NMR (500MHz, DMSO-d6) δ 12.83(s, 1H),8.84 (s,1H), 8.65(s, 1H),8.29 – 8.05(m, 1H),7.55 (s,1H), 7.43(s, 1H),7.22 (s,1H), 4.64(d, J = 4.1Hz, 1H),4.22 – 4.14(m, 1H),4.14 – 4.08(m, 1H),3.63 (s,3H), 2.59(s, 3H),2.25 – 2.11(m, 1H),1.98 – 1.84(m, 1H),1.80 – 1.71(m, 1H),1.68 – 1.53(m, 2H),1.50 – 1.40(m, 1H). <!-- 96 -->]]> ​ <![CDATA[ Example 50 5 2'-chloro-5'-methoxy-6-methyl-N-{5-[(3R)-3-methylmorpholin-4-yl]-[l,3]thiazolo[5,4- d]pyrimidin-2-yl}-[4,4'-bipyridin]-3-carboxamide 12 95 3.18 512.1 / 514.1 B 1 H NMR (500MHz, DMSO-d6) δ 12.90(s, 1H),8.83 (s,1H), 8.78(s, 1H),8.16 (s,1H), 7.56(s, 1H),7.45 (s,1H), 4.66 –4.60 (m,1H), 4.24(d, J = 11.9Hz, 1H),3.95 – 3.90(m, 1H),3.72 (d, J =11.4 Hz,1H), 3.62(s, 3H),3.61 – 3.57(m, 1H),3.47 – 3.40(m, 1H),3.20 (dd, J= 13.2, 3.3Hz, 1H),2.59 (s,3H), 1.19(d, J = 6.9Hz, 3H). <!-- 97 -->]]> ​ Example 51 5 2'-chloro-5'-methoxy-6-methyl-N-{5-[(3S)-3-methylmorpholin-4-yl]-[l,3]thiazolo[5,4- d]pyrimidin-2-yl}-[4,4'-bipyridin]-3-carboxamide ​ 14 96 3.18 512.1 / 514.1 B 1 H NMR (500MHz, DMSO-d6) δ 12.91(s, 1H),8.82 (s,1H), 8.80(s, 1H),8.17 (s,1H), 7.57(s, 1H),7.46 (s,1H), 4.63(dd, J =6.9, 2.9 Hz,1H), 4.24(dd, J =13.6, 2.9Hz, 1H),3.93 (dd, J= 11.1, 3.7Hz, 1H),3.72 (d, J =11.4 Hz,1H), 3.62(s, 3H),3.61 – 3.57(m, 1H),3.44 (td, J= 11.4, 3.1Hz, 1H),3.23 – 3.16(m, 1H),2.60 (s,3H), 1.20(d, J = 6.7Hz, 3H)。 <!-- 98 -->]]> ​ Example 52 5 2'-chloro-5'-methoxy-6-methyl-N-{5-[(prop-2-yl)amino]-[l,3]thiazolo[5,4- d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide ​ 3 97 2.07 470.3 / 472.3 B 1 H NMR (500MHz, DMSO-d6) δ 12.83(s, 1H),8.84 (s,1H), 8.65(s, 1H),8.16 (s,1H), 7.53(s, 1H),7.42 (s,1H), 7.20(s, 1H),4.09 – 4.01(m, 1H),3.63 (s,3H), 2.59(s, 3H),1.16 (d, J =6.6 Hz, 6H).]]> ​ Example 53 1 2'-chloro-5'-methoxy-6-methyl-N-(5-{2-oxa-7-azaspiro[3.5]non-7-yl}-[1,3]thiazolo[5,4- d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide ​ 10 96 3.12 538.1 / 540.1 B 1 H NMR (500MHz, DMSO-d6) 12.86(s, 1H),8.86 (s,1H), 8.67(s, 1H),8.15 (s,1H), 7.52(s, 1H),7.39 (s,1H), 4.35(s, 4H),3.74-3.67(m, 4H),3.62 (s,3H), 2.58(s, 3H),1.85-1.76(m, 4H) <!-- 99 -->]]> ​ Intermediate 7 2 3-(2-{2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-amino}-[1,3]thiazolo[5,4- b]pyridin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester ​ 96 88 1.08 623.3 / 625.3 A Intermediate 8 2 4-(2-{2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-amino}-[1,3]thiazolo[5,4- b]pyridin-5-yl)piperazine-1-carboxylic acid tert-butyl ester ​ 88 100 1.03 597.2 / 599.2 A

[1296] Table 8 shows the reaction solvents and temperatures used in the preparation examples in Table 7 above.

[1297] n-Butanol General procedure E for Boc deprotection reaction temperature o C 1 Example 54 Synthesis of 2'-chloro-N-(5-{3,8-diazabicyclo[3.2.1]oct-3-yl}-[1,3]thiazolo[5,4- d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide 80 2 Table 9 100 3 Example 80 4 Yield 80 5 LCMS purity (%) 110

[1298] LCMS RT (min)

[1299] At room temperature, a 1,4-dioxane solution of 4M hydrogen chloride (10 equivalents) was added to the desired Boc-protected amine precursor (obtained using conventional method D, 1 equivalent). The mixture was stirred at room temperature and monitored by LCMS until the reaction was complete. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC method B to give the desired product.

[1300] m / z LCMS Method

[1301]

[1302] A 1,4-dioxane solution (250 µL, 1 mmol) of 4 M hydrogen chloride was added to 3-(2-{2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-amino}-[1,3]thiazo[5,4-b]pyridin-5-yl)-3,8-diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester (200 mg, 0.1 mmol, intermediate 7 prepared using general procedure D), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC method B to give the title compound (15 mg, 30% yield) as a yellow powder. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 8.93 (s, 1H), 8.56 (s, 1H), 8.13 (s, 1H), 7.44 (s, 1H), 7.29 (s, 1H), 4.26 (dd, J = 13.1, 2.4 Hz, 2H), 3.81 – 3.75 (m, 2H), 3.62 (s, 3H), 3.08 (dd, J = 13.0, 2.1 Hz, 2H), 2.56 (s, 3H), 1.83 – 1.61 (m, 4H). No exchangeable protons were observed. LCMS (Method D); RT 1.83 min (99%), m / z 523.4 / 525.3 (M+H) +

[1303] Example 55 in Table 9 below was prepared using the general procedure E described above.

[1304] 1H NMR

[1305] Examples 56 and 57 Table 10 Example Yield LCMS purity (%) LCMS RT (min) m / z Example 55 5'-chloro-5'-methyl-6-methyl-N-[5-(piperazin-1-yl)-[1,3]thiazolo[5,4- d]pyrimidin-2-yl]-[4,4'-bipyridin]-3-carboxamide 23 100 1.64 497.2 / 499.2 B 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.57 (s, 1H), 8.14 (s, 1H), 7.44 (s, 1H), 7.29 (s, 1H), 3.74 (t, J = 5.0 Hz, 4H), 3.62 (s, 3H), 2.90 (t, J = 5.1 Hz, 4H), 2.56 (s, 3H), two exchangeable protons not observed. ​

[1306] LCMS Method

[1307] Examples 56 and 57 in Table 10 below were prepared in the same manner as in Example 36B above.

[1308] ​

[1309] ​ ​ ​ ​ ​ LCMS method 1H NMR Example 56 5'-Chloro-5'-methoxy-6-methyl-N-[6-(2-oxopyrrolidin-1-yl)-1,3- benzothiazol-2-yl]-[4,4'-bipyridin]-3-carboxamide 14 90 2.77 494.1 / 496.1 B 1 H NMR (500 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.17 - 8.04 (m, 2H), 7.78 - 7.63 (m, 2H), 7.50 (s, 1H), 7.37 (s, 1H), 3.88 (t, J = 7.0 Hz, 2H), 3.59 (s, 3H), 2.58 (s, 3H), 2.08 (p, J = 7.6 Hz, 2H) one methylene signal obscured by solvent peak, one exchangeable proton not observed. <!-- 101 -->]]> ​ Example 57 5'-Chloro-5'-methoxy-6-methyl-N-[6-(3-oxomorpholin-4-yl)-l,3- benzothiazol-2-yl]-[4,4'-bipyridin]-3-carboxamide 25 99 2.50 510.1 / 512.1 B 1 H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.86 (s, 1H), 8.16 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.51 - 7.42 (m, 2H), 4.23 (s, 2H), 4.04 - 3.96 (m, 2H), 3.81 - 3.74 (m, 2H), 3.60 (s, 3H), 2.61 (s, 3H). ​

[1310] General procedure F for Ullman coupling

[1311] Add the desired amount of amide (2 equivalents), cesium carbonate (3 equivalents), and copper iodide (I) (3 equivalents) to a DMSO solution of the desired iodobenzothiazole (1 equivalent). Degas the mixture under nitrogen, then add 1,2-dimethylethylenediamine (3 equivalents). Stir the mixture at 100°C and monitor the reaction by LCMS until complete. Cool the mixture to room temperature, dilute with DCM, wash with a saturated ammonium chloride solution, and then wash with water. Treat the organic phase with SMOPEX™ cleaning resin. Filter through the resin and concentrate the filtrate under reduced pressure. Then pass through Biotage Isolera. TM The residue was purified by automated chromatography to obtain the desired product.

[1312] Example 58 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-[6-(3-methyl-2-oxoimidazolidin-1-yl)- 1,3-benzothiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide 1,3-benzothiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide

[1313]

[1314] To a solution of 2'-chloro-N-(6-iodo-1,3-benzothiazolyl-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Example 4, 100 mg, 0.17 mmol) in DMSO (2 mL), 1-methylimidazolidine-2-one (35 mg, 0.35 mmol), cesium carbonate (169 mg, 0.52 mmol), and copper iodide (I) (99 mg, 0.52 mmol) were added. The mixture was degassed under a stream of nitrogen, and then 1,2-dimethylethylenediamine (56 µL, 0.52 mmol) was added. The mixture was then heated at 100 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with DCM (25 mL), and washed successively with saturated ammonium chloride solution (20 mL, then 2 × 10 mL), water (10 mL), and brine (10 mL). The organic phase was passed through a Telos™ phase separator, treated with SMOPEX™ metal scavenging resin, and stirred overnight. The solution was filtered and concentrated under reduced pressure. The solution was then processed through a Biotage Isolera. TM Automated chromatography (C18 Duo, 12 g) was used to purify the crude residue using a gradient of 0-100% acetonitrile (0.1% formic acid) aqueous solution. Fractions containing the product were combined and purified by Biotage Isolera. TM Automated chromatography (Sfar Duo 10g) was used to further purify the compound using a gradient of 0-10% methanol in DCM to give the title compound (8.7 mg, 10% yield) as a colorless powder. 1H NMR (500MHz, DMSO-d6) δ 12.83 (s, 1H), 8.84 (s, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.84– 7.76 (m, 1H), 7.76 – 7.65 (m, 1H), 7.56 (s, 1H), 7.44 (s, 1H) 3.92 – 3.79 (m, 2H), 3.60 (s, 3H), 3.51 – 3.41 (m, 2H), 2.78 (s, 3H), 2.59 (s, 3H). LCMS (Method D); RT 1.57 min (99%), m / z 509.3 / 511.2 (M+H) + .

[1315] Examples 59 and 60 in Table 11 below were prepared using the general procedure F described above.

[1316] Table 11

[1317] Example Yield LCMS purity (%) LCMS Rt (min) m / z LCMS method 1H NMR Example 59 5'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxo-l,3-oxazolidin-3-yl)-l,3- benzothiazol-2-yl]-[4,4'-bipyridin]-3-carboxamide 18 100 1.39 496.2 / 498.2 D <![CDATA[ 1 H NMR (500MHz DMSO-d6) δ 12.92 (s, 1H), 8.85 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.84 - 7.68 (m, 2H), 7.57 (s, 1H), 7.45 (s, 1H), 4.53 - 4.39 (m, 2H), 4.22 - 4.06 (m, 2H), 3.60 (s, 3H), 2.60 (s, 3H). <!-- 103 -->]]> Example 60 5'-Chloro-5'-methoxy-6-methyl-N-[6-(2-oxoimidazolidin-l-yl)-l,3- benzothiazol-2-yl]-[4,4'-bipyridin]-3-carboxamide 12 100 2.39 495.1 / 497.0 B 1 H NMR (400MHz, DMSO) d 12.84 (s, 1H), 8.84 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.83-7.73 (m, 1H), 7.73-7.63 (m, 1H), 7.56 (s, 1H), 7.44 (s, 1H), 6.98 (s, 1H), 3.95-3.85 (m, 2H), 3.60 (s, 3H), 3.46-3.39 (m, 2H), 2.60 (s, 3H).]] ​

[1318] Examples 61 to 75

[1319] Examples 61 to 75 listed in Table 12 were prepared in a manner similar to the general procedure described above, similar to that described in Table 12. In parentheses, (1) indicates that the reaction was carried out at room temperature, (2) at 80°C, (3) at 90°C, and (4) at 50°C. When the reactants were heated, the components were first mixed at room temperature.

