Thiazolopyridylamide derivatives as inhibitors of DNA polymerase theta.

Abstract

The present invention relates to compounds that include a thiazolopyridylamide structure, methods for their synthesis, and the use of such compounds to inhibit DNA polymerase theta (Pol theta) and in the treatment of various diseases, including cancer.

Description

[Technical field]

[0001] The present disclosure relates to compounds that include a thiazolopyridylamide structure, their use for inhibiting DNA polymerase theta (Pol theta), and methods for the synthesis and use of such compounds in the treatment of various diseases, including cancer. [Background technology]

[0002] Double-stranded nucleic acid (DNA), the basis of genetic information in all organisms, constantly encounters damage from both intrinsic and exogenous factors. These damages are classified into various types and repaired by corresponding DNA repair pathways. DNA double-strand breaks (DSBs) are the most lethal damage type due to their potential for cell apoptosis and toxic chromosomal rearrangements. The comprehensive protein network responsible for regulating and coordinating DSB repair is called the DNA damage response (DDR). Dysfunction of the DDR results in inaccurate and ineffective DNA repair, affecting genome stability involved in cancer biology (e.g., tumorigenesis, tumor progression, drug resistance).

[0003] Two canonically predominant repair pathways cooperatively repair DSBs in the context of cell cycle and DNA end resection life: 1) homologous recombination (HR), which is active during S / G2 phase and requires isolated single-stranded overhangs, and 2) classical non-homologous end joining (c-NHEJ), which is specifically active during G1 / G2 phase and relies on limited end resection. In addition, another repair pathway, alternative non-homologous end joining (alt-NHEJ), is generally considered as a backup pathway when HR or c-NHEJ are impaired [Scully, R., et al., Nat Rev Mol Cell Biol, 2019, 20(11): p. 698-714].

[0004] DNA polymerase theta is a key effector in the alt-NHEJ pathway. It is a large protein composed of an N-terminal helicase domain, a central domain, and a C-terminal polymerase domain [Seki, M., et al., Nucleic Acids Rs, 2003, 31(21), 6117-26]. The function of DNA polymerase theta is to participate in DNA synthesis activity, strand annealing, and end processing and regulation of HR activity [Acharya, N., et al., Curr Genet, 2020, 66(4), 635-55; Ceccaldi, R., et al., Nature, 2015, 518(7538), 258-62; Mateos-Gomez, PA, et al., Nature, 2015, 518(7538), 254-7; Newman, JA, et al., Structure, 2015, 23(12), 2319-30; Ozdemir, AY, et al., J Biol Chem, 2018, 293(14), 5259-69]. DNA polymerase theta is widely overexpressed in various cancer types and is associated with resistance to DNA damaging therapy and reduced survival in breast cancer [Higgins,GS,et al.,Oncotarget,2010,1(3),175-84]. The POLQ gene (DNA polymerase theta gene) has been identified as a synthetic lethal for BRCA genes and other genes involved in the HR pathway [Ceccaldi,R.,et al.,Nature,2015,518(7538),258-62;Feng,W.,et al.,Nat Commun,2019,10(1),4286;Mateos-Gomez,PA,et al.,Nature,2015,518(7538),254-7;Mengwasser,et al.,Mol Cell,2019,73(5),885-99]. Based on the hypothesis that cancer cells rely on specific DNA repair pathways to quell excessive genetic stress and promote cell survival, targeting DNA repair is an effective and well-proven strategy in cancer therapy. The synthetic lethality of poly(ADP-ribose) polymerase (PARP) inhibitors is exemplified in BRCA-deficient cancer subtypes. Therefore, DNA polymerase theta is a promising target for novel synthetic lethal therapy in cancer types with defects in DSB repair pathways. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Scully, R., et al., Nat Rev Mol Cell Biol,2019,20(11):p.698-714 [Non-Patent Document 2] Seki, M., et al., Nucleic Acids Rs, 2003, 31(21), 6117-26 [Non-Patent Document 3] Acharya, N., et al., Curr Genet, 2020, 66(4), 635-55 [Non-Patent Document 4] Ceccaldi,R.,et al.,Nature,2015,518(7538),258-62 [Non-Patent Document 5] Mateos-Gomez,PA,et al.,Nature,2015,518(7538),254-7 [Non-Patent Document 6] Newman,JA,et al.,Structure,2015,23(12),2319-30 [Non-Patent Document 7] Ozdemir,AY,et al.,J Biol Chem,2018,293(14),5259-69 [Non-Patent Document 8] Higgins, GS, et al., Oncotarget, 2010, 1(3), 175-84 [Non-Patent Document 9] Feng,W.,et al.,Nat Commun,2019,10(1),4286 [Non-Patent Document 10] Mengwasser,et al.,Mol Cell,2019,73(5),885-99 Summary of the Invention

[0006] One object of the present invention is to provide compounds and derivatives thereof that are useful as Pol theta inhibitors.