[1320] Table 12

[1321] Example Yield LCMS purity (%) LCMS Rt (min) m / z LCMS method 1 H NMR <!-- 104 -->]]> ​ Example 61 (2) 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxopiperidin-1-yl)- [1,3]thiazolo[4,5-c]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide 15 100 2.64 509.4 / 507.4 B 1 H NMR (400MHz, DMSO-d6) δ 13.16 (s, 1H), 8.89 (s, 2H), 8.16 (s, 2H), 7.58 (s, 1H), 7.46 (s, 1H), 3.88 - 3.81 (m, 2H), 3.61 (s, 3H), 2.61 (s, 3H), 2.46 - 2.43 (m, 2H), 1.92 - 1.83 (m, 4H). ​ Example 62 (2) 2'-chloro-5'-methoxy-6-methyl-N-{[l,3]thiazolo[4,5-c]pyridin-2-yl}-[4,4'- bipyridine]-3-carboxamide 20 99 1.17 412.2 / 414.1 D 1 H NMR (500MHz, DMSO-d6) δ 13.54 (s, 1H), 9.36 (s, 1H), 8.90 (s, 1H), 8.60 (d, J = 6.0 Hz, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 3.59 (s, 3H), 2.62 (s, 3H). Example 2 ​ Example 63 (1) 2'-chloro-N-{6-chloro-[1,3]thiazolo[5,4-c]pyridin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide 5 100 3.01 446.0 / 448.0 D <![CDATA[ 1 H NMR (500MHz, CDCl3) δ8.83 (s, 1H),8.79 (s, 1H),8.07 (s, 1H),7.24 (s, 1H),7.09 (s, 1H),6.57 (s, 1H),3.70 (s, 3H),2.69 (s, 3H). <!-- 105 -->]]> Example 64 (2) 2'-chloro-N-{6-chloro-[l,3]thiazolo[4,5-c]pyridin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide 83 100 3.12 446.0 / 448.0 B 1 H NMR (500MHz, DMSO-d6) δ 13.29 (s, 1H), 8.88 (s, 1H), 8.83 (s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 3.59 (s, 3H), 2.60 (s, 3H). MS (ESI) m / z 323.0 (M+H). Example 2 ​ Example 65 (2) 2'-chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-[l,3]thiazolo[4,5- c]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide 56 100 2.57 497.1 / 499.1 B 1 H NMR (500MHz, DMSO-d6) δ 12.88 (s, 1H), 8.83 (s, 1H), 8.63 (s, 1H), 8.16 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 3.80 - 3.69 (m, 4H), 3.61 (s, 3H), 3.46 - 3.43 (m, 4H), 2.60 (s, 3H). ​ Example 66 (1) 2'-chloro-N-[6-(dimethylsulfamoyl)-1,3-benzothiazol-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide 26 99 3.07 518.1 / 520.1 B 1 H NMR (400MHz, DMSO-d6) δ 13.25 (s, 1H), 8.87 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 3.60 (s, 3H), 2.63 (s, 6H), 2.61 (s, 3H). <!-- 106 -->]]> ​ Example 67 (2) 2'-chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-[l,3]thiazolo[4,5- b]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide 73 98 2.65 497.1 / 499.1 B 1 H NMR (500MHz, DMSO-d6) δ 13.00 (s, 1H), 8.85 (s, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.16 (s, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 3.81 - 3.75 (m, 4H), 3.60 (s, 3H), 3.20 - 3.16 (m, 4H), 2.60 (s, 3H). ​ Example 68 (2) 2'-chloro-N-[6-(4-hydroxypiperidin-l-yl)-[l,3]thiazolo[4,5- c]pyridin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide 11 100 2.05 511.2 / 513.2 B 1 H NMR (500MHz, DMSO-d6) δ 12.82 (s, 1H), 8.83 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 4.48 (d, J = 4.3 Hz, 1H), 4.05 - 3.95 (m, 2H), 3.75 - 3.64 (m, 1H), 3.61 (s, 3H), 3.16 - 3.00 (m, 2H), 2.60 (s, 3H), 1.85 - 1.73 (m, 2H), 1.47 - 1.30 (m, 2H). <!-- 107 -->]]> ​ Example 69 (1) N-(1,3-benzothiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'- bipyridine]-3-carboxamide 17 100 2.22 411.1 / 413.1 F 1 H NMR (600MHz, DMSO-d6) δ 12.92 (s, 1H), 8.85 (s, 1H), 8.15 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.57 (s, 1H), 7.50 - 7.39 (m, 2H), 7.39 - 7.19 (m, 1H), 3.59 (s, 3H), 2.60 (s, 3H). ​ Example 70 (2) 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxopiperidin-1-yl)- [1,3]thiazolo[4,5-b]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide 72 98 2.57 509.1 / 511.1 B 1 H NMR (500MHz, DMSO-d6) δ 13.25 (s, 1H), 8.88 (s, 1H), 8.48 (d, J = 2.5 Hz, 1H), 8.38 (d, J = 2.5 Hz, 1H), 8.16 (s, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 3.68 (t, J = 5.7 Hz, 2H), 3.60 (s, 3H), 2.61 (s, 3H), 2.44 (t, J = 6.3 Hz, 2H), 1.93 - 1.85 (m, 4H). <!-- 108 -->]]> ​ Example 71 (2) 2'-chloro-N-[6-(4-hydroxypiperidin-l-yl)-[l,3]thiazolo[4,5- b]pyridin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide 26 98 2.32 511.1 / 513.1 B 1 H NMR (500MHz, DMSO-d6) δ 12.97 (s, 1H), 8.85 (s, 1H), 8.36 (d, J = 2.8 Hz, 1H), 8.17 (s, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 4.71 (d, J = 4.1 Hz, 1H), 3.69 - 3.63 (m, 1H), 3.61 (s, 3H), 3.59 - 3.52 (m, 2H), 2.93 - 2.90 (m, 2H), 2.61 (s, 3H), 1.88 - 1.82 (m, 2H), 1.56 - 1.49 (m, 2H). ​ Example 72 (2) 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[l,3]thiazolo[5,4- b]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide 25 100 2.82 497.1 / 499.1 B 1 H NMR (500MHz, DMSO-d6) δ 8.84 (s, 1H), 8.15 (s, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 6.97 (d, J = 9.0 Hz, 1H), 3.74 - 3.69 (m, 4H), 3.61 (s, 3H), 3.49 - 3.44 (m, 4H), 2.59 (s, 3H). <!-- 109 -->]]> ​ Example 73 (4) 2'-chloro-5'-methoxy-6-methyl-N-[5-(2-oxopiperidin-1-yl)- [1,3]thiazolo[5,4-b]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide 84 100 2.69 509.3 / 511.3 B 1 H NMR (500MHz, DMSO-d6) δ 13.06 (s, 1H), 8.87 (s, 1H), 8.16 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 3.85 (t, J = 5.9 Hz, 2H), 3.61 (s, 3H), 2.60 (s, 3H), 2.48 - 2.45 (m, 2H), 1.93 - 1.78 (m, 4H). ​ Example 74 (4) 2'-chloro-N-[5-(4-hydroxypiperidin-l-yl)-[l,3]thiazolo[5,4- b]pyridin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide 20 99 2.46 511.1 / 513.1 B <![CDATA[ 1 H NMR (500MHz, DMSO-d6) δ 12.67 (s, 1H), 8.82 (s, 1H), 8.16 (s, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 6.98 (d, J = 9.1 Hz, 1H), 4.70 (d, J = 4.3 Hz, 1H), 4.07 - 3.96 (m, 2H), 3.75 - 3.65 (m, 1H), 3.62 (s, 3H), 3.19 - 3.05 (m, 2H), 2.59 (s, 3H), 1.86 - 1.74 (m, 2H), 1.44 - 1.30 (m, 2H). <!-- 110 -->]]> Example 75 (3) 2'-chloro-5'-methoxy-N-{5-methoxy-[l,3]thiazolo[5,4-d]pyrimidin-2-yl}-6- methyl-[4,4'-bipyridinyl]-3-carboxamide 59 99 1.77 443.2 / 445.2 G 1 H NMR (600MHz, DMSO-d6) δ 13.15 (s, 1H), 8.99 (s, 1H), 8.85 (s, 1H), 8.17 (s, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 3.97 (s, 3H), 3.61 (s, 3H), 2.60 (s, 3H).]]> ​

[1322] Examples 76 to 82

[1323] Examples 76 to 82 in Table 13 below were prepared in a manner similar to the general procedure D described above. In parentheses, (1) indicates the use of nBuOH at 100°C, and (2) indicates the use of EtOH at 80°C.

[1324] Table 13

[1325] Example Yield LCMS purity (%) LCMS Rt (min) m / z LCMS method 1 H NMR ​ Example 76 (2) 2'-chloro-5'-methoxy-6-methyl-N-(5-{2-oxa-6-azaspiro[3.4]oct-6-yl}- [1,3]thiazolo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide 43 100 2.72 524.1 / 526.1 B 1 H NMR (400MHz, DMSO-d6) δ 12.87 (s, 1H), 8.83 (s, 1H), 8.74 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 4.61 (d, J = 6.0 Hz, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.77 (s, 2H), 3.62 (s, 3H), 3.55 (d, J = 6.9 Hz, 2H), 2.59 (s, 3H), 2.25 (t, J = 7.0 Hz, 2H). <!-- 111 -->]]> ​ Example 77 (1) 2'-chloro-N-{5-[(2-hydroxy-2-methylpropyl)amino]-[1,3]thiazolo[5,4- d]pyrimidin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide 31 100 2.54 500.1 / 502.1 B 1 H NMR (400MHz, DMSO-d6) δ 12.85 (s, 1H), 8.82 (s, 1H), 8.67 (s, 1H), 8.17 (s, 1H), 7.56 (s, 1H), 7.44 (s, 1H), 6.97 (s, 1H), 4.52 (s, 1H), 3.63 (s, 3H), 2.59 (s, 3H), 1.12 (s, 6H).]]> ​ Example 78 (1) 2'-chloro-5'-methoxy-6-methyl-N-{5-[(2-methylpropyl)amino]- [1,3]thiazolo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridin]-3-carboxamide 29 98 3.33 484.1 / 486.1 B 1 H NMR (400MHz, DMSO-d6) δ 12.84 (s, 1H), 8.83 (s, 1H), 8.67 (s, 1H), 8.17 (s, 1H), 7.57 (s, 1H), 7.45 (s, 2H), 3.63 (s, 3H), 3.19 - 3.07 (m, 2H), 2.60 (s, 3H), 1.88 (hept, J = 6.6 Hz, 1H), 0.92 - 0.88 (m, 6H). ​ Example 79 (1) 2'-chloro-N-[5-(cyclobutylamino)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide 27 91 3.20 482.1 / 484.1 B 1 H NMR (400MHz, DMSO-d6) δ 8.85 (s, 1H), 8.61 (s, 1H), 8.15 (s, 1H), 7.45 (s, 1H), 7.37 (s, 1H), 7.28 (brs, 1H), 4.42-4.36 (m, 1H), 3.67 (s, 3H), 2.60 (s, 3H), 2.31 - 2.24 (m, 2H), 2.04-1.96 (m, 2H), 1.72 -1.64 (m, 2H). <!-- 112 -->]]> ​ Example 80 (2) 2'-chloro-5'-methoxy-N-[5-(4-methoxy-piperidin-l-yl)-[l,3]thiazolo[5,4- d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridinyl]-3-carboxamide 17 100 3.34 526.2 / 528.2 B 1 H NMR (400MHz, CDC13) δ 10.47 (s, 1H), 8.81 (s, 1H), 8.10 - 7.95 (m, 2H), 7.20 - 7.13 (m, 2H), 4.36 - 4.24 (m, 2H), 3.74 (s, 3H), 3.52 - 3.41 (m, 3H), 3.40 (s, 3H), 2.67 (s, 3H), 2.00 - 1.90 (m, 2H), 1.65 - 1.58 (m, 2H). ​ Example 81 (2) 2'-chloro-N-(5-{6-hydroxy-2-azaspiro[3.3]heptan-2-yl}-[1,3]thiazolo[5,4- d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide 38 100 1.22 524.3 / 526.3 B 1 H NMR (500 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.84 (s, 1H), 8.71 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 5.06 (d, J = 6.2 Hz, 1H), 4.08 - 3.98 (m, 5H), 3.62 (s, 3H), 2.60 (s, 3H), 2.05 - 1.99 (m, 2H). <!-- 113 -->]]> ​ Example 82 (2) 2'-chloro-5'-methoxy-6-methyl-N-(5-{6-oxa-2-azaspiro[3.4]oct-2-yl}- [1,3]thiazolo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide 8 100 2.77 524.1 / 526.1 B 1 H NMR (400MHz, CDC13) δ 8.84 (s, 1H), 8.04 (s, 1H), 7.19 (s, 1H), 7.16 (s, 1H), 4.17 (s, 4H), 3.94 (s, 2H), 3.90 (t, J = 7.0 Hz, 3H), 3.74 (s, 3H), 2.69 (s, 3H), 2.23 (t, J = 7.0 Hz, 2H). ​

[1326] Example 83

[1327] Scheme 1 Synthesis of Example 83

[1328]

[1329] Note: Example = Implementation example, the same below.

[1330] Example 83 - 2'-chloro-N-{6-[imino(methyl)oxo-λ 6 - sulfanyl]-1,3-benzothiazol-2-yl}- 5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1331]

[1332] 2'-Chloro-5'-methoxy-6-methyl-N-[6-(methylthio)-1,3-benzothiazo-2-yl]-[4,4'-bipyridine]-3-carboxamide (Example 43, 170 mg, 0.37 mmol) was dissolved in methanol (5.7 mL), and the mixture was then irrigated with N... 2(g) Purge. Add a 2.8 mL solution of ammonium carbonate (54 mg, 0.56 mmol) in methanol to the stirred mixture, followed by a 2.8 mL solution of diacetoxyiodobenzene (275 mg, 0.85 mmol) in methanol. Incubate the mixture at room temperature in an N2 atmosphere. 2(g) Stir for 18 h. Filter the mixture and concentrate the filtrate under reduced pressure. Separately analyze the solution using a Biotage Isolera. TM Automated chromatography (Sfar Duo 10g) was used to purify the residue using a gradient of 0-10% methanol in DCM. Biotage Isolera was employed. TM The partially purified product was further purified by automated chromatography (C18 Duo, 12 g) using a gradient of 0-100% acetonitrile (0.1% formic acid) in water to give the title compound (16 mg, 9%) as a colorless powder. 1 H NMR (500 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.89 (s, 1H),8.58 (s, 1H), 8.16 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 8.2 Hz,1H), 7.58 (s, 1H), 7.46 (s, 1H), 4.22 (s, 1H), 3.59 (s, 3H), 3.10 (s, 3H), 2.60 (s, 3H). LCMS (Method B); Rt 2.24 min (100%), m / z 488.1 / 490.0 (M+H) +

[1333] General procedure G for Ullman coupling (as described previously)

[1334] Add the required amount of amide (2 equivalents), cesium carbonate (3 equivalents), and copper iodide (I) (3 equivalents) to a DMSO solution of the desired iodobenzothiazole (1 equivalent). Place the mixture in N... 2(g) Degas the mixture, then add 1,2-dimethylethylenediamine (3 equivalents). Heat the mixture at 100°C and monitor the reaction by LCMS until completion. Cool the mixture to room temperature, dilute with DCM, and wash with saturated ammonium chloride solution and water. Combine the organic extracts and treat with SMOPEX™ metal scavenging resin. Filter through the resin and concentrate the filtrate under reduced pressure. Separately analyze the reaction mixture through Biotage Isolera. TM The residue was purified by automated chromatography to obtain the desired coupling product.