[0007] Aspect 1. A compound of formula (I): [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof. [In the formula, Ring CyA is a 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O, or S as ring member(s); R 1 -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, haloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 1a , -SO 2 R 1a , -SO 2 NR 1a R 1b , -P(O)R 1a R 1b , -COR 1a , -CO 2 R 1a , -CONR 1a R 1b , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CO 2 R1b , -NR 1a CONR 1b R 1c , or -NR 1a SO 2 R 1b and C 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R 1d is replaced by R 1a , R 1b , and R 1c are each independently hydrogen, -C 1-8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R 1f is replaced by, or (R 1a and R 1b ), (R 1b and R 1c ), or (R 1a and R 1c ) together with the atom(s) to which they are attached form a 3-12 membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R 1f is replaced by R 1d and R 1f are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 1g , -SO 2R 1g , -SO 2 NR 1g R 1h , -P(O)R 1g R 1h , -COR 1g , -CO 2 R 1g , -CONR 1g R 1h , -NO 2 , -NR 1g R 1h , -NR 1g COR 1h , -NR 1g CO 2 R 1h , -NR 1g CONR 1h R 1i , or -NR 1g SO 2 R 1h -C is selected from 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R 1j is replaced by, or The Two R's 1d Or two R's 1f are taken together with the atom(s) to which they are attached to form a 3-12 membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R 1k is replaced by R 1g , R 1h , and R 1i are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 1j and R 1k are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 1l , -SO 2 R 1l , -SO 2 NR 1l R 1m , -COR 1l , -CO 2 R 1l , -CONR 1l R 1m , -NO 2 , -NR 1l R 1m , -NR 1l COR 1m , -NR 1l CO 2 R 1m , -NR 1l CONR 1m R 1n , or -NR 1l SO 2 R 1m -C is selected from 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl. R 1l , R 1m , and R 1n are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 2 is hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R 2a is replaced by R 2a are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 2b , -SO 2 R 2b , -SO 2 NR 2b R 2c , -COR 2b , -CO 2 R 2b , -CONR 2b R 2c , -NO 2 , -NR 2b R 2c , -NR 2b COR 2c , -NR 2b CO 2 R 2c , -NR 2b CONR 2c R 2d , or -NR 2b SO 2 R 2c -C is selected from 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R 2e is replaced by, or The Two R's 2a are taken together with the atom(s) to which they are attached to form a 3-12 membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R 2f is replaced by R 2b , R 2c , and R 2d are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 2e and R 2f are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Alkynyl, said -C 1-8 Each of the alkoxy, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally have at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 3 and R 4 are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 3a , -SO 2R 3a , -SO 2 NR 3a R 3b , -COR 3a , -CO 2 R 3a , -CONR 3a R 3b , -NR 3a R 3b , -NR 3a COR 3b , -NR 3a CO 2 R 3b , -NR 3a CONR 3b R 3c , or -NR 3a SO 2 R 3b and said -C 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R 3d is replaced by R 3a , R 3b , and R 3c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R 3f is replaced by, or (R 3a and R 3b ), (R 3b and R 3c ), or (R 3a and R 3c) together with the atom(s) to which they are attached form a 3-12 membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R 3f is replaced by R 3d and R 3f are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 3g , -SO 2 R 3g , -SO 2 NR 3g R 3h , -COR 3g , -CO 2 R 3g , -CONR 3g R 3h , -NO 2 , -NR 3g R 3h , -NR 3g COR 3h , -NR 3g CO 2 R 3h , -NR 3g CONR 3h R 3i , or -NR 3g SO 2 R 3h -C is selected from 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 3g , R 3h , and R 3i are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 5 is halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 5a , -SR 5a , -SO 2 R 5a , -P(O)R 5a R 5b , -SO 2 NR 5a R 5b , -COR 5a , -CO 2 R 5a , -CONR 5a R 5b , -NR 5a R 5b , -NR 5a COR 5b , -NR5a CO 2 R 5b , -NR 5a CONR 5b R 5c , or -NR 5a SO 2 R 5b and C 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R 5d is replaced by R 5a , R 5b , and R 5c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R 5f is replaced by, or (R 5a and R 5b ), (R 5b and R 5c ), or (R 5a and R 5c ) together with the atom(s) to which they are attached form a 3-12 membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R 5f is replaced by R 5d and R 5f are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 5g , -SO 2 R 5g , -SO 2 NR 5g R 5h , -COR 5g , -CO 2 R 5g , -CONR 5g R 5h , -NO 2 , -P(O)R 5g R 5h , -NR 5g R 5h , -NR 5g COR 5h , -NR 5g CO 2 R 5h , -NR 5g CONR 5h R 5i , or -NR 5g SO 2 R 5h -C is selected from 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R 5j is replaced by, or The Two R's 5d Or two R's 5f are taken together with the atom(s) to which they are attached to form a 3-12 membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R 5k is replaced by R 5g , R 5h , and R 5i are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl optionally contains at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; (R 5g and R 5h ), (R 5h and R 5i ), or (R 5g and R 5i ) together with the atoms to which they are attached form a 3-12 membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 5j and R 5k are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 5l , -SO 2 R5l , -SO 2 NR 5l R 5m , -COR 5l , -CO 2 R 5l , -CONR 5l R 5m , -NO 2 , -NR 5l R 5m , -NR 5l COR 5m , -NR 5l CO 2 R 5m , -NR 5l CONR 5m R 5n , or -NR 5l SO 2 R 5m -C is selected from 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl. R 5l , R 5m , and R 5n are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R z In each of its occurrences, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR za , -SO 2 R za , -SO 2 NR za R zb , -COR za , -CO 2 R za , -CONR za R zb , -NR za R zb , -NR za COR zb , -NR za CO 2 R zb , -NR za CONR zb R zc , or -NR za SO 2 R zb and said -C 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R zd is replaced by R za , R zb , and R zc are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R zf is replaced by, or (R za and R zb ), (R zb and R zc ), or (R za and R zc ) together with the atom(s) to which they are attached form a 3-12 membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R zf is replaced by R zd and R zf are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR zg , -SO 2 R zg , -SO 2 NR zg R zh , -COR zg , -CO 2 R zg , -CONR zg R zh , -NO 2 , -NR zg R zh , -NR zg COR zh , -NR zg CO 2 R zh , -NR zg CONR zh R zi , or -NR zg SO2 R zh -C is selected from 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent R zj is replaced by, or The Two R's zd Or two R's zf are taken together with the atom(s) to which they are attached to form a 3-12 membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R zk is replaced by R zg , R zh , and R zi are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R zj and R zk are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Alkynyl, said -C 1-8 Each of the alkoxy, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; n1 is 0, 1, 2, 3, 4, 5, 6, 7, or 8]

[0008] Aspect 2. The compound of aspect 1, wherein said compound is selected from formula (IIa), (IIb), (IIc), (IId), or (IIe). [ka] [In the formula, Z 1 , Z 2 , Z 3 , and Z 4 are each independently N or CR z and Z 5 is NR z , O, or S; R 1 , R 2 , R 3 , R 4 , and R 5 are each defined as claim 1.

[0009] Aspect 3. The compound of any one of the preceding aspects, wherein said compound is selected from formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), or (IIIk). [ka] [ka] [where n1, R z , R 1 , R 2 , R 3 , R 4 , and R 5 are each defined as claim 1.