[1335] The following examples were prepared in a similar manner:

[1336] Example Yield LCMS purity (%) LCMS Rt (min) m / z LCMS method 1H NMR Example 84 2'-chloro-N-[6-(1,1-dioxo-1 lambda 6 ,2-thiazolidin-2-yl)-1,3-benzothiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide]]> ​ 9 99 2.84 530.1 / 532.1 B 1 H NMR (500 MHz, DMSO-de) δ 12.93 (s, 1H), 8.88 (s, 1H), 8.14 (s, 1H), 7.76 (s, 1H), 7.74 - 7.68 (m, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.38 - 7.33 (m, 1H), 3.78 (t, J = 6.5 Hz, 2H), 3.60 (s, 3H), 3.51 (t, J = 7.5 Hz, 2H), 2.59 (s, 3H), 2.46 - 2.39 (m, 2H). ​ Example 8 2'-chloro-N-{6-[(4R)-4-hydroxy-2-oxopiperidin-1-yl]-1,3-benzothiazol-2-yl}- 5'-methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide 3 97 2.29 524.1 / 526.1 B 1 H NMR (400 MHz, CDC13) δ 12.15 (s, 1H), 8.75 (s, 1H), 8.01 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.13 (s, 1H), 7.09 - 7.01 (m, 2H), 6.91 - 6.80 (m, 1H), 4.43 - 4.34 (m, 1H), 3.98 - 3.87 (m, 1H), 3.65 (s, 3H), 3.62 - 3.52 (m, 1H), 2.82 (dd, J = 17.6, 4.5 Hz, 1H), 2.64 - 2.56 (m, 4H), 2.21 - 2.01 (m, 2H).<!-- 115 -->]]> ​ Example 86 2'-chloro-5'-methoxy-6-methyl-N-[6-(4-methyl-2-oxopiperazin-1-yl)-1,3- benzothiazol-2-yl]-[4,4'-bipyridin]-3-carboxamide 6 100 1.31 523.3 / 525.3 D 1 H NMR (500 MHz, DMSO-de) δ 12.96 (s, 1H), 8.86 (s, 1H), 8.16 (s, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 7.39 (dd, J = 8.6, 2.2 Hz, 1H), 3.72 - 3.67 (m, 2H), 3.60 (s, 3H), 3.14 (s, 2H), 2.79 - 2.72 (m, 2H), 2.61 (s, 3H), 2.31 (s, 3H). ​

[1337] Example 87

[1338] Scheme 2 Synthesis of Example 87

[1339]

[1340] Note: 1,4-dioxane-water = 1,4-dioxane-water, the same applies below.

[1341] Intermediate 11 - tert-butyl N-{5-chloro-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}carbamate

[1342]

[1343] 5-Chloro-[1,3]thiazo[5,4-d]pyrimidine-2-amine (1.53 g, 8.2 mmol), DMAP (200 mg, 1.64 mmol), and Et3N (1.14 mL, 8.2 mmol) in 2-methylTHF (120 mL) were treated in portions with tert-butyloxycarbonyl tert-butyl carbonate (3.65 g, 16.4 mmol). The reaction mixture was stirred at room temperature for 3 days, followed by concentration under reduced pressure. The resulting solid was ground with n-heptane (30 mL), filtered, and dried under vacuum to give the title compound (2.42 g, 93%) as a white powder. LCMS (Method H); Rt 1.68 min (90%), m / z 231.1 (Mt-bu) +

[1344] Intermediate 12 - 5-(3,6-dihydro-2H-pyran-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-amine

[1345]

[1346] The tert-butyl N-{5-chlorothiazo[5,4-d]pyrimidin-2-yl}carbamate (intermediate I1, 200 mg, 0.670 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxabortiacyclopentane (296 mg, 1.34 mmol) and 2 M K2CO 3(aq) (1.0 mL, 2.01 mmol) of a stirred suspension in 1,4-dioxane (8 mL) and water (1.5 mL) at N 2(g) Degas for 5 min. Add SPhos (56 mg, 0.134 mmol) and Pd2(dba)3 (65 mg, 0.067 mmol), and stir the mixture overnight at 100 °C in a sealed pressure vessel. Cool the mixture to room temperature and partition it between water and EtOAc. Separate the layers and further extract the aqueous layer with EtOAc (× 2). Dry the combined organic matter on hydrophobic filter paper and concentrate under reduced pressure. Reversed-phase column chromatography (30 g, Redisep gold C18 aq, 0-100% acetonitrile in water, neutral) gives the title compound (64 mg, 41%) as a grayish-white solid. 1 ¹H NMR (500 MHz, DMSO-d⁶) δ 8.59 (s, 1H), 8.10 (s, 2H), 7.06 – 7.05 (m, 1H), 4.30 – 4.28 (m, 2H), 3.81 (t, J = 5.5 Hz, 2H), 2.59 – 2.56 (m, 2H). LCMS (Method E); Rt 0.54 min (100%), m / z 235.2 (M+H) +

[1347] Example 87 - 2'-chloro-N-[5-(3,6-dihydro-2H-pyran-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide Example 88

[1348]

[1349] Prepared at 90 °C in a manner similar to general procedure C, followed by reversed-phase column chromatography (30 g, Redisep Aq18, 0-100% acetonitrile in water, neutral), and then ground with methanol to give the title compound (70 mg, 47%) as a white powder. 1H NMR (600 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.16 (s, 1H), 8.86 (s, 1H), 8.17(s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 7.25 – 7.24 (m, 1H), 4.32 (br d, 2H, J =2.8 Hz), 3.83 (s, 2H), 3.61 (s, 3H), 2.61 (s, 5H). LCMS (Method G); Rt 2.19 min(97%), m / z 495.1 / 497.1 (M+H) +

[1350] Scheme 3 Synthesis of Example 88

[1351] Intermediate 13 - 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)pyridine

[1352]

[1353] Note: cat. = catalyst, dioxane = dioxane, amine = amine, the same below.

[1354] Intermediate 14 - methyl 5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3- carboxylate Intermediate 15 - 5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxylic acid

[1355]

[1356] Di-Mµ-methanolatodiiridium(Ir-Ir)-cycloocta-1,5-diene (Di-Mµ-methanolatodiiridium(Ir-Ir)-cycloocta-1,5-diene) (1:2) (37 mg, 0.057 mmol) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (30 mg, 0.113 mmol) were added to a vacuum-sealed container and treated with N2O. 2(g) The mixture was packed into a Schlenk flask three times. 4,4,5,5-Tetramethyl-1,3,2-dioxaborhexacyclopentane (1.23 mL, 8.47 mmol) and 5-methoxy-2-(trifluoromethyl)pyridine (0.79 mL, 5.65 mmol) were added via syringe. The flask was sealed, and the mixture was heated at 80 °C for 2 h. The mixture was cooled to room temperature and diluted with EtOAc. The resulting mixture was concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography (SiO2, 40 g Redisep gold, 0–100% EtOAc-EtOH (3:1) in heptane) to give the title compound (1.66 g, 81%) as a beige solid. 1¹H NMR (400 MHz, DMSO-d⁶) δ 8.56 (s, 1H), 7.80 (d, J = 0.6 Hz, 1H), 3.98 (s, 3H), 1.31 (s, 12H). LCMS (Method F); Rt 0.93 min (94%), m / z 222.2.

[1357] Intermediate 16 - 1-{2-amino-[1,3]thiazolo[5,4-d]pyrimidin-5-yl}piperidin-4-ol

[1358]

[1359] In a sealed vial, a stirred suspension of 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)-2-(trifluoromethyl)pyridine (intermediate I3, 640 mg, 1.82 mmol), methyl 4-bromo-6-methylpyridine-3-carboxylate (220 mg, 0.956 mmol), and K₂CO₃ (396 mg, 2.87 mmol) in 1,4-dioxane (17.2 mL) and water (5.0 mL) was prepared in N₂O₃. 2(g) Degas for 5 min. Add palladium dichloride (DTBPF) (125 mg, 0.191 mmol) and stir the mixture at 100 °C for 3 h. Cool the mixture to room temperature and dilute with water and EtOAc. Wash the organic layer with brine, dry on hydrophobic filter paper, and concentrate under reduced pressure. Reversed-phase column chromatography (0-100% ACN in water, redisep C18 aq 50 g) yields the title compound (316 mg, 96%) as a brown gel. LCMS (Method F); Rt 1.23 min (94%), m / z 327.3 (M+H) + .

[1360] Example 88 - N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxamide

[1361]

[1362] The title compound (300 mg, quantified) was prepared using intermediate I4 in a manner similar to general procedure B, as a brown foam. 1 H NMR (500 MHz, DMSO-d6) δ 12.3 – 13.5 (m, 1H), 8.92 (s, 1H), 8.59(s, 1H), 7.81 (s, 1H), 7.34 (s, 1H), 3.90 (s, 3H), 2.57 (s, 3H). LCMS (Method F); Rt 0.91 min (96%), m / z 313.2 (M+H)+ .

[1363] Example 89

[1364]

[1365] Piperidine-4-ol (130 mg, 1.29 mmol) was added to a suspension of 5-chlorothiazo[5,4-d]pyrimidine-2-amine (50 mg, 0.26 mmol) in n-butanol (1.3 mL). The reaction mixture was stirred overnight at 100 °C. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water, followed by washing with brine. The organic phase was dried over (Na₂SO₄) and concentrated under reduced pressure to give an orange solid. The solid was co-evaporated with diethyl ether to remove residual n-butanol, and the resulting solid was ground with diethyl ether and filtered under vacuum. 2(g) The dried filter cake was drained to give the title compound (56 mg, 82%) as an orange powder. 1 H NMR (500MHz, DMSO-d6) δ 8.25 (s, 1H), 7.48 (s, 2H), 4.68 (d, J = 4.3 Hz, 1H), 4.19(dt, J = 12.7, 4.4 Hz, 2H), 3.73 – 3.66 (m, 1H), 3.21 – 3.15 (m, 2H), 1.78 –1.72 (m, 2H), 1.35 – 1.27 (m, 2H) . LCMS (Method A); Rt 0.43 min (100%), m / z 252.1 (M+H) +

[1366] Scheme 4 Synthesis of Example 89 Example 89 - N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxamide

[1367]

[1368] The compound was prepared at 80 °C using intermediates I5 and I6 in a manner similar to general procedure C. Purification was performed by reversed-phase chromatography (30 g Redisep Aq18) using a gradient of 0% to 100% acetonitrile in aqueous solution (neutral). The title compound (23 mg, 28%) was given as a brown powder. 11H NMR (600 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.84 (s, 1H), 8.74(s, 1H), 8.54 (s, 1H), 7.94 (s, 1H), 7.51 (s, 1H), 4.72 (d, J = 4.25 Hz, 1H),4.27 (dt, J = 13.3, 4.6 Hz, 2H), 3.71 – 3.76 (m, 4H), 3.29 – 3.30 (m, 2H),2.61 (s, 3H), 1.75 – 1.82 (m, 2H), 1.31 – 1.38 (m, 2H). LCMS (Method G); Rt 1.9min (99%), m / z 546.3 (M+H) +

[1369] Example 90

[1370] Scheme 5 Synthesis of Example 90

[1371]

[1372] Intermediate 11 - tert-butyl N-{5-chloro-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}carbamate Intermediate 12 - 5-(3,6-dihydro-2H-pyran-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-amine

[1373]

[1374] Under N2(g), Pd2(dba)3 (13 mg, 0.01 mmol) and DPEPos (15 mg, 0.028 mmol) were added to a stirred solution of 4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-N-(5-morpholinothiazo[5,4-d]pyrimidin-2-yl)pyridine-3-carboxamide (Example 22, 70 mg, 0.141 mmol) in anhydrous toluene (1.8 mL, degassed under bubbling N2(g) for 10 min before use), followed by the addition of [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-1-onthiol-2-yl]-(difluoromethyl)silver (100 mg, 0.183 mmol). The mixture was stirred at 80 °C for 18 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, and then the gel was purified by normal-phase column chromatography (10 g sfar, 0–100% EtOAc in heptane, followed by 0–20% methanol in EtOAc). Partially purified products were further purified by preparative HPLC (Method C), followed by further purification by preparative HPLC under the following conditions: column: Sunfire C18, 150 x 19 mm, 5 µm; flow rate: 20 mL / min, using 5–95% acetonitrile solution of 0.1% formic acid in aqueous solution of 0.1% formic acid for 18 min. Freeze-drying from acetonitrile-water yielded the title compound (4 mg, 6%) as a grayish-white solid. 1 H NMR (500 MHz, DMSO-d6) δ8.99 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.55 (s, 1H), 7.21(s, 1H), 6.95 (t, J = 55.2 Hz, 1H), 3.70 (s, 3H), 3.68 – 3.61 (m, 8H), 2.54 (s, 3H). LCMS (Method B); Rt 2.79 min (94%), m / z 514.1 (M+H) +

[1375] Example 87 - 2'-chloro-N-[5-(3,6-dihydro-2H-pyran-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1376] Example 88

[1377]

[1378] Scheme 3 Synthesis of Example 88 Intermediate 13 - 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)pyridine Intermediate 14 - methyl 5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3- carboxylate Intermediate 15 - 5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxylic acid Intermediate 16 - 1-{2-amino-[1,3]thiazolo[5,4-d]pyrimidin-5-yl}piperidin-4-ol Example 88 - N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxamide Example 89 Scheme 4 Synthesis of Example 89 Example 89 - N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxamide Example 90 Scheme 5 Synthesis of Example 90 Intermediate 11 - tert-butyl N-{5-chloro-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}carbamate Intermediate 12 - 5-(3,6-dihydro-2H-pyran-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-amine

[1379]

[1380] 1-Bromopyrrolidine-2,5-dione (628 mg, 3.49 mmol) was added fractionally to a stirred solution of 2-(trifluoromethyl)pyrimidin-5-amine (500 mg, 2.91 mmol) in anhydrous acetonitrile (5 mL). The mixture was stirred at room temperature for 17 h. While stirring, the mixture was poured into 1 N Na₂S₂O₃. 3(aq) The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (SiO₂, Biotage, Redisep 24 g) using a gradient of 70–100% DCM in heptane to give the title compound (266 mg, 38%) as an orange powder. 1 H NMR (600 MHz, DMSO-d6,) δ8.22 (s, 1H), 6.63 (s, 2H).

[1381] Intermediate 112 - 5-(trifluoromethyl)-[l,3]thiazolo[5,4-d]pyrimidin-2-amine

[1382]

[1383] Add 4-bromo-2-(trifluoromethyl)pyrimidine-5-amine (intermediate I11, 257 mg, 1.06 mmol) to a stirred suspension of potassium thiocyanate (120 mg, 1.17 mmol) in acetic acid (1.5 mL). Stir the mixture overnight at 80 °C. Pour the mixture into diethyl ether, filter the resulting solid, treat the filtrate with water, and add 17 mL of 2 M NaOH. (aq) The organic layer was dried with Na2SO4 and then concentrated to dryness. The residue was ground with DCM, filtered, washed several times with n-pentane, and dried overnight under vacuum at 50°C to give the title compound (146 mg, 62%) as a beige powder. 1 ¹H NMR (600 MHz, DMSO-d⁶) δ 8.76 (s, 1H), 8.56 (s, 2H). LCMS (Method E); Rt 0.64 min (99%), m / z 221.1 (M+H). +

[1384] Example 90 - 2'-chloro-5'-methoxy-6-methyl-N-[5-(trifluoromethyl)-[l,3]thiazolo[5,4- d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide Example 91

[1385]

[1386] The title compound (33 mg, 16%) was prepared at 80 °C using a method similar to general procedure C, and was obtained as a white powder. 1H NMR (600 MHz, DMSO-d6) δ 13.65 (br s, 1H), 9.39 (s, 1H), 8.89 (s, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.50 (s, 1H), 3.60 (s, 3H), 2.61 (s, 3H). LCMS (Method F); Rt 1.51 min (100%), m / z 481.1 / 482.9 (M+H) +

[1387] Scheme 6 Synthesis of Example 91

[1388] Intermediate 17 - 5-methyl-[l,3]thiazolo[5,4-d]pyrimidin-2-amine

[1389]

[1390] Example 91 - 2'-chloro-5'-methoxy-6-methyl-N-{5-methyl-[l,3]thiazolo[5,4-d]pyrimidin-2- yl}-[4,4'-bipyridine]-3-carboxamide

[1391]

[1392] It is prepared using the corresponding commercial aryl chloride as a starting material in a manner similar to intermediate I12. 1 H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.00 (s, 2H), 2.58 (s, 3H).

[1393] Example 92 Scheme 7 Synthesis of Example 92

[1394]

[1395] Prepared at 80 °C using a procedure similar to general procedure C. The mixture contained a precipitate, which was filtered and washed successively with water and acetonitrile to give a white solid. Purified by reversed-phase column chromatography (10-100 acetonitrile in water, 0.1% AcOH) to give the title compound (100 mg, 39%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 9.08 (s, 1H), 8.86 (s, 1H), 8.17 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 3.61 (s, 3H), 2.72 (s, 3H), 2.61 (s, 3H). LCMS (Method G); Rt 1.86 min (100%), m / z427.1 / 429.1 (M+H) +

[1396] Example 92 - 5'-methoxy-2',6-dimethyl-N-[5-(morpholin-4-yl)-[l,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridine]-3-carboxamide

[1397] Example 93

[1398]

[1399] Scheme 8 Synthesis of Example 93 Intermediate 18 - 2'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester

[1400]

[1401] 4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-N-(5-morpholinothiazo[5,4-d]pyrimidin-2-yl)pyridine-3-carboxamide (Example 22, 120 mg, 0.241 mmol), trimethylboroxane (121 mg, 0.964 mmol), and Cs₂CO₂ (236 mg, 0.723 mmol) were stirred in 1,4-dioxane (0.66 mL) and water (0.28 mL), and the mixture was then placed in N… 2(g) Degas under bubbling for 5 min. Add Pd(dppf)Cl2·DCM (20 mg, 0.0241 mmol) and simmer the mixture in N2O2. 2(g) Degas for another 5 min. Stir the mixture at 100 °C (in a pressure vessel) for 18 h. After cooling to room temperature, further treat the mixture with trimethylboroxane (121 mg, 0.964 mmol), Cs₂CO₂ (236 mg, 0.723 mmol), and Pd(dppf)Cl₂.DCM (20 mg, 0.0241 mmol). The mixture is then subjected to N₂O₃ treatment. 2(g) Degas under bubbling for 5 min, then stir at 100 °C for 6 h. After cooling to room temperature, dilute the mixture with DCM (6 mL), which immediately forms a precipitate. Filter the mixture and wash the filter cake with DCM. Treat the filtrate as follows: separate the organic phase and concentrate under reduced pressure. Dissolve the residue in DMSO (2.5 mL, containing 1 drop of water). Perform preparative HPLC (Method A), followed by freeze-drying from acetonitrile / water to give a partially purified product. Perform normal-phase column chromatography (0–10% MeOH in DCM), followed by freeze-drying from acetonitrile / water to give the title compound (24 mg, 20%) as a grayish-white powder. 1¹H NMR (400 MHz, CDCl₃): 10.18 – 9.99 (m, 1H), 8.75 (s, 1H), 8.17 – 8.08 (m, 2H), 7.09 (s, 1H), 6.94 (s, 1H), 3.79 – 3.70 (m, 8H), 3.69 (s, 3H), 2.60 (s, 3H), 2.48 (s, 3H). LCMS (Method B): Rt 1.89 min (100%), m / z 478.1 (M+H). +

[1402] Intermediate 19 - 2'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid sodium salt

[1403] Intermediate 110 - 5-(morpholin-4-yl)-[l,3]thiazolo[5,4-d]pyrimidin-2-amine

[1404]

[1405] Note: sealed tube = sealed tube, the same below.

[1406] Example 93 - 2'-fluoro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[l,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridine]-3-carboxamide

[1407]

[1408] Prepared in a manner similar to general procedure A, the title compound (296 mg, 65%) was obtained as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.37(s, 1H), 7.22 (d, J = 2.9 Hz, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 2.58 (s, 3H). LCMS (Method F); Rt 0.96 min (98%), m / z 277.2 (M+H)

[1409] Example 94

[1410]

[1411] At room temperature, 1 M NaOH was added to a stirred solution of methyl 2'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (intermediate I8, 296 mg, 1.05 mmol) in methanol (3 mL). (aq)(3.0 mL, 3.0 mmol). The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give the title compound (406 mg, 95%) as a yellow solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 8.73 (s, 1H), 7.83 (d, J = 1.8 Hz, 1H), 6.94 (s, 1H), 6.87 (d, J = 2.8 Hz, 1H), 3.72 (s, 3H), 2.44 (s, 3H). LCMS (Method F); Rt 0.72 min (97%), m / z (free acid) 263.3 (M+H) +

[1412] Scheme 9 Synthesis of Example 94

[1413]

[1414] Morpholine (9.88 mL, 115 mmol) was added to a suspension of 5-chloro-[1,3]thiazo[5,4-d]pyrimidine-2-amine (2.25 g, 11.5 mmol) in ethanol (43 mL) at room temperature. The vial was sealed, and the mixture was stirred at 110 °C for 6 h. The mixture was cooled to room temperature and stirred overnight at room temperature. The precipitate was filtered, washed with ethanol (x2) and diethyl ether (x3), and dried under vacuum overnight to give a pink powder. This powder was ground with water (x3), filtered, and dried under vacuum at 45 °C to give the title compound (1.27 g, 47%) as a pink powder. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 8.29 (s, 1H), 7.54 (s, 2H), 3.75–3.51 (m, 8H). LCMS (Method E); Rt 0.55 min (95%), m / z 238.2 (M+H). +

[1415] Intermediate 113 - tert-butyl N-[5-(2-oxopiperidin-l-yl)-[l,3]thiazolo[5,4-d]pyrimidin-2- yl]carbamate Intermediate 114 - l-{2-amino-[l,3]thiazolo[5,4-d]pyrimidin-5-yl}piperidin-2-one hydrochloride

[1416]

[1417] Prepared at 90 °C in a manner similar to general procedure C, followed by column chromatography (SiO2, 0-100% EtOAc / EtOH (3 / 1) in heptane) to give the title compound (94 mg, 47%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.84 (s, 1H), 8.80 (s, 1H), 7.92 (d, J = 1.6 Hz,1H), 7.45 (s, 1H), 7.30 (d, J = 2.7 Hz, 1H), 3.77 – 3.64 (m, 8H), 3.60 (s, 3H), 2.61 (s, 3H). LCMS (Method F); Rt 1.23 min (100%), m / z 482.3 (M+H) +

[1418] Example 94 - 2'-chloro-5'-methoxy-6-methyl-N-[5-(2-oxopiperidin-l-yl)-[l,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridine]-3-carboxamide

[1419] Bioassay 1

[1420]

[1421] Note: HCl in dioxane = HCl in dioxane solution, the same applies below.

[1422] Example Number Compound

[1423]

[1424] N-{5-chlorothiazo[5,4-d]pyrimidin-2-yl}carbamate tert-butyl ester (intermediate I1, 750 mg, 2.48 mmol), piperidin-2-one (493 mg, 4.97 mmol), and Cs2CO3 (2.89 g, 8.70 mmol) were stirred in anhydrous 1,4-dioxane (28 mL) and N 2(g) Degas under bubbling for 10 min. Add Pd2(dba)3 (228 mg, 0.248 mmol) and Xantphos (288 mg, 0.497 mmol), and then degas the mixture under N2S conditions. 2(g) Degas again after purging for 5 minutes. Incubate the mixture at 105°C with N2. 2(g) The mixture was stirred for 18 h. After cooling to room temperature, it was diluted with water (6 mL) and EtOAc (20 mL). The organic phase was separated and the aqueous phase was further extracted with EtOAc (2 x 20 mL). The combined organics were washed with brine (20 mL). The aqueous phase was extracted with EtOAc (2 x 20 mL), and the combined organics were dried (MgSO4) and concentrated under reduced pressure. Column chromatography (0-10% methanol in DCM) gave the title compound (812 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.05 (s, 1H), 3.77 (t, J = 5.6 Hz, 2H), 2.44 (t, J = 6.2 Hz, 2H), 1.95 – 1.80 (m, 4H), 1.53(s, 9H). LCMS (Method A); Rt 0.76 min (96%), m / z 350.1 (M+H) +

[1425] PolQ ATPase assay IC50

[1426]

[1427] N-[5-(2-oxo-1-piperidinyl)thiazo[5,4-d]pyrimidin-2-yl]carbamate tert-butyl ester (intermediate I13, 390 mg, 0.726 mmol) was stirred for 1 h in a 1,4-dioxane solution (5.0 mL, 20.0 mmol) of 4 M HCl. The mixture was diluted with anhydrous 1,4-dioxane (5 mL) and stirred for 24 h. The reactants were concentrated under reduced pressure and co-evaporated sequentially with acetonitrile (10 mL) and heptane (10 mL) to give the title compound (406 mg, 92%). 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 8.58 (s, 1H), 7.62–7.24 (m, 3H), 3.69 (t, J = 5.6 Hz, 2H), 2.40 (t, J = 6.3 Hz, 2H), 1.91–1.78 (m, 4H). LCMS (Method A); Rt 0.43 min (86%), m / z 250.0 (M+H) +

[1428] ND ND

[1429]

[1430] The compound was prepared at 80 °C in a manner similar to general procedure C, yielding the title compound (23 mg, 13%) as a grayish-white solid. 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.94 (s, 1H), 8.74 (s, 1H), 8.05 (s, 1H), 7.29 (s, 1H), 7.20 (s, 1H), 3.92 (t, J = 5.6 Hz, 2H), 3.75 (s, 3H), 2.71 (s, 3H), 2.60 (t, J = 6.4 Hz, 2H), 2.06 – 1.92 (m, 4H). LCMS (Method B); Rt 2.58 min (99%), m / z 510.2 / 512.1 (M+H) + .

[1431] 2'-chloro-N-(5-{3,8-diazabicyclo[3.2.1]oct-3-yl}-[l,3]thiazolo[5,4-d]pyrimidin-2-yl)-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1432] The Polθ ATPase assay was used to assess the inhibitors of Polθ ATPase activity in vitro. The experiment was conducted using a truncated Polθ protein (Polθ-Hel, containing the helicase domain (67-894)), ATP, and a single-stranded DNA oligonucleotide (5'-CTGTCCTGCATGATG-3') in Polθ assay buffer (20 mM Tris-HCl (pH 8.8), MgCl2 5 mM, Tween20 0.01%, NP40 0.01%, BSA 0.01%, DTT 1 mM). 2 µL of assay buffer containing Polθ-Hel protein (0.5 nM) and DNA substrate (500 nM) was transferred to an assay preparation plate containing 0.04 µL of the compound diluted in DMSO. After incubation in the dark at 23°C for 30 min, the reaction was triggered by adding 2 µL of ATP (60 µM) to the assay buffer. After incubating at 23°C for 60 min, 4 µl of ADP-Glo™ reagent (Glo 1) was added, followed by incubation for 40 min. Then, 8 µl of ADP-Glo™ kinase detection reagent (Glo 2) was added, and the mixture was incubated at 23°C for another 60 min. The luminescence was then measured using a Tecan F200 Infinite microplate reader. The raw data were analyzed using GeneData to generate IC50 values.

[1433] The results are shown in Table A below.