[0010] Aspect 4. The compound of any one of the preceding aspects, wherein said compound is selected from formula (IVa), (IVb), (IVc), or (IVd). [ka] [In the formula, CyB and CyC are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl; AlkD and AlkE are -C 1-8 Alkyl, -C 2-8 Alkenyl, or -C 2-8 is alkynyl, n2 and n3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; R 1 , R 2 , R 3 , R 4 , R 5d , R 5f , R z , n1, and CyA are each defined as in any one of the preceding claims.

[0011] Aspect 5. The compound according to any one of aspects 2 to 4, wherein the compound is selected from formula (Va), (Vb), (Vc), or (Vd). [ka] [In the formula, CyB, CyC, AlkD, AlkE, R 1 , R 2 , R 3 , R 4 , R 5d , R 5f , Z 1 , Z 2 , Z 3 , Z 4 , n2, and n3 are defined as in any one of the preceding claims.

[0012] Embodiment 6. A compound according to any one of the preceding embodiments, wherein the ring CyA is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O, or S as ring member(s).

[0013] Embodiment 7. A compound according to any one of the preceding embodiments, wherein the ring CyA is a 5- or 6-membered heteroaromatic ring containing 1-2 heteroatoms selected from N, O, or S as ring member(s), and is preferably pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, isoimidazolyl, oxazolyl, thiazolyl, furanyl, or thiophenyl.

[0014] Aspect 8.R 1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, -OR 1a , -SO 2 R 1a , -SO 2 NR 1a R 1b , -COR 1a , -CO 2 R 1a , -CONR 1a R 1b , -NR 1a R 1b , -NR1a COR 1b , -NR 1a CO 2 R 1b , -NR 1a CONR 1b R 1c , or -NR 1a SO 2 R 1b wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R 1d is replaced by R 1a , R 1b , and R 1c each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R 1f is replaced by, or (R 1a and R 1b ), (R 1b and R 1c ), or (R 1a and R 1c), taken together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R 1f is replaced by R 1d and R 1f each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, the heteroaryl, oxo, -CN, -OR 1g , -SO 2 R 1g , -SO 2 NR 1g R 1h , -COR 1g , -CO 2 R 1g , -CONR 1g R 1h , -NO 2 , -NR 1g R 1h , -NR 1g COR 1h , -NR 1g CO 2 R 1h , -NR 1g CONR 1h R 1i , or -NR 1g SO 2 R 1h, the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R 1j is replaced by, or The Two R's 1d Or two R's 1f together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R 1k is replaced by R 1g , R 1h , and R 1i each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; 2-8 alkenyl, said -C 2-8 The alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 1j and R 1k each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 1l , -SO 2 R 1l , -SO 2 NR 1l R 1m , -COR 1l , -CO 2 R 1l , -CONR 1l R 1m , -NO 2 , -NR 1l R 1m , -NR 1l COR 1m , -NR 1l CO 2 R 1m , -NR 1l CONR 1m R 1n , or -NR 1l SO 2 R 1m the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 1l , R 1m , and R 1n each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8The compound of any one of the preceding aspects is substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl.

[0015] Aspect 9.R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, dihydropiperazinyl, phenyl, indazolyl, benzodioxolyl, benzoxazinyl, dihydrobenzoxazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, quinolinyl, or isoquinolinyl, and Each of the cyclohexyl, the cycloheptyl, the cyclooctyl, the morpholinyl, the piperidinyl, the piperazinyl, the dihydropyridinyl, the dihydropiperazinyl, the phenyl, the indazolyl, the benzodioxolyl, the benzoxazinyl, the dihydrobenzoxazinyl, the indolyl, the benzimidazolyl, the benzoxazolyl, the benzofuranyl, the quinolinyl, or the isoquinolinyl may optionally be selected from the group consisting of at least one substituent R 1d is replaced by R 1d each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 6-membered heterocyclyl, aryl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, the heteroaryl, oxo, -CN, -OR 1g , -SO 2 R 1g , -SO 2 NR 1g R 1h , -COR 1g , -CO 2 R 1g , -CONR 1g R 1h , -NO 2 , -NR 1g R 1h , -NR 1g COR 1h , -NR 1g CO 2 R 1h , -NR 1g CONR 1h R 1i , or -NR 1g SO 2 R 1h , the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R 1j is replaced by, or The Two R's 1d together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R 1k is replaced by R 1g , R 1h , and R 1ieach independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; 2-8 alkenyl, said -C 2-8 The alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 1j and R 1k each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 1l , -SO 2 R 1l , -SO 2 NR 1l R 1m , -COR 1l , -CO2 R 1l , -CONR 1l R 1m , -NO 2 , -NR 1l R 1m , -NR 1l COR 1m , -NR 1l CO 2 R 1m , -NR 1l CONR 1m R 1n , or -NR 1l SO 2 R 1m the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 1l , R 1m , and R 1n each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding aspects is substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl.

[0016] Aspect 10.R 1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, dihydropiperazinyl, phenyl, indazolyl, benzodioxolyl, benzoxazinyl, dihydrobenzoxazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, quinolinyl, or isoquinolinyl, and Each of the cyclohexyl, the cycloheptyl, the cyclooctyl, the morpholinyl, the piperidinyl, the piperazinyl, the dihydropyridinyl, the dihydropiperazinyl, the phenyl, the indazolyl, the benzodioxolyl, the benzoxazinyl, the dihydrobenzoxazinyl, the indolyl, the benzimidazolyl, the benzoxazolyl, the benzofuranyl, the quinolinyl, or the isoquinolinyl may optionally be selected from the group consisting of at least one substituent R 1d is replaced by R 1d each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, oxo, -CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, methoxy, ethoxypropoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, pyranyl, morpholinyl, oxiranyl, azetidinyl, azocanyl, thiiranyl, azetidinyl, -CF 3 , -CONH 2 , -CH 2 OCH 3 , -SO 2 (CH 3 ) 2 , -CH 2 OH, -NO 2 Selected from, or The Two R's 1dtogether with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R 1k is replaced by R 1k each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -CF 3 , -CONH 2 , -CH 2 OCH 3 , -SO 2 (CH 3 ) 2 , -CH 2 OH, -NO 2 wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8The compound of any one of the preceding aspects is substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl.