[1434] Table A - IC50 results of Polθ ATPase assay

[1435] Example - Part B Analysis Experiment 1 N-(6-chloro-1,3-benzothiazol-2-yl)-4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl- pyridine-3-carboxamide *** 2 2'-chloro-N-(6-methanesulfonyl-1,3-benzothiazol-2-yl)-5'-methoxy-6-methyl- [4,4'-bipyridine]-3-carboxamide *** 3 2'-chloro-N-(6-cyano-1,3-benzothiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3- carboxamide *** 4 2'-chloro-N-(6-iodo-1,3-benzothiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3- carboxamide *** 5 N-(6-bromo-1,3-benzothiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3- carboxamide *** 6 2'-chloro-N-{5-chloro-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6-methyl- [4,4'-bipyridinyl]-3-carboxamide *** 7 2'-chloro-N-{5-chloro-[1,3]thiazolo[5,4-b]pyridin-2-yl}-5'-methoxy-6-methyl- [4,4'-bipyridinyl]-3-carboxamide *** 8 3-(2-methoxyphenyl)-N-{[1,3]thiazolo[5,4-d]pyrimidin-2-yl}pyridine-4-carboxamide ** 9 N-(6-bromo-1,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide ** 10 3-(2-methoxyphenyl)-N-{[1,3]thiazolo[4,5-c]pyridine-2-yl}pyridine-4-carboxamide * 11 3-(2-methoxyphenyl)-N-{[1,3]thiazolo[4,5-b]pyridine-2-yl}pyridine-4-carboxamide * 12 3-(2-methoxyphenyl)-N-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]pyridine-4- carboxamide * 13 N-(5-chloro-1,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide * 14 3-(2-methoxyphenyl)-N-{[1,3]thiazolo[5,4-b]pyridine-2-yl}pyridine-4-carboxamide * 15 N-(1,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide * 16 N-(5-cyano-1,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide Example 17 2'-chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-1,3-benzothiazol-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 18 2'-chloro-5'-methoxy-6-methyl-N-(6-nitro-l,3-benzothiazol-2-yl)-[4,4'-bipyridin]-3- carboxamide Yield 19 4-(2-chloro-5-methoxy-4-pyridyl)-N-[5-[(3R)-3-hydroxypyrrolidin-1-yl]thiazolo[5,4- d]pyrimidin-2-yl]-6-methyl-pyridine-3-carboxamide *** 20 2'-chloro-5'-methoxy-6-methyl-N-[5-(piperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridinyl]-3-carboxamide *** 21 2'-chloro-N-[5-(4,4-difluoropiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 22 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 23 2'-chloro-N-{5-[(3S)-3-hydroxypyrrolidin-1-yl]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 24 2'-chloro-5'-methoxy-6-methyl-N-[5-(pyrrolidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide *** 25 2'-chloro-N-[5-(3,3-difluoropyrrolidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 26 2'-chloro-N-{5-[(3R)-3-hydroxypyrrolidin-1-yl]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 27 2'-chloro-N-[5-(1,1-dioxo-1 lambda 6 - thiomorpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl- [4,4'-bipyridinyl]-3-carboxamide ]]> *** 28 2'-chloro-5'-methoxy-6-methyl-N-[5-(4-methylpiperazin-1-yl)-[1,3]thiazolo[5,4- d]pyrimidin-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 29 2'-chloro-5'-methoxy-6-methyl-N-(5-{2-oxa-6-azaspiro[3.3]heptan-6-yl}- [1,3]thiazolo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridin]-3-carboxamide *** 30 2'-chloro-5'-methoxy-N-{5-[(2-methoxyethyl)amino]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-6-methyl-[4,4'-bipyridin]-3-carboxamide *** 31 2'-chloro-N-[5-(3-hydroxyazetidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 32 2'-chloro-5'-methoxy-N-[5-(3-methoxypyrrolidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 33 2'-chloro-N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 34 2'-chloro-5'-methoxy-6-methyl-N-{5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]- [1,3]thiazolo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridin]-3-carboxamide *** 35 2'-chloro-N-[5-(3-cyanopiperidin-l-yl)-[l,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 36A N-(6-amino-l,3-benzothiazol-2-yl)-4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl- pyridine-3-carboxamide ** 36B 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxopiperidin-1-yl)-1,3-benzothiazol-2-yl]- [4,4'-bipyridin]-3-carboxamide *** 37 4-(2-chloro-5-methoxy-4-pyridyl)-N-[5-(3,6-dihydro-2H-pyran-5-yl)thiazolo[5,4- b]pyridin-2-yl]-6-methyl-pyridine-3-carboxamide *** 38 4-(2-chloro-5-methoxy-4-pyridyl)-N-[6-(5-chloro-2-pyridyl)-1,3-benzothiazol-2-yl]- 6-methyl-pyridine-3-carboxamide *** 39 N-[6-(5-chloropyridin-2-yl)-1,3-benzothiazol-2-yl]-3-(2-methoxyphenyl)pyridine-4-carboxamide ** 40 2'-chloro-N-[6-(3-hydroxyoxolan-3-yl)-1,3-benzothiazol-2-yl]-5'-methoxy-6- methyl-[4,4'-bipyridinyl]-3-carboxamide ** 41 2'-chloro-N-(6-methanesulfonamido-1,3-benzothiazol-2-yl)-5'-methoxy-6-methyl- [4,4'-bipyridin]-3-carboxamide *** 42 2'-chloro-5'-methoxy-6-methyl-N-{[l,3]thiazolo[5,4-d]pyrimidin-2-yl}-[4,4'- bipyridine]-3-carboxamide *** 43 2'-chloro-5'-methoxy-6-methyl-N-[6-(methylthio)-1,3-benzothiazol-2-yl]-[4,4'- bipyridin]-3-carboxamide *** 44 2'-chloro-5'-methoxy-6-methyl-N-{[l,3]thiazolo[5,4-c]pyridin-2-yl}-[4,4'- bipyridin]-3-carboxamide *** 45 N-[5-(4-acetylpiperazin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-2'-chloro-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide *** 46 2'-chloro-N-{5-[(2-hydroxyethyl)amino]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide *** 47 2'-chloro-5'-methoxy-N-[5-(3-methoxyazetidin-l-yl)-[l,3]thiazolo[5,4- d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridin]-3-carboxamide *** 48 2'-chloro-N-{5-[(4-hydroxycyclohexyl)amino]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide *** 49 rac-2'-chloro-N-(5-{[(1 R,3S)-3-hydroxycyclopentyl]amino}-[1,3]thiazolo[5,4- d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide *** 50 2'-chloro-5'-methoxy-6-methyl-N-{5-[(3R)-3-methylmorpholin-4-yl]-[1,3]thiazolo[5,4- d]pyrimidin-2-yl}-[4,4'-bipyridin]-3-carboxamide *** 51 2'-chloro-5'-methoxy-6-methyl-N-{5-[(3S)-3-methylmorpholin-4-yl]-[1,3]thiazolo[5,4- d]pyrimidin-2-yl}-[4,4'-bipyridin]-3-carboxamide *** 52 2'-chloro-5'-methoxy-6-methyl-N-{5-[(prop-2-yl)amino]-[1,3]thiazolo[5,4- d]pyrimidin-2-yl}-[4,4'-bipyridin]-3-carboxamide *** 53 2'-chloro-5'-methoxy-6-methyl-N-(5-{2-oxa-7-azaspiro[3.5]non-7-yl}-[1,3]thiazolo[5,4- d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide *** 54 LCMS purity (%) LCMS Rt (min) ]]> ​ *** 55 2'-chloro-5'-methoxy-6-methyl-N-[5-(piperazin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridinyl]-3-carboxamide *** 56 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxopyrrolidin-1-yl)-1,3-benzothiazol-2-yl]- [4,4'-bipyridine]-3-carboxamide *** 57 2'-chloro-5'-methoxy-6-methyl-N-[6-(3-oxomorpholin-4-yl)-1,3-benzothiazol-2-yl]- [4,4'-bipyridin]-3-carboxamide *** 58 2'-chloro-5'-methoxy-6-methyl-N-[6-(3-methyl-2-oxoimidazolidin-1-yl)-1,3- benzothiazol-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 59 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxo-l,3-oxazolidin-3-yl)-l,3-benzothiazol-2-yl]- [4,4'-bipyridine]-3-carboxamide *** 60 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxoimidazolidin-1-yl)-1,3-benzothiazol-2-yl]- [4,4'-bipyridine]-3-carboxamide *** 61 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxopiperidin-1-yl)-[1,3]thiazolo[4,5-c]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 62 2'-chloro-5'-methoxy-6-methyl-N-{[l,3]thiazolo[4,5-c]pyridine-2-yl}-[4,4'- bipyridine]-3-carboxamide *** 63 2'-chloro-N-{6-chloro-[1,3]thiazolo[5,4-c]pyridin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 64 2'-chloro-N-{6-chloro-[1,3]thiazolo[4,5-c]pyridin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 65 2'-chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-[1,3]thiazolo[4,5-c]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 66 2'-chloro-N-[6-(dimethylsulfamoyl)-1,3-benzothiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide *** 67 2'-chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-[1,3]thiazolo[4,5-b]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 68 2'-chloro-N-[6-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[4,5-c]pyridin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 69 N-(1,3-benzothiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3- carboxamide *** 70 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxopiperidin-1-yl)-[1,3]thiazolo[4,5- b]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 71 2'-chloro-N-[6-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyridin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 72 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-b]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 73 2'-chloro-5'-methoxy-6-methyl-N-[5-(2-oxopiperidin-1-yl)-[1,3]thiazolo[5,4- b]pyridin-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 74 2'-chloro-N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[5,4-b]pyridin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 75 2'-chloro-5'-methoxy-N-{5-methoxy-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-6-methyl-[4,4'-bipyridin]-3-carboxamide *** 76 2'-chloro-5'-methoxy-6-methyl-N-(5-{2-oxa-6-azaspiro[3.4]oct-6-yl}-[1,3]thiazolo[5,4- d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide *** 77 2'-chloro-N-{5-[(2-hydroxy-2-methylpropyl)amino]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide *** 78 2'-chloro-5'-methoxy-6-methyl-N-{5-[(2-methylpropyl)amino]-[1,3]thiazolo[5,4- d]pyrimidin-2-yl}-[4,4'-bipyridin]-3-carboxamide *** 79 2'-chloro-N-[5-(cyclobutylamino)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 80 2'-chloro-5'-methoxy-N-[5-(4-methoxy-piperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridinyl]-3-carboxamide *** 81 2'-chloro-N-(5-{6-hydroxy-2-azaspiro[3.3]heptan-2-yl}-[1,3]thiazolo[5,4- d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide *** 82 2'-chloro-5'-methoxy-6-methyl-N-(5-{6-oxa-2-azaspiro[3.4]oct-2-yl}-[1,3]thiazolo[5,4- d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide *** 83 2'-chloro-N-{6-[imino(methyloxy-λ 6 - sulfanyl]-1,3-benzothiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide]]> ​ *** 84 2'-chloro-N-[6-(1,1-dioxo-1 lambda 6 ,2-oxazolidin-2-yl)-1,3-benzothiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide]]> ​ *** 85 2'-chloro-N-{6-[(4R)-4-hydroxy-2-oxopiperidin-1-yl]-1,3-benzothiazol-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide *** 86 2'-chloro-5'-methoxy-6-methyl-N-[6-(4-methyl-2-oxopiperazin-1-yl)-1,3-benzothiazol-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 87 2'-chloro-N-[5-(3,6-dihydro-2H-pyran-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridin]-3-carboxamide *** 88 N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridinyl]-3-carboxamide *** 89 N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridinyl]-3-carboxamide *** 90 2'-chloro-5'-methoxy-6-methyl-N-[5-(trifluoromethyl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 91 2'-chloro-5'-methoxy-6-methyl-N-{5-methyl-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-[4,4'- bipyridin]-3-carboxamide *** 92 5'-Methoxy-2',6-dimethyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]- [4,4'-bipyridin]-3-carboxamide *** 93 2'-fluoro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridin]-3-carboxamide *** 94 2'-chloro-5'-methoxy-6-methyl-N-[5-(2-oxopiperidin-1-yl)-[1,3]thiazolo[5,4- d]pyrimidin-2-yl]-[4,4'-bipyridin]-3-carboxamide ***

[1436] *** indicates that IC50 is less than 100 nM

[1437] **Indicates IC50 is between 100 nM and 000 nM.

[1438] * indicates that IC50 is greater than 1000 nM

[1439] m / z

[1440] LCMS Method

[1441] All solvents and chemical reagents were obtained from commercial sources and were ready for use without further purification or drying. NMR spectra were recorded on Bruker Avance III HD 400 MHz, Bruker NEO 400 MHz, Bruker Avance IIIHD 500 MHz, Bruker Avance NEO 500 MHz, or Bruker Avance III HD 600 MHz spectrometers. Chemical shifts are given in ppm using residual undeuterated solvents as an internal reference.

[1442] LCMS spectra were recorded on a Waters Aquity UPLC using the following methods: Method A: At 40°C, using a Waters UPLC® BEHTM C18 2.1 x 50 mm 1.7 µm column, eluted with 0.1% formic acid in acetonitrile and 0.1% formic acid in aqueous solution, using a 5-100% gradient, for 1.35 min at a flow rate of 0.9 mL / min; Method B: At 40°C, using a Phenomenex XB C18 2.1 x 100 mm 1.7 µm column, eluted with 0.1% formic acid in acetonitrile and 0.1% formic acid in aqueous solution, using a 5-100% gradient, for 5.8 min at a flow rate of 0.6 mL / min; Method C: At 55°C, using a Waters UPLC® BEHTMC18 2.1 x 50 mm 1.7 µm column, eluted with 2 mL of water buffered to pH 10. Method D: Eluting with an aqueous solution of 2 mM ammonium bicarbonate and acetonitrile at a gradient of 1-100%, lasting 1.10 min at a flow rate of 1 mL / min. Method E: Eluting with an aqueous solution of 2 mM ammonium bicarbonate buffered to pH 10 and acetonitrile at a gradient of 5-100%, lasting 5.30 min at a flow rate of 0.6 mL / min. Method E: Eluting with a CSH C18 2.1 x 50 mm, 1.7 µm column at 55 °C, using an aqueous solution of 0.035% TFA in acetonitrile and an aqueous solution of 0.05% TFA at a gradient of 2%-98%, lasting 1.5 min at a flow rate of 0.8 mL / min. Method F: Eluting with a Waters CSH C18 2.1 x 50 mm, 1.7 µm column at 55 °C. Method G: At 55°C, using a CSH C18 2.1 x 50 mm, 1.7 µm column, eluted with 0.035% TFA in acetonitrile and 0.05% TFA in aqueous solution, using a gradient of 2%–98%, for 2.4 min at a flow rate of 0.8 mL / min. Method H: At 55°C, using a CSH C18 2.1 x 50 mm, 1.7 µm column, eluted with 0.02% formic acid in acetonitrile and 0.02% formic acid in aqueous solution, using a gradient of 2%–98%, for 4.5 min at a flow rate of 1 mL / min. Mass spectrometry was obtained using electrospray ionization in positive or negative modes with a Waters SQD, SQD2, or QDA detector.LCMS purity was determined using AUC monitoring at 215, 220, 254, or 280 nm.

[1443] Preparative HPLC was performed using any of the following methods: Method A: At room temperature, using a Waters Sunfire C18 30 mm × 100 mm, 5 μm column, incubation was performed for 1.9 min with a solution of 30% 0.1% formic acid in acetonitrile and 70% 0.1% formic acid in aqueous solution, followed by a gradient of 30-95% 0.1% formic acid in acetonitrile for 9.6 min at a flow rate of 40 mL / min; Method B: At room temperature, using a Waters XBridge C18 30 mm × 100 mm, 5 μm column, incubation was performed for 2 min with a solution of 30% acetonitrile and 70% 0.2% ammonium hydroxide in aqueous solution, followed by a gradient of 30-95% acetonitrile for 9.5 min at a flow rate of 40 mL / min; or Method C: Using a Waters Sunfire™ C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), injection volume of 1500 μL, flow rate of 40 mL / min, and 10% formic acid in aqueous solution. B was incubated for 1.90 min, followed by a 10–95% B gradient for 14.10 min, and held for 2.0 min, where A was an aqueous solution of 0.1% formic acid and B was an acetonitrile solution of 0.1% formic acid. UV spectra were recorded at 215 nm using a Gilson detector.

[1444] General procedure H for the preparation of 5-alkoxy-l,3-benzothiazol-2-amines

[1445] The embodiments listed in the table below are prepared in a manner similar to the general procedure D described above.

[1446] Intermediate 115 2-[(2-amino-l,3-benzothiazol-5-yl)oxy]acetonitrile Intermediate Yield LCMS purity (%) LCMS Rt (min) m / z 1 H NMR ​ Example 95 2'-chloro-N-(5-{[(2R)-2-hydroxypropyl]amino}-[1,3]thiazolo[5,4- d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide 6.5 95 2.41 486.3 / 488.3 B 1 H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.85 (s, 1H), 8.66 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.20 (s, 1H), 4.70 (d, J = 4.8 Hz, 1H), 3.86 - 3.75 (m, 1H), 3.63 (s, 3H), 3.28 - 3.22 (m, 2H), 2.60 (s, 3H), 1.08 (d, J = 6.2 Hz, 3H). <!-- 139 -->]]> ​ Example 96 5'-chloro-N-(5-{[(2S)-2-hydroxypropyl]amino}-[1,3]thiazolo[5,4- d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide 8.8 95 2.43 486.3 / 488.3 B 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.62 (s, 1H), 8.15 (s, 1H), 7.56 - 7.36 (m, 2H), 4.68 (d, J = 4.8 Hz, 1H), 3.86 - 3.72 (m, 1H), 3.62 (s, 3H), 3.28 - 3.18 (m, 3H), 2.58 (s, 3H), 2.06 - 1.94 (m, 1H), 1.06 (d, J = 6.2 Hz, 3H).]]> ​ Example 9 2'-chloro-5'-methoxy-N-[5-(3-methoxy-3-methylazetidin-l-yl)- [l,3]thiazolo[5,4-d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridin]-3-carboxamide 41 100 2.92 512.3 / 514.3 B 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.82 (s, 1H), 8.77 (s, 1H), 8.17 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 4.06 - 3.97 (m, 2H), 3.94 - 3.86 (m, 2H), 3.62 (s, 3H), 3.21 (s, 3H), 2.60 (s, 3H), 1.47 (s, 3H).]]> ​

[1447] LCMS Method

[1448] Add the desired haloalkane (1.2 equivalents) to a solution of 2-amino-1,3-benzothiazol-5-ol (1 equivalent) and potassium carbonate or cesium carbonate (2 equivalents) in acetone, DMF, or acetonitrile (0.2 mmol / mL), and stir the reaction mixture at 50 °C until the reaction is confirmed to be complete by LCMS. Dilute the reaction mixture with water; if the product precipitates, filter it and dry it in a vacuum oven. If the product does not precipitate, extract the aqueous mixture with ethyl acetate. Wash the organic extract with a brine solution, dry it, and concentrate it under reduced pressure. The residue is used as the crude product in the next step, or via Biotage Isolera. TM Automated chromatographic purification yields the desired alkylated product.

[1449] ​

[1450]

[1451] Bromoacetonitrile (100 μL, 1.39 mmol) was added to a stirred suspension of 2-amino-1,3-benzothiazol-5-ol (202 mg, 1.2 mmol) and potassium carbonate (330 mg, 2.4 mmol) in acetone (6.0 mL). The mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The organic extract was washed with brine and filtered through hydrophobic filter paper and dried. The extract was analyzed by Biotage Isolera. TM The crude residue was purified by automated chromatography (25 g, Sfar Duo) and eluted with a solvent gradient of 0-10% methanol in DCM to give the title compound (45 mg, 19%) as a beige powder. 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 8.6 Hz, 1H), 7.53 (s, 2H), 7.06 (d, J = 2.6 Hz, 1H), 6.74 (dd, J = 8.6, 2.6 Hz, 1H), 5.16 (...

Claims

1. A compound or a pharmaceutically acceptable salt thereof having the following structural formula (I): ， in: Ring A is selected from the group consisting of phenyl groups and 5 to 10-membered heteroaryl groups; R1 is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic. (i) R1is optionally substituted by one or more R 100 substituents; or two R 100 substituents on adjacent ring atoms in R1may be joined to form a fused (3-6C)cycloalkyl ring; or (ii) When R1 is a 5- to 6-membered heterocyclic group, a 6- to 10-membered bicyclic heterocyclic group, a 6- to 10-membered bridged heterocyclic group, or a 6- to 12-membered spirocyclic group, it may be optionally substituted with an oxo group; wherein R 100 halogen, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)haloalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy, -Q 100 -OH, -Q 100 -O-(1-4C)alkyl, -C(O)-(1-4C)alkyl and -Q 100 -cyano; wherein Q 100 is a bond or (1-4C)alkylene; Integers a and b are each independently 0 or 1; R2 and R3, when present, are each independently selected from the group consisting of halogen, cyano, -O-, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)hydroxyalkyl, (1-4C)haloalkoxy, -Q1-O-(1-4C)alkyl, -C(O)OH, -Q1-C(O)-NH2, -Q1-C(O)-NHMe and -Q1-C(O)-NMe2, wherein Q1 is a bond or (1-4C)alkylene; X4is selected from CR x4 or N; X5is selected from CR x5 or N; X6is selected from CR x6 or N; X7is selected from CR x7 or N; R x4 is hydrogen, fluorine, chlorine, methyl or a group of the formula: -YQ in: Y is -O-, -O-CH2-, -S-, -NH-, -CH2-, or -CH2-CH2-; Q is selected from: hydrogen, (1-6C)alkyl, -C(O)-NH2, -C(O)-NHMe, -C(O)-NMe2, (3-8C)cycloalkyl, phenyl, heteroaryl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl, and 6- to 12-membered spiroheterocyclyl, each of which is optionally substituted with one or more R 100 substituted, and (3-8C)cycloalkyl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl, and 6- to 12-membered spiroheterocyclyl are optionally oxo-substituted; R x5 or R x6 selected from the group consisting of: Hydrogen, halogen, cyano, nitro or groups of the following formula: -L1-Y1-L2-Q1 in: L1 is absent or is a (1-2C) alkylene group; Y1is absent or is -O-, -S-, -SO-, -SO2-, -S(O)(=NR y1 )-, -N(R y1 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R y1 )-, -N(R y1 )C(O)-, -S(O)2N(R y1 )-, -N(R y1 )SO2-, or -N(R y1a )C(O)-N(R y1 )-, wherein R y1 and R y1a are selected from hydrogen or (1-2C)alkyl; L2 is absent or is a (1-2C) alkylene group; and Q1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)ynyl, (3-8C)cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic. in: (i) When Q1 is (1-6C)alkyl, (2-6C)alkenyl, or (2-6C)ynyl, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula: -Y2-Q2 in: Y2 is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R y2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R y2 )-, -N(R y2 )C(O)-, -S(O)2N(R y2 )- or -N(R y2 )SO2-, wherein R y2 is selected from hydrogen or (1-2C)alkyl; Q2 is selected from: hydrogen; Optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, or (1-4C)alkoxy; or Optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, (1-4C)alkyl or (1-4C)alkoxy, a 4- to 7-membered heterocycle; (ii) When Q1 is a (3-8C)cycloalkyl, 4- to 7-membered heterocyclic, 6- to 10-membered bicyclic heterocyclic, 6- to 10-membered bridged heterocyclic, and 6- to 12-membered spirocyclic, it may optionally be further substituted by one or more substituents independently selected from oxo, halogen, or cyano groups, or by one or more groups of the following formula: -Y3-Q3 in: Y3is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R y2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R y3 )-, -N(R y3 )C(O)-, -S(O)2N(R y3 )- or -N(R y3 )SO2-, wherein R y3 is selected from hydrogen or (1-2C)alkyl; Q3 is selected from: hydrogen; Optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, or (1-4C)alkoxy; or Optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, (1-4C)alkyl or (1-4C)alkoxy, a 4- to 7-membered heterocycle; (iii) when Q1is phenyl or 5- to 6-membered heteroaryl, it is optionally further substituted by one or more substituents independently selected from halogen, cyano or by one or more groups of the formula -Y3-Q3as defined above; R x7 selected from hydrogen, fluorine, chlorine, hydroxyl, NH2, methyl or CF3; or R x4 and R x5 , R x5 and R x6 or R x6 and R x7 are linked such that, together with the carbon atom to which they are attached, they form a fused (5-6C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 5- or 6-membered heterocycle, each of which is optionally substituted by fluorine, chlorine, methyl or hydroxyl; with the proviso that: (i) when X5is CR x5 and Rx5is a group of the formula -L1-Y1-L2-Q1, then X6is selected from N, C-H, C-F, C-CN, C-Cl or C-Me; and (ii) when X6is CR x6 and R x6 is a group of formula -L1-Y1-L2-Q1, then X5is selected from N, C-H, C-F, C-Cn, C-Cl or C-Me.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) when X5is CR x5 and R x5 is cyano or a group of the formula -L1-Y1-L2-Q1, then: X4is selected from N, C-H, C-F, C-Cl, or C-Me; X6is selected from N, C-H, C-F, C-CN, C-Cl, or C-Me; X7is selected from N, C-H, C-F, C-Cl, or C-Me; and (ii) when X6is CR x6 and R x6 is cyano or a group of the formula -L1-Y1-L2-Q1, then: X4is selected from N, C-H, C-F, C-Cl, or C-Me; X5is selected from N, C-H, C-F, C-Cl, or C-Me; X7is selected from N, C-H, C-F, C-Cl, or C-Me.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl or 5-, 6-, 9- or 10-membered heteroaryl.

4. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: (i) phenyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, imidazo[l,2- a]pyridinyl, [l,2,3]triazolo[l,5-a]pyridinyl, imidazo[l,5-a]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrazolo[l,5-a]pyridinyl, [l,2,4]triazolo[l,5-a]pyridinyl, 1,6- naphthyridinyl or 1,7-naphthyridinyl; (ii) phenyl, pyridyl, pyrimidinyl and imidazo[l,2-a]pyridinyl, 1,2,3-triazolyl, pyrazolyl, isoxazolyl, imidazo[l,5-a]pyridinyl; (iii) phenyl, pyridyl, pyrimidinyl and imidazo[l,2-a]pyridinyl; (iv) phenyl or pyridyl; (v) pyridyl.

5. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: ; ; ; ; ; ; ; ; ; or , wherein represents the point of attachment to the amide group of Formula I; and R1, R2, R3, a, and b are as defined in claim 1.

6. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: ; ; or ; wherein represents the point of attachment to the amide group of Formula I; and R1, R2, R3, a, and b are each as defined herein.

7. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: ; or ; wherein represents the point of attachment to the amide group of Formula I; and R1, R2, R3, a, and b are as defined in claim 1.

8. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: (i) ; ; or ; or (ii) ; or ; wherein represents the point of attachment to the amide group of Formula I; and R1, R2, R3, a, and b are as defined in claim 1.

9. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1is selected from one of the following options: (i) phenyl or 5- to 6-membered heteroaryl, each optionally substituted with one or more R 100 two R substituents on adjacent ring atoms in R1may be joined to form a fused (3-6C)cycloalkyl ring; or 100 two R substituents on adjacent ring atoms in R1may be joined to form a fused (3-6C)cycloalkyl ring; or (ii) phenyl or 6-membered heteroaryl, each optionally substituted with one or more R 100 two R substituents on adjacent ring atoms in R1may be joined to form a fused (3-6C)cycloalkyl ring. 100 two R substituents on adjacent ring atoms in R1may be joined to form a fused (3-6C)cycloalkyl ring.

10. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1is selected from one of the following options: (i) a group of the formula or , wherein: represents the point of attachment to ring A of formula I; X8is CH or N; R 100a , R 100b and R 100c are substituents R 100 as defined in claim 1 ; and the integers c, d and e are 0, 1 or 2; (ii) a group of the formula: ， wherein: represents the point of attachment to ring A of formula I; X8is CH or N; R 100a and R 100b are each a substituent R as defined in claim 1 100 ; and the integers c and d are 0, 1 or 2; (iii) a group of the formula: , , , or , wherein: represents the point of attachment to ring A of formula I; X8is CH or N; R 100a , R 100b , and R 100c are substituents R 100 as defined in claim 1 ; and the integers d and e are 0 or 1; (iv) a group of the formula: , or , wherein: represents the point of attachment to ring A of formula I; X8is CH or N; R 100a and R 100b All are substituents R as defined in claim 1 100 And the integer d is either 0 or 1; (v) a group of the formula: , , , wherein: represents the point of attachment to ring A of formula I; R 100b is methyl, fluoro or chloro; R 100c is fluorine or chlorine, in particular fluorine; (vi) a group of the formula: ， wherein: represents the point of attachment to ring A of formula I; R 100b is fluorine or chlorine; or (vii) a group of the formula: ， wherein: represents the point of attachment to ring A of formula I.

11. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein R 100 is selected from one of the following options: (i) halogen, (1-3C)alkyl, (1-3C)haloalkyl, (1-3C)haloalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy, -Q 100 -OH, -Q 100 -O-(1-3C)alkyl, -C(O)-(1-3C)alkyl and -Q 100 -cyano; wherein Q 100 is a bond or (1-3C)alkylene; (ii) halo, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)haloalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy, -Q 100 -OH, -Q 100 -O-(1-2C)alkyl, -C(O)-(1-2C)alkyl and -Q 100 -cyano; wherein Q 100 is a bond or (1-2C)alkylene; (iii) halogen, (1-2C)alkyl, (1-2C)fluoroalkyl, (1-2C)fluoroalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy, -Q 100 -OH, -Q 100 -O-(1-2C)alkyl, -C(O)-(1-2C)alkyl and -Q 100 -cyano; wherein Q 100 is a bond or (1-2C)alkylene; (iv) halo, (1-2C)alkyl, (1-2C)fluoroalkyl, -Q-OH, -Q 100 -O-(1-2C)alkyl, -C(O)-(1-2C)alkyl and -Q 100 -cyano; wherein Q 100 is a bond or (1-2C)alkylene; (v) halo, (1-2C)alkyl, (1-2C)fluoroalkyl, -Q-OH and -Q-O-(1-2C)alkyl; wherein Q is a bond or (1-2C)alkylene; (vi) fluoro, chloro, (1-2C)alkyl, (1-2C)fluoroalkyl, -Q 100 -OH and -Q 100 -O-(1-2C)alkyl; wherein Q 100 is a bond or (1-2C)alkylene; or (vii) fluoro, chloro, methyl, (1-2C)fluoromethyl and -Q 100 -O-(1-2C)alkyl; wherein Q 100 is a bond or methylene.

12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: (i) the integer a is 0 or 1 and the integer b is 0; (ii) the integer a is 0 and the integer b is 0; (iii) the integer a is 1 and the integer b is 0.

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2and R3, when present, are each independently selected from: (i) the group consisting of fluoro, chloro, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkoxy, -Q1-O-(1-2C)alkyl and -C(O)OH, wherein Q1is a bond or (1-2C)alkylene; (ii) the group consisting of fluoro, chloro, (1-2C)alkyl, (1-2C)alkoxy or (1-2C)haloalkyl; (iii) the group consisting of fluoro, (1-2C)alkyl or (1-2C)alkoxy; or (iv) methyl.

14. A compound, or a pharmaceutically acceptable salt thereof, having one of the following formulae la to Iac shown below: wherein: Ring A, R1, integer a, integer b, R2, R3, X4, X5, X6, X7, R x5 and R x6 as defined in any one of claims 1 to 13 or 15 to 21; X8is CH or N; R 100a , R 100b , and R 100c are each R 100 as defined in claim 1 ; and the integers c, d and e are 0 or 1.

15. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X4, X5, X6and X7are selected according to one of the following options: (i) X4is selected from CR x4 or N; X5is selected from CR x5 or N; X6is selected from CR x6 ; X7is selected from CR x7 or N; (ii) X4is selected from CR x4 ; X5is selected from CR x5 or N; X6is selected from CR x6 ; X7is selected from CR x7 or N; (iii) X4is selected from CR x4 ; X5is selected from CR x5 or N; X6is selected from CR x6 ; X7is selected from CH or N; (iv) X4is selected from CH; X5is selected from CR x5 or N; X6is selected from CR x6 ; X7is selected from CH or N; (v) X4is selected from CH; X5is selected from CH or N; X6is selected from CR x6 ; X7is selected from CH or N; (vi) X4is selected from CH; X5is selected from CH; X6is selected from CR x6 ; X7is selected from CH or N; (vii) X4is selected from CH; X5is selected from CH or N; X6is selected from CR x6 ; X7is selected from CH; (viii) X4is selected from CH; X5is selected from CH; X6is selected from CR x6 ; X7is selected from CH; (ix) X4is selected from CH; X5is selected from N; X6is selected from CR x6 ; X7is selected from CH; (x) X4is selected from CH; X5is selected from CH; X6is selected from CR x6 ; X7is selected from N; (xi) X4is selected from CH; X5is selected from N; X6is selected from CR x6 ; X7is selected from N; (xii) X4is selected from CH or N; X5is selected from CR x5 ; X6is selected from CH or N; X7is selected from CH or N; (xiii) X4is selected from CH; X5is selected from CR x5 ; X6is selected from CH; X7is selected from CH; (xiv) X4is selected from CH; X5is selected from CR x5 ; X6is selected from N; X7is selected from CH; (xv) X4is selected from CH; X5is selected from CR x5 ; X6is selected from CH; X7is selected from N; (xvi) X4is selected from N; X5is selected from CR x5 ; X6is selected from CH; X7is selected from CH; (xvii) X4is selected from N; X5is selected from CR x5 ; X6is selected from N; X7is selected from CH.

16. A compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein X4, X5, X6and X7are selected according to one of the following options: (i) X4is selected from CH; X5is selected from CH or N; X6is selected from CR x6 ; X7is selected from CH or N; (ii) X4is selected from CH; X5is selected from CH; X6is selected from CR x6 ; X7is selected from CH or N; (iii) X4is selected from CH; X5is selected from CH or N; X6is selected from CR x6 ; X7is selected from CH; (iv) X4is selected from CH; X5is selected from CH; X6is selected from CR x6 ; X7is selected from CH; (v) X4is selected from CH; X5is selected from N; X6is selected from CR x6 ; X7is selected from CH; (vi) X4is selected from CH; X5is selected from CH; X6is selected from CR x6 ; X7is selected from N; (vii) X4is selected from CH; X5is selected from N; X6is selected from CR x6 ; X7is selected from N; (viii) X4is selected from CH; X5is selected from CR x5 ; X6is selected from CH; X7is selected from CH.

17. A compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein X4, X5, X6and X7are selected according to one of the following options: (i) X4is selected from CH; X5is selected from CH; X6is selected from CR x6 ; X7is selected from CH; (ii) X4is selected from CH; X5is selected from N; X6is selected from CR x6 ; X7is selected from CH; (iii) X4is selected from CH; X5is selected from CH; X6is selected from CR x6 ; X7is selected from N; (iv) X4is selected from CH; X5is selected from N; X6is selected from CR x6 ; X7is selected from N; (v) X4is selected from CH; X5is selected from CR x5 ; X6is selected from CH; X7is selected from CH.

18. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein R x4 is selected from one of the following options: (i) hydrogen, fluorine, chlorine, methyl or a group of the following formula: -Y-Q wherein: Y is -0-, -S-, -NH- or -CH2-; Q is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 5- or 6- membered heteroaryl, 4- to 7-membered heterocyclyl, each of which is optionally substituted by one or more R 100 substituted by one or more R substituted by one or more R (ii) hydrogen, fluorine, methyl or a group of the following formula: -Y-Q wherein: Y is -0-, -S-, -NH- or -CH2-; Q is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 5- or 6- membered heteroaryl, 4- to 7-membered heterocyclyl; (iii) hydrogen, fluorine, chlorine or methyl; or (iv) hydrogen.

19. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein R x5 or R x6 is selected from hydrogen, halogen, cyano, nitro, or a group of the formula: -L1-Y1-L2-Q1 wherein: L1is absent or (1-2C)alkylene; Y1is absent, -O-, -S-, -SO-, -SO2-, -S(O)(=NR y1 )-, -N(R y1 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R y1 )-, -N(R y1 )C(O)-, -S(O)2N(R y1 )-, -N(R y1 )SO2-, or -N(R y1a )C(O)-N(R y1 )-, wherein R y1 and R y1a are selected from hydrogen or (1-2C)alkyl; L2is absent or (1-2C)alkylene; and Q1is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl and 6- to 12-membered spiroheterocyclyl, wherein: (i) when Q1is (1-6C)alkyl, it is optionally further substituted by one or more substituents independently selected from oxo, halogen, cyano or by one or more groups of the following formula: -Y2-Q2 wherein: Y2 is absent or selected from -O-, -SO2-, -N(R y2 )-, -C(O)-, -C(O)N(R y2 )-, -N(R y2 )C(O)-, -S(O)2N(R y2 )- or -N(R y2 )SO2-, wherein R y2 is selected from hydrogen or methyl; Q2is selected from: hydrogen; (1-4C)alkyl optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino or (1-4C)alkoxy; or 4- to 7-membered heterocycle optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino (1-4C)alkyl or (1-4C)alkoxy; (ii) when Q1is (3-8C)cycloalkyl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl and 6- to 12-membered spiroheterocyclyl, it is optionally further substituted by one or more substituents independently selected from oxo, halogen, cyano or by one or more groups of the following formula: -Y3-Q3 wherein: Y3is absent or selected from -O-, -SO2-, -N(R y3 )-, -C(O)-, -C(O)N(R y3 )-, -N(R y3 )C(O)-, -S(O)2N(R y3 )- or -N(R y3 )SO2-, wherein R y3 is selected from hydrogen or methyl; Q3is selected from: hydrogen; (1-4C)alkyl optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino or (1-4C)alkoxy; or 4- to 7-membered heterocycle optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino (1-4C)alkyl or (1-4C)alkoxy; 4- to 7-membered heterocyclyl optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino(l-4C)alkyl or (l-4C)alkoxy; (iii) when Q1is phenyl or 5- to 6-membered heteroaryl, it is optionally further substituted by one or more substituents independently selected from halogen, cyano or by one or more groups of the formula -Y3-Q3as defined above.

20. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein R x5 or R x6 is selected from hydrogen, halogen, cyano, nitro, or a group of the formula: -L1-Y1-L2-Q1 wherein: L1is absent or methylene; Y1is absent or is -O-, -SO2-, -S(O)(=NR y1 )-, -N(R y1 )-, -C(O)N(R y1 )-, -N(R y1 )C(O)-, -S(O)2N(R y1 )- or -N(R y1 )SO2-, wherein R y1 and R y1a are selected from hydrogen or (1-2C)alkyl; L2is absent or methylene; and Q1is hydrogen, (l-4C)alkyl, (3-4C)cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl and 6- to 12-membered spiroheterocyclyl, wherein: (i) when Q1is (l-4C)alkyl, it is optionally further substituted by one or more substituents independently selected from halogen, cyano or by one or more groups of the formula: -Y2-Q2 wherein: Y2 is absent or selected from -0-, -SO2-, -N(R y2 )-, -C(O)-, -C(O)N(R y2 )- or -N(R y2 )C(O)-, -S(O)2N(R y2 )- or -N(R y2 )SO2-, wherein R y2 is selected from hydrogen or methyl; Q2is selected from: hydrogen; (l-4C)alkyl optionally substituted by one or more halogens; or 4- to 7-membered heterocyclyl; (ii) when Q1is (3-6C)cycloalkyl, 4- to 7-membered heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, 6- to 10-membered bridged heterocyclyl and 6- to 12-membered spiroheterocyclyl, it is optionally further substituted by one or more substituents independently selected from oxo, halogen, cyano or by one or more groups of the formula: -Y3-Q3 wherein: Y3is absent or selected from -0-, -SO2-, -N(R y3 )-, -C(O)-, -C(O)N(R y3 )-, -N(R y3 )C(O)-, -S(O)2N(R y3 )- or -N(R y3 )SO2-, wherein R y3 is selected from hydrogen or methyl; Q3is selected from: hydrogen; (l-4C)alkyl optionally substituted by one or more halogens; or 4- to 7-membered heterocyclyl; (iii) when Q1is phenyl or 5- to 6-membered heteroaryl, it is optionally further substituted by one or more substituents independently selected from halogen, cyano or by one or more groups of the formula -Y3-Q3as defined above.

21. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein R x7 is selected from one of the following options: (i) hydrogen, fluoro, chloro or methyl; or (ii) hydrogen.

22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 14 to 21, wherein: (i) X8is N; R 100a and R 100b are each R 100 as defined in claim 1 or 11 ; and the integers c and d are 0 or 1; (ii) X8is CH; R 100a and R 100b are each R 100 as defined in claim 1 or 11 ; and the integers c and d are 0 or 1; (iii) X8is N; R 100a and R 100b are each R 100 as defined in claim 11 ; and the integers c and d are 0 or 1; (iv) X8is CH; R 100a and R 100b are each R 100 ; and the integers c and d are 0 or 1.

23. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein X4, X5, X6and X7are selected from one of the following options: (i) X4is selected from CH; X5is selected from N; X6is selected from CR x6 ; and X7is selected from N; or (ii) X4is selected from CH; X5is selected from N; X6is selected from CR x6 ; and X7is selected from CH.

24. The compound or pharmaceutically acceptable salt thereof according to claim 23, wherein R1is selected from a group of the formula: or wherein represents the point of attachment to the ring A of formula I.

25. The compound or pharmaceutically acceptable salt thereof according to claim 23 or 24, wherein ring A is selected from: ; or ; wherein represents the point of attachment to the amide group of Formula I; and R1and R2are as defined in claim 1.