[0017] In some embodiments, R 1 is phenyl, which optionally contains at least one substituent R 1d In some further embodiments, R 1 is phenyl, which may contain one or two substituents R 1d In some embodiments, R 1d each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, oxo, -CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, methoxy, ethoxypropoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, pyranyl, morpholinyl, oxiranyl, azetidinyl, azocanyl, thiiranyl, azetidinyl, -CF 3 , -CONH 2 , -CH 2 OCH 3 , -SO 2 (CH 3 ) 2 , -CH 2 OH, -NO 2 In some embodiments, two R 1d are taken together with the atom(s) to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which contains as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, which ring optionally contains at least one substituent R 1k is replaced by R 1kare each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -CF 3 , -CONH 2 , -CH 2 OCH 3 , -SO 2 (CH 3 ) 2 , -CH 2 OH, -NO 2 and this methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl may contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 Substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl.

[0018] Aspect 11.R 1 but, [ka] The compound of any one of the preceding aspects, wherein

[0019] Aspect 12.R z is, at each occurrence, independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR za , -SO 2 R za , -SO 2 NR za R zb , -COR za , -CO 2 R za , -CONR za R zb , -NR za R zb , -NR za COR zb , -NR za CO 2 R zb , -NR za CONR zb R zc , or -NR za SO 2 R zb wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R zd is replaced by R za , R zb , and R zc each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R zf is replaced by, or (R za and R zb ), (R zb and R zc ), or (R za and R zc ) taken together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R zf is replaced by R zd and R zf each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR zg , -SO 2 R zg , -SO 2 NR zg R zh , -COR zg , -CO 2 R zg , -CONR zg R zh , -NO2 , -NR zg R zh , -NR zg COR zh , -NR zg CO 2 R zh , -NR zg CONR zh R zi , or -NR zg SO 2 R zh the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R zj is replaced by, or The Two R's zd Or two R's zf together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R zk is replaced by R zg , R zh , and R zi each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R zj and R zk each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl optionally has at least one substituent. -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding aspects is substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

[0020] Aspect 13.R z is, independently at each occurrence, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR za , -COR za , -CO 2 R za , -CONR za R zb , or -NR za R zb wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl optionally comprises at least one substituent R zd is replaced by R za and R zb each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl; or R zd are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 The compound according to any one of the preceding aspects, wherein the aryl is selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, or -OH.

[0021] Aspect 14.R z is, at each occurrence, independently H, -CN, -CH 3 , -Cl, -CH 2 CN, -CF 3 , -F, -COOH, or -CH 2 The compound of any one of the preceding aspects, wherein R is OH.

[0022] Aspect 15. The above [ka] The part is, [ka] The compound of any one of the preceding aspects,

[0023] Aspect 16. The above [ka] The part is, [ka] [ka] The compound of any one of the preceding aspects,

[0024] Aspect 17.R 2 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R 2a is replaced by R 2a each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, -OR 2b , -SO 2 R 2b , -SO 2 NR 2b R 2c , -COR 2b , -CO 2 R 2b , -CONR 2b R 2c , -NO 2 , -NR 2b R 2c , -NR 2b COR 2c , -NR 2b CO 2 R 2c , -NR 2b CONR2c R 2d , or -NR 2b SO 2 R 2c the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R 2e is replaced by, or The Two R's 2a together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R 2f is replaced by R 2b , R 2c , and R 2d each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, 5-10 membered heteroaryl, or haloheteroaryl; R 2e and R 2f each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl, and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8Each of the alkynyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptoxy, the octoxy, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5-8 membered heterocyclyl, the phenyl, or the 5-10 membered heteroaryl optionally contains at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding aspects is substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

[0025] Aspect 18.R 2 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, and the 5- to 10-membered heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; Preferably, R 2 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; More preferably, R 2 The compound of any one of the preceding aspects, wherein is hydrogen.

[0026] Aspect 19.R 3 and R 4 each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, -OR 3a , -SO 2 R 3a , -SO 2 NR 3a R 3b , -COR 3a , -CO 2 R 3a , -CONR 3a R 3b , -NR 3a R 3b , -NR 3a COR 3b , -NR 3a CO 2R 3b , -NR 3a CONR 3b R 3c , or -NR 3a SO 2 R 3b wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R 3d is replaced by R 3a , R 3b , and R 3c each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R 3f is replaced by, or (R 3a and R 3b ), (R 3b and R 3c ), or (R 3a and R 3c), taken together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R 3f is replaced by R 3d and R 3f each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, -OR 3g , -SO 2 R 3g , -SO 2 NR 3g R 3h , -COR 3g , -CO 2 R 3g , -CONR 3g R 3h , -NO 2 , -NR 3g R 3h , -NR 3g COR 3h , -NR 3g CO 2 R 3h , -NR 3g CONR 3h R 3i , or -NR 3g SO 2 R 3h the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R 3g , R 3h , and R 3i each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8The compound of any one of the preceding aspects is substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

[0027] Aspect 20.R 3 and R 4 each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, and the 5- to 10-membered heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, -NO 2 , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy.

[0028] Aspect 21.R 3 and R4 each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy; Preferably, R 3 and R 4 The compound of any one of the preceding aspects, wherein each is independently hydrogen.

[0029] Aspect 22.R 5 -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, -OR 5a , -SO 2 R 5a , -SO 2 NR 5a R 5b , -COR 5a , -CO 2 R 5a , -CONR 5a R 5b , -NR 5a R 5b , -NR 5a COR 5b , -NR 5a CO 2 R 5b , -NR 5a CONR 5b R 5c , or -NR 5a SO 2 R 5bwherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R 5d is replaced by R 5a , R 5b , and R 5c each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, and the 5- to 10-membered heteroaryl may optionally be selected from the group consisting of at least one substituent R 5f is replaced by, or (R 5a and R 5b ), (R 5b and R 5c ), or (R 5a and R 5c ), taken together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R 5f is replaced by R 5d and R 5f each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, -OR 5g , -SO 2 R 5g , -SO 2 NR 5g R 5h , -COR 5g , -CO 2 R 5g , -CONR 5g R 5h , -NO 2 , -NR 5g R 5h , -NR 5g COR 5h , -NR 5g CO 2 R 5h , -NR 5g CONR 5h R 5i , or -NR 5g SO 2 R 5h the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R 5j is replaced by, or The Two R's 5d Or two R's 5ftogether with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R 5k is replaced by R 5g , R 5h , and R 5i each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, or 5-10 membered heteroaryl; (R 5g and R 5h ), (R 5h and R 5i ), or (R 5g and R 5i), taken together with the atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R 5j and R 5k each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR 5l , -SO 2 R 5l , -SO 2 NR 5l R 5m , -COR 5l , -CO 2 R 5l , -CONR 5l R 5m , -NO 2 , -NR 5l R 5m , -NR 5l COR 5m , -NR 5l CO 2 R 5m , -NR 5l CONR 5m R 5n, or -NR 5l SO 2 R 5m the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5-8 membered heterocyclyl, the phenyl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R 5l , R 5m , and R 5n each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5-8 membered heterocyclyl, the phenyl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding embodiments is substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

[0030] Aspect 23.R 5 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, -OR 5a , -CONR 5a R 5b , -COR 5a , -CO 2 R 5a , -NR 5a R 5b , or -NR 5a COR 5b wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R 5dis replaced by R 5a , R 5b , and R 5c each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, and the 5- to 10-membered heteroaryl may optionally be selected from the group consisting of at least one substituent R 5f is replaced by, or (R 5a and R 5b ), (R 5b and R 5c ), or (R 5a and R 5c ), taken together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R 5f is replaced by R 5d and R 5f each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, -OR5g , -SO 2 R 5g , -SO 2 NR 5g R 5h , -COR 5g , -CO 2 R 5g , -CONR 5g R 5h , -NO 2 , -NR 5g R 5h , -NR 5g COR 5h , -NR 5g CO 2 R 5h , -NR 5g CONR 5h R 5i , or -NR 5g SO 2 R 5h the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R 5j is replaced by, or The Two R's 5d Or two R's 5f together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R 5k is replaced by R 5g , R 5h , and R 5i each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, or 5-10 membered heteroaryl; (R 5g and R 5h ), (R 5h and R 5i ), or (R 5g and R 5i ), taken together with the atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R 5j and R 5k each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR 5l , -SO 2 R 5l , -SO 2 NR 5l R 5m , -COR 5l , -CO 2 R 5l , -CONR 5l R 5m , -NO 2 , -NR 5l R 5m , -NR 5l COR 5m , -NR 5l CO 2 R 5m , -NR 5l CONR 5m R 5n , or -NR 5l SO 2 R 5m the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, said -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5-8 membered heterocyclyl, the phenyl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R 5l , R 5m , and R 5n each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5-8 membered heterocyclyl, the phenyl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8The compound of any one of the preceding embodiments is substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

[0031] Aspect 24.R 5 but, [ka] The compound of any one of the preceding aspects, [In the formula, CyB, AlkD, CyC, AlkE, R 5d , R 5f , n2, and n3 are each defined as in any one of the preceding claims.

[0032] Aspect 25.R 5 but, [ka] [ka] The compound of any one of the preceding aspects,

[0033] Aspect 26. The compound of any one of the preceding aspects, wherein the compound is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0034] In a second aspect, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, and at least one pharma- ceutically acceptable carrier or excipient.

[0035] In a third aspect, disclosed herein is a method of inhibiting Pol theta ATPase activity in a subject, comprising administering to an individual an individual compound disclosed herein, or a pharma- ceutically acceptable salt or stereoisomer thereof (including a compound of formula (I) or the specific compounds exemplified herein), or disclosed herein is the use of an individual compound disclosed herein, or a pharma- ceutically acceptable salt or stereoisomer thereof (including a compound of formula (I) or the specific compounds exemplified herein), in the manufacture of a medicament for inhibiting Pol theta ATPase activity in a subject, or disclosed herein is an individual compound disclosed herein, or a pharma- ceutically acceptable salt or stereoisomer thereof (including a compound of formula (I) or the specific compounds exemplified herein), for use in inhibiting Pol theta ATPase activity in a subject.

[0036] In a fourth aspect, disclosed herein is a method of treating a disease or disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein as a Pol theta inhibitor, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the compound disclosed herein comprises a compound of formula (I) or a specific compound exemplified herein; alternatively disclosed herein is the use of an individual compound disclosed herein, a pharma- ceutically acceptable salt or stereoisomer thereof (including a compound of formula (I) or a specific compound exemplified herein) as a Pol theta inhibitor in the manufacture of a medicament for treating a disease or disorder in a subject; alternatively disclosed herein is an individual compound disclosed herein, a pharma- ceutically acceptable salt or stereoisomer thereof (including a compound of formula (I) or a specific compound exemplified herein) as a Pol theta inhibitor for use in treating a disease or disorder in a subject. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] The following terms have the meanings indicated throughout this specification. Unless otherwise defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0038] The following terms have the meanings indicated throughout this specification.

[0039] As used in this specification, including the appended claims, singular forms of words (e.g., "a," "an," and "the") include the corresponding plural references unless the context clearly dictates otherwise.

[0040] The term "or" is used interchangeably with the term "and / or," unless context clearly dictates otherwise.

[0041] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing 1 to 18 (for example, 1 to 12, as a further example, 1 to 10, and as yet further examples, 1 to 8, or 1 to 6, or 1 to 4) carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl ... Examples of such alkyl groups include aryl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0042] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0043] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu").

[0044] The term "pentyl" includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.

[0045] The term "hexyl" includes 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0046] The term "alkylene" refers to a divalent alkyl group formed by removing two hydrogens from an alkane. Alkylenes include, but are not limited to, methylene, ethylene, propylene, and the like.

[0047] The term "halogen" includes fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0048] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens are replaced by one or more halogen atoms, such as fluoro, chloro, bromo, and iodo. Examples of haloalkyl include haloC 1 -8 Alkyl, haloC 1-6 Alkyl or haloC 1 -4 Alkyl includes, but is not limited to, -CF 3 , -CH 2 Cl, -CH 2 CF 3 , -CHCl 2 , C.F. 3 etc.

[0049] The term "alkenyl" includes hydrocarbon groups selected from linear and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 (for example, 2 to 8, and further example, 2 to 6) carbon atoms. Alkenyl groups, such as C 2~6Examples of alkenyl include, but are not limited to, ethenyl or vinyl groups, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl groups.

[0050] The term "alkenylene" refers to a divalent alkenyl group formed by removing two hydrogens from an alkene. Alkenylene includes, but is not limited to, vinylidene, butenylene, and the like.

[0051] The term "alkynyl" includes hydrocarbon groups selected from linear and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 (for example, 2 to 8, and further example, 2 to 6) carbon atoms. Alkynyl groups, such as C 2~6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0052] The term "alkynylene" refers to a divalent alkynyl group formed by removing two hydrogens from an alkyne. Alkenylene includes, but is not limited to, ethynylene.

[0053] The term "alkyloxy" or "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Examples of alkyloxy, e.g., C1-6 alkyloxy or C1-4 alkyloxy, include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0054] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0055] For example, the cycloalkyl group can contain 3 to 12 (for example, 3 to 10, as a further example, 3 to 8, as a further example, 3 to 6, 3 to 5, or 3 to 4) carbon atoms. By way of yet further example, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12 (for example, 3 to 10, as a further example, 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups.

[0056] In particular, saturated monocyclic cycloalkyl groups such as C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0057] In a preferred embodiment, cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (C 3-6 Examples of bicyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include groups having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane.

[0058] Further examples of bicyclic cycloalkyl groups include groups (examples) arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems, where the wavy line indicates the point of attachment. The ring may be saturated or may have at least one double bond (i.e., may be partially unsaturated), but is not fully conjugated and is not aromatic as defined herein.

[0059] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings that share one atom.

[0060] "Heterocyclyl", "heterocycle", or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl group that contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, and includes monocyclic, fused, bridged, and spiro rings, i.e., monocyclic heterocyclyl groups, bridged heterocyclyl groups, spiro heterocyclyl groups, and fused heterocyclyl groups.

[0061] Exemplary 3- to 8-membered heterocyclyl groups include, but are not limited to, (numbered from the bond position assigned priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholin ... No, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl , piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathienyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathienyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl , dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

[0062] The term "fused cycloalkyl" includes bicyclic cycloalkyl groups, as defined herein, that are saturated and are formed by two or more rings sharing two adjacent atoms.

[0063] The term "bridged cycloalkyl" includes a cyclic structure formed by two rings containing carbon atoms and sharing two non-adjacent atoms. The term "7-10 membered bridged cycloalkyl" includes a cyclic structure formed by two rings containing 7-12 carbon atoms and sharing two non-adjacent atoms.

[0064] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include, but are not limited to, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo 3-8 membered cycloalkyl, benzo C 4-6 Examples include cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8-9 membered fused rings, which refers to cyclic structures containing 8-9 ring atoms in the above examples.

[0065] The term "aryl", used alone or in combination with other terms, includes a group selected from: (a) 5- and 6-membered carbocyclic aromatic rings, e.g., phenyl; (b) bicyclic ring systems in which at least one ring is carbocyclic and aromatic (e.g., 7- to 12-membered bicyclic ring systems), such as naphthyl and indanyl; and (c) Tricyclic ring systems in which at least one ring is carbocyclic and aromatic (eg, 10-15 membered tricyclic ring systems), such as fluorenyl.

[0066] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0067] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. An exemplary bicyclic fused aryl is naphthalene.

[0068] The terms "heteroaryl" and "heteroaromatic ring" are interchangeable and include groups selected from: Monocyclic Rings (Monocyclic Heteroaryl Groups). The term "monocyclic heteroaryl" refers to a monocyclic ring containing one or two heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 5-7 membered heteroaryl ring that is monocyclic and has one or two heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O).

[0069] Bicyclic Rings (Bicyclic Heteroaryl Groups). The term "bicyclic heteroaryl" refers to an 8-12 membered heteroaryl ring that is bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0070] Examples of monocyclic or bicyclic heteroaryls include, but are not limited to, (numbered from the attachment position assigned priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, azolyl, or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (e.g., , 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1 -oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0071] The term "at least one substituent" disclosed herein includes, for example, 1 to 4 (for example, 1 to 3, and further example, 1 or 2) substituents, provided that valence theory is satisfied. For example, "at least one substituent F" disclosed herein includes 1 to 4 (for example, 1 to 3, and further example, 1 or 2) substituents F.

[0072] The term "divalent" refers to a linking group capable of forming a covalent bond with two other moieties. For example, a "divalent cycloalkyl group" refers to a cycloalkyl group obtained by removing two hydrogens from the corresponding cycloalkane to form a linking group. The terms "divalent aryl group," "divalent heterocyclyl group," or "divalent heteroaryl group" are intended to be understood in a similar manner.

[0073] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they can further exist as diastereomers. Enantiomers and diastereomers are included in the broader classification of stereoisomers. All possible stereoisomers are intended to be included, such as substantially pure separated enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharma- ceutically acceptable salts are intended to be included. Unless otherwise specifically stated, a reference to an isomer applies to any possible isomer. In any case where the isomeric composition is not specified, all possible isomers are included.

[0074] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, such double bonds are intended to include both E and Z geometric isomers.

[0075] When the compounds disclosed herein contain disubstituted cyclic ring systems, the substituents found in such ring systems can be in cis and trans form.Cis form means that both substituents are found on the top side of the arrangement of the two substituents on carbon, while trans form means that they are on the opposite sides.For example, disubstituted cyclic ring systems can be cyclohexyl or cyclobutyl rings.

[0076] It may be advantageous to separate reaction products from each other and / or from starting materials. The desired products at each step or sequence of steps are separated and / or purified (hereinafter, separated) to the desired degree of homogeneity by techniques common in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any method, including, for example, reversed and normal phase, size exclusion, ion exchange, high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus, small-scale analytical, simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. It is believed that one skilled in the art can select and apply the technique most likely to achieve the desired separation.

[0077] "Diastereomers" refer to stereoisomers of a compound that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by using a chiral HPLC column.

[0078] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolving the racemic mixture using methods such as diastereomer formation using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3)(1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers under direct chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0079] Some of the compounds disclosed herein may exist with different points of attachment of hydrogen, referred to as tautomers. For example, carbonyl-CH 2 Compounds containing a C(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Both the keto and enol forms, individually and mixtures thereof, are intended to be included where applicable.

[0080] "Prodrug" refers to a derivative of an active agent that requires a transformation within the body to release the active agent. In some embodiments, the transformation is enzymatic. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the active agent.

[0081] "Pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans or lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or may be prepared separately by reacting free base functions with a suitable organic acid, or acidic groups with a suitable base. The term also includes salts of stereoisomers (e.g., enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the invention.

[0082] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an acid addition salt, for example a pharma- ceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharma-ceutically acceptable addition salts without undue experimentation.

[0083] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to contacting an exogenous pharmaceutical, therapeutic, diagnostic, or composition with an animal, human, experimental subject, cell, tissue, organ, or biological fluid. Treatment of a cell includes contacting a reagent with the cell and, in cases where the fluid is in contact with the cell, contacting a reagent with a biological fluid. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment, e.g., of a cell with a reagent, diagnostic, binding compound, or another cell. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0084] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient (e.g., a compound) that, when administered to a subject to treat a disease or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. The term "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case may be apparent to one of ordinary skill in the art or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer, or prodrug thereof, and / or at least one pharma- ceutically acceptable salt thereof, effective to "treat" a disease or disorder in a subject, as defined herein. In the case of a combination therapy, the term "therapeutically effective amount" refers to the total amount of the combination objects to effectively treat a disease, disorder, or condition.

[0085] The term "disease" refers to any disease, ailment, illness, symptom, or indication, and may be interchangeable with the terms "disorder" or "condition."

[0086] Throughout this specification and the claims which follow, unless the context requires otherwise, the term "comprise" and variations thereof (e.g., "comprises" and "comprising") are intended to specify the presence of the feature which follows it but do not exclude the presence or addition of one or more other features. As used herein, "comprising" can be substituted with "containing," "including," or, in some cases, "having."

[0087] Throughout this specification and the claims that follow, n-m " denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbon atoms. Examples include 1-8 , C 1-6 etc.

[0088] Unless otherwise defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0089] Therapeutic utility The compounds of the present invention, sub-groups and examples thereof, are inhibitors of DNA polymerase theta ATPase activity and may be useful in the prevention and treatment of the disease states or conditions described herein.

[0090] In addition to treating the adult population, the compounds of the invention may also be useful in treating the pediatric population.

[0091] It is expected that the compounds may be useful in diseases that depend on alt-NHEJ and MMEJ activity for survival, including but not limited to cancer and other disorders associated with dysfunctional DNA repair or excessive cell accumulation.

[0092] The present invention is expected to be typical for the treatment of certain cancers.POLQ gene (DNA polymerase theta gene) has been identified as a synthetic lethal gene of BRCA genes and other genes involved in HR pathway.In one embodiment, the compounds of the present invention are useful for the treatment of BRCA1 or BRCA2 defective primary and secondary solid tumors, including but not limited to breast, ovarian, prostate and pancreatic.

[0093] In further embodiments, DNA polymerase theta inhibitors are expected to show efficacy in tumor subtypes with a genetic background of HR deficiency other than BRCA1 and BRCA2, including but not limited to ATR, RAD51, ATM, BARD1, RAD51C, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2, FANCP, ERCC4, PTEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN, RPA2, and BRIP1.

[0094] In a further embodiment, the compounds of the invention are useful for delaying the onset of PARPi resistance based on the hypothesis that secondary BRCA revision mutations are dependent on the MMEJ pathway. Thus, in one embodiment, the compounds of the invention have the potential to increase the time to recurrence of HRD primary and secondary tumors (including but not limited to breast, ovarian, prostate, and pancreatic) in combination with PARPis in clinical practice.

[0095] In further embodiments, DNA polymerase theta inhibitors are expected to be used in PARPi-resistant cases (post- or post-exposure to PARPi) due to their mechanism of action of HR pathway restoration, including but not limited to secondary BRCA reversion mutations, defects in the 53BP1 / shield-in complex, and loss of RAD51c.

[0096] Since DNA polymerase theta is generally considered as a backup pathway when c-NHEJ is impaired, the compounds of the present invention are expected to show synthetic lethality in various solid cancers with defects in the c-NHEJ pathway. Defect refers to any genetic mutation that leads to the loss / deletion of the core effective protein involved in c-NHEJ. In one embodiment, the genetic variation includes mutation, substitution, insertion, deletion, and copy number variation (CNV). In another embodiment, the c-NHEJ gene is selected from any of LIG4, LIG3, POLL, POLM, PRKDC, XRCC4, XRCC5, and XRCC6.

[0097] DNA damaging therapy, including radiation therapy and partial chemotherapy, kills cancer cells by inducing cell apoptosis followed by DNA damage. DNA polymerase theta is associated with resistance to DNA damaging therapy in certain cancer types, especially those subtypes with NHEJ deficiency. In further embodiments, the compounds of the present invention have the potential to sensitize various cancer types to these conventional therapies.

[0098] In one embodiment, radiation therapy includes EBRT and brachytherapy and radioligand-based therapy, which are useful in the management of NSCLC, HNSCC, rectal cancer, prostate cancer, and pancreatic cancer.

[0099] In one embodiment, chemotherapy includes a topoisomerase inhibitor (e.g., etoposide, doxorubicin, hydroxycamptothecin, irinotecan), which is useful in managing disease progression in SCLC, rectal cancer, CRC, and STS.

[0100] In a further embodiment, since DNA polymerase theta acts as a translesion synthesis polymerase (TLS), it is expected that DNA polymerase theta inhibitors will reduce DNA replication stress response.Therefore, it is believed that the compounds of the present invention can be used to sensitize primary and secondary tumors (e.g., breast cancer, ovarian cancer, CRC, pancreatic cancer, esophageal cancer, leukemia) to drugs that induce DNA replication stress (e.g., cisplatin, mitomycin, cyclophosphamide, cytarabine, hydroxyurea, gemcitabine).In addition, any of the above combination therapies are expected to reduce the acquisition of drug-induced resistance and increase the time to recurrence. EXAMPLES

[0101] The compounds disclosed herein (including salts thereof) may be prepared using known organic synthesis techniques, or may be synthesized according to any of a number of possible synthetic routes.

[0102] The reaction for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with starting materials, intermediates, or products at the temperature at which the reaction is carried out (for example, the temperature can range from the boiling temperature of the solvent).A given reaction can be carried out in one solvent or a mixture of solvents.

[0103] The selection of an appropriate protecting group can be readily determined by one of skill in the art.

[0104] Reactions can be monitored according to any suitable method known in the art (e.g., NMR, UV, HPLC, LC-MS, and TLC). Compounds can be purified by a variety of methods, including HPLC and normal phase silica chromatography.

[0105] Chiral analytical HPLC was used for the retention time analysis of various chiral examples. Depending on the column, mobile phase, and solvent allocation used, the conditions were classified into the following methods. [Table 2-1] [Table 2-2]

[0106] Example 1: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-morpholinonicotinamide [ka] Step 1: Methyl 6-chloro-2-morpholinonicotinate [ka] To a solution of morpholine (1.69 g, 19.4 mmol) in N,N-dimethylformamide (60 mL) was added dropwise methyl 2,6-dichloropyridine-3-carboxylate (3.8 g, 18.4 mmol) in N,N-dimethylformamide (20 mL) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. After consumption of the starting material, the reaction was quenched by adding water (50 mL). The resulting solution was extracted with ethyl acetate (3×70 mL). The organic phases were combined, washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate in petroleum ether (gradient of 0%→15%, v / v) to give the title compound (1.27 g, 27%). LC-MS (M+H) + = 257.2.

[0107] Step 2: Methyl 6-cyano-2-morpholinonicotinate [ka] Methyl 6-chloro-2-morpholinonicotinate (595 mg, 2.33 mmol) and Pd(PPh 3 ) 4 (512 mg, 0.444 mmol) in N,N-dimethylformamide (20 mL) was added to Zn(CN) 2 (517 mg, 4.403 mmol) was added at room temperature. The resulting mixture was stirred at 80° C. for 3 h under nitrogen atmosphere. After consumption of the starting material, the reaction was quenched by adding water (30 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The organic phases were combined, washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate in petroleum ether (0%→25% gradient, v / v) to give the title compound (470 mg, 80%). LC-MS (M+H) + = 248.2.

[0108] Step 3: 6-Cyano-2-morpholinonicotinic acid [ka] To a stirred solution of methyl 6-cyano-2-morpholinonicotinate (470 mg, 1.899 mmol) in THF (5 mL) was added LiOH (95 mg, 3.94 mmol) and water (2 mL) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 5 h. Upon completion of the reaction, the resulting mixture was diluted with water (10 mL) and washed with ethyl acetate (3×10 mL). The aqueous layer was acidified to pH=5 with 2N HCl aqueous solution. The precipitate was collected by filtration and washed with water (2×5 mL) to give the title compound (303 mg, 68%). LC-MS (M+H) + = 234.1.

[0109] Step 4: tert-Butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate [ka] A reaction mixture of 5-bromothiazolo[5,4-b]pyridin-2-amine (1 g, 4.35 mmol), di-tert-butyl dicarbonate (1.42 g, 6.52 mmol), and 4-dimethylaminopyridine (80 mg, 0.65 mmol) in dichloromethane (30 mL) was stirred at room temperature for 12 h. The mixture was concentrated to about 8 mL and the precipitate was filtered off. The filtrate was purified on silica gel by CombiFlash using methanol in dichloromethane (0% to 10%, v / v) to give the title compound (400 mg, 27%). LC-MS (M+H) + = 330.0, 331.9.

[0110] Step 5: tert-Butyl (5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] tert-Butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate (400 mg, 1.21 mmol), (4-chlorophenyl)boronic acid (284 mg, 1.82 mmol), Pd(PPh 3 ) 4 (70 mg, 0.061 mmol), and K 2 CO 3 The reaction mixture of (501 mg, 3.63 mmol) in 1,4-dioxane / water (35 mL, 6:1 v / v) under nitrogen was stirred at 100° C. for 12 h. The solvent was evaporated and the residue was purified on silica gel by CombiFlash (eluting with methanol in dichloromethane (0%→10%, v / v)) to give the title compound (180 mg, 41%). LC-MS (M+H) + = 362.0.

[0111] Step 6: 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine [ka] To a reaction mixture of tert-butyl (5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (180 mg, 0.5 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) and stirred at room temperature for 2 h. The solvent was evaporated and the residue was dissolved in NaHCO 3 The precipitate was filtered, washed with water and dried to give the crude product (110 mg, 84%), which was used directly in the next step without further purification. LC-MS (M+H) + = 262.1.

[0112] Step 7: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-morpholinonicotinamide To a mixture of 6-cyano-2-morpholinonicotinic acid (105 mg, 0.453 mmol) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (219 mg, 0.681 mmol) in N,N-dimethylformamide (3 mL) was added N,N-diisopropylethylamine (237 uL, 1.361 mmol) dropwise at room temperature. The resulting mixture was stirred at 50° C. under nitrogen atmosphere for 2 hours. To the above mixture was added 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine (118 mg, 0.454 mmol) in N,N-dimethylformamide (2 mL) dropwise at 50° C. under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under nitrogen atmosphere. After consumption