26. A compound or pharmaceutically acceptable salt thereof selected from any one of: N-(6-chloro-l,3-benzothiazol-2-yl)-4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl- pyridine-3-carboxamide; and N-(6-chloro-l,3-benzothiazol-2-yl)-4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl- pyridine-3-carboxamide; and 2'-chloro-N-(6-methoxycarbonyl-1,3-benzothiazol-2-yl)-5'-methoxy-6-methyl- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(6-methoxycarbonyl-1,3-benzothiazol-2-yl)-5'-methoxy-6-methyl- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(6-methoxycarbonyl-1,3-benzothiazol-2-yl)-5'-methoxy-6-methyl- [4,4'-bipyridine]-3-carboxamide; N-(6-bromo-1,3-benzothiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]- 3-carboxamide; 2'-chloro-N-{5-chloro-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6-methyl- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-{5-chloro-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6-methyl- [4,4'-bipyridine]-3-carboxamide; 3-(2-methoxyphenyl)-N-{[1,3]thiazolo[5,4-d]pyrimidin-2-yl}pyridine-4-carboxamide; N-(6-bromo-1,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide; 3-(2-methoxyphenyl)-N-{[1,3]thiazolo[4,5-c]pyridin-2-yl}pyridine-4-carboxamide; 3-(2-methoxyphenyl)-N-{[1,3]thiazolo[4,5-c]pyridin-2-yl}pyridine-4-carboxamide; 3-(2-methoxyphenyl)-N-{[1,3]thiazolo[4,5-c]pyridin-2-yl}pyridine-4-carboxamide; 3-(2-methoxyphenyl)-N-{[1,3]thiazolo[4,5-c]pyridin-2-yl}pyridine-4-carboxamide; N-(5-chloro-1,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide; 3-(2-methoxyphenyl)-N-{[1,3]thiazolo[5,4-b]pyridin-2-yl}pyridine-4-carboxamide; N-(1,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide; N-(5-cyano-1,3-benzothiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-1,3-benzothiazol-2-yl]- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(6-nitro-1,3-benzothiazol-2-yl)-[4,4'-bipyridine]- 3-carboxamide; 4-(2-chloro-5-methoxy-4-pyridyl)-N-[5-[(3R)-3-hydroxypyrrolidin-1 -yl]thiazolo[5,4- d]pyrimidin-2-yl]-6-methyl-pyridine-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-{5-[(3S)-3-hydroxypyrrolidin-1-yl]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-{5-[(3S)-3-hydroxypyrrolidin-1-yl]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-{5-[(3S)-3-hydroxypyrrolidin-1-yl]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-[5-(1,1-dioxo-1 lambda 6 - thiomorpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl- [4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-{5-[(1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]hept-5-yl]- [1,3]thiazolo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridin]-3-carboxamide; 2'-chloro-N-[5-(3-cyanopiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6- methyl-[4,4'-bipyridin]-3-carboxamide; N-(6-amino-1,3-benzothiazol-2-yl)-4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3- carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxopiperidin-1-yl)-1,3-benzothiazol-2-yl]-[4,4'- bipyridin]-3-carboxamide; 4-(2-chloro-5-methoxy-4-pyridyl)-N-[5-(3,6-dihydro-2H-pyran-5-yl)thiazolo[5,4-b]pyridin- 2-yl]-6-methyl-pyridine-3-carboxamide; 4-(2-chloro-5-methoxy-4-pyridyl)-N-[6-(5-chloro-2-pyridyl)-1,3-benzothiazol-2-yl]-6- methyl-pyridine-3-carboxamide; N-[6-(5-chloropyridin-2-yl)-1,3-benzothiazol-2-yl]-3-(2-methoxyphenyl)pyridine-4- carboxamide; 2'-chloro-N-[6-(3-hydroxyoxolan-3-yl)-1,3-benzothiazol-2-yl]-5'-methoxy-6-methyl- [4,4'-bipyridin]-3-carboxamide; 2'-chloro-N-(6-methanesulfonamido-1,3-benzothiazol-2-yl)-5'-methoxy-6-methyl-[4,4'- bipyridin]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-{[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridin]-3- carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(methylthio)-1,3-benzothiazol-2-yl]-[4,4'-bipyridin]- 3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-{[1,3]thiazolo[5,4-c]pyridin-2-yl}-[4,4'-bipyridin]-3- carboxamide; N-[5-(4-acetylpiperazin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-2'-chloro-5'-methoxy-6- methyl-[4,4'-bipyridin]-3-carboxamide; 2'-chloro-N-{5-[(2-hydroxyethyl)amino]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6- methyl-[4,4'-bipyridin]-3-carboxamide; 2'-chloro-5'-methoxy-N-[5-(3-methoxyazetidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-{5-[(4-hydroxycyclohexyl)amino]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; rac-2'-chloro-N-(5-{[(1R,3S)-3-hydroxycyclopentyl]amino}-[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-{5-[(3R)-3-methylmorpholin-4-yl]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-{5-[(3S)-3-methylmorpholin-4-yl]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-{5-[(prop-2-yl)amino]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-{2-oxa-7-azaspiro[3.5]non-7-yl}-[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-{3,8-diazabicyclo[3.2.1]oct-3-yl}-[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(piperazin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxopyrrolidin-1-yl)-1,3-benzothiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(3-oxomorpholin-4-yl)-1,3-benzothiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(3-methyl-2-oxoimidazolidin-1-yl)-1,3-benzothiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxa-1,3-oxazolidin-3-yl)-1,3-benzothiazol-2-yl]-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxoimidazolidin-l-yl)-l,3-benzothiazol-2-yl]- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxoimidazolidin-l-yl)-l,3-benzothiazol-2-yl]- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-{[l,3]thiazolo[4,5-c]pyridin-2-yl}-[4,4'-bipyridine]-3- carboxamide; 2'-chloro-N-{6-chloro-[l,3]thiazolo[5,4-c]pyridin-2-yl}-5'-methoxy-6-methyl-[4,4'- bipyridine]-3-carboxamide; 2'-chloro-N-{6-chloro-[l,3]thiazolo[5,4-c]pyridin-2-yl}-5'-methoxy-6-methyl-[4,4'- bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-[l,3]thiazolo[4,5-c]pyridin-2-yl]- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-[6-(dimethylsulfamoyl)-l,3-benzothiazol-2-yl]-5'-methoxy-6-methyl-[4,4'- bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(morpholin-4-yl)-[l,3]thiazolo[4,5-b]pyridin-2-yl]- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-[6-(4-hydroxypiperidin-l-yl)-[l,3]thiazolo[4,5-c]pyridin-2-yl]-5'-methoxy-6- methyl-[4,4'-bipyridine]-3-carboxamide; N-(l,3-benzothiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(2-oxoimidazolidin-l-yl)-l,3-benzothiazol-2-yl]- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-[6-(4-hydroxypiperidin-l-yl)-[l,3]thiazolo[4,5-b]pyridin-2-yl]-5'-methoxy-6- methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[l,3]thiazolo[5,4-b]pyridin-2-yl]- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(2-oxopiperidin-l-yl)-[l,3]thiazolo[5,4-b]pyridin-2- yl]-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-[5-(4-hydroxypiperidin-l-yl)-[l,3]thiazolo[5,4-b]pyridin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-N-{5-methoxy-[l,3]thiazolo[5,4-d]pyrimidin-2-yl}-6-methyl- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-{2-oxa-6-azaspiro[3.4]oct-6-yl}-[l,3]thiazolo[5,4- d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-{5-[(2-hydroxy-2-methylpropyl)amino]-[l,3]thiazolo[5,4-d]pyrimidin-2-yl}- 5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-{5-[(2-methylpropyl)amino]-[l,3]thiazolo[5,4- d]pyrimidin-2-yl}-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-[5-(cyclobutylamino)-[l,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6- methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-N-[5-(4-methoxypiperidin-l-yl)-[l,3]thiazolo[5,4-d]pyrimidin-2- yl]-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-{6-hydroxy-2-azaspiro[3.3]heptan-2-yl}-[l,3]thiazolo[5,4-d]pyrimidin-2- yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-{6-oxa-2-azaspiro[3.4]octan-2-yl}-[l,3]thiazolo[5,4- d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-{6-[imino(methyloxy-λ 6 - sulfanyl]-1,3-benzothiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3- carboxamide; 2'-Chloro-N-[6-(1,1-dioxo-1λ) 6 [2-Thiazolidin-2-yl]-1,3-benzothiazolidin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-{6-[(4R)-4-hydroxy-2-oxopiperidin-l-yl]-l,3-benzothiazol-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(4-methyl-2-oxopiperazin-l-yl)-l,3-benzothiazol-2- yl]-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-[5-(3,6-dihydro-2H-pyran-4-yl)-[l,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridinyl]-3-carboxamide; N-[5-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(trifluoromethyl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-{5-methyl-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-[4,4'-bipyridinyl]-3-carboxamide; 5'-methoxy-2',6-dimethyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-fluoro-5'-methoxy-6-methyl-N-[5-(morpholin-4-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(2-oxopiperidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-(5-{[(2R)-2-hydroxypropyl]amino}-[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-(5-{[(2S)-2-hydroxypropyl]amino}-[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-N-[5-(3-methoxy-3-methylazetidin-1-yl)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; N-(4-bromo-1,3-benzothiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-{4-[2-(dimethylcarbamoyl)ethyl]-1,3-benzothiazol-2-yl}-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-[5-(cyanomethoxy)-1,3-benzothiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-{5-[(dimethylcarbamoyl)methoxy]-1,3-benzothiazol-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; N-(5-bromo-1,3-benzothiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'- bipyridine]-3-carboxamide; 2'-chloro-N-{5-[(dimethylcarbamoyl)difluoromethoxy]-1,3-benzothiazol-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(methylcarbamoyl)-1,3-benzothiazol-2-yl]- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-N-(5-methoxy-1,3-benzothiazol-2-yl)-6-methyl-[4,4'- bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-N-{5-[(2-methoxyethyl)carbamoyl]-1,3-benzothiazol-2-yl}-6- methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-{7-[(dimethylcarbamoyl)methoxy]-[1,3]thiazolo[5,4-d]pyrimidin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; N-{5-[(1-acetylpiperidin-4-yl)methoxy]-1,3-benzothiazol-2-yl}-2'-chloro-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-{5-[(dimethylcarbamoyl)methoxy]-1,3-benzothiazol-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-{5-[2-(morpholin-4-yl)ethoxy]-1,3-benzothiazol-2- yl}-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(propan-2-yloxy)-1,3-benzothiazol-2-yl]- [4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-{5-[(1,1-dioxido-1-λ6-thietan-3-yl)methoxy]-1,3-benzothiazol-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-ethoxy-1,3-benzothiazol-2-yl)-5'-methoxy-6-methyl-[4,4'- bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-{5-[2-(trifluoromethoxy)ethoxy]-1,3-benzothiazol-2- yl}-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-N-[6-(3-methoxyazetidin-l-yl)-[l,3]thiazolo[4,5-c]pyridin-2-yl]-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-{6-[(2-hydroxy-2-methylpropyl)amino]-[l,3]thiazolo[4,5-c]pyridin-2-yl}-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-N-[6-(3-methoxy-3-methylazetidin-l-yl)-[l,3]thiazolo[4,5-c]pyridin-2-yl]-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 6-[(dimethylcarbamoyl)methyl]-5'-methoxy-N-{[l,3]thiazolo[5,4-d]pyrimidin-2-yl}-2'-(trifluoromethyl)-[4,4'-bipyridinyl]-3-carboxamide; N-[5-(4-hydroxypiperidin-l-yl)-[l,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'-methoxy-2',6-dimethyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[5-(2-oxopiperidin-l-yl)-[l,3]thiazolo[5,4-b]pyridin-2-yl]-[4,4'-bipyridinyl]-3-carboxamide; 5-[(2-{2'-chloro-5'-methoxy-6-methyl]-[4,4'-bipyridinyl]-3-amino}-[l,3]thiazolo[4,5-c]pyridin-6-yl)amino]pentanoic acid; 5-[(2-{2'-chloro-5'-methoxy-6-methyl]-[4,4'-bipyridinyl]-3-amino}-[l,3]thiazolo[5,4-b]pyridin-5-yl)amino]pentanoic acid; 2'-chloro-5'-methoxy-6-methyl-N-{5-[(2H-l,2,3,4-tetrazol-5-yl)methoxy]-l,3-benzothiazol-2-yl}-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-(5-hydroxy-l,3-benzothiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2-[(2-{2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-amino}-l,3-benzothiazol-5-yl)oxy]ethyl acetate; 2'-chloro-N-[5-(2-hydroxyethoxy)-l,3-benzothiazol-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-l-methyl-6-oxo-l,6-dihydro-[3,4'-bipyridinyl]-4-carboxylic acid 5-(4-hydroxypiperidin-l-yl)-[l,3]thiazolo[5,4-d]pyrimidin-2-yl ester; 2'-chloro-N-[7-(cyanomethoxy)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; N-[7-(carbamoylmethoxy)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-2'-chloro-5'- methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-[6-(morpholin-3-yl)-1,3-benzothiazol-2-yl]- [4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-[5-(4-hydroxypiperidin-1-yl)-7-methyl-[1,3]thiazolo[5,4-d]pyrimidin- 2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide; 2'-chloro-N-[5-(2-hydroxy-2-methylpropoxy)-[1,3]thiazolo[5,4-d]pyrimidin-2-yl]- 5'-methoxy-6-methyl-[4,4'-bipyridinyl]-3-carboxamide, or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

28. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use in: (i) therapy; (ii) the treatment of a disease characterised by PolQ overexpression; (iii) the treatment of cancer; (iv) the treatment of homologous recombination (HR) deficient cancer; (v) the treatment of cancer characterised by reduced or absent BRCA gene expression, BRCA gene deletion or reduced BRCA protein function; and / or (vi) the treatment of lymphoma, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdoid sarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper respiratory and digestive tract cancer, leukemia, kidney cancer, skin cancer, esophageal cancer and pancreatic cancer.

29. A method of: (i) treating a disease characterised by PolQ overexpression; (ii) treating cancer (iii) treating homologous recombination (HR) deficient cancer; (iv) treating cancer characterised by reduced or absent BRCA gene expression, BRCA gene deletion or reduced BRCA protein function; and / or (v) treating lymphoma, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdoid sarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper respiratory and digestive tract cancer, leukemia, kidney cancer, skin cancer, esophageal cancer and pancreatic cancer. The method includes administering to a patient in need of such treatment a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, or a pharmaceutical composition according to claim 27.

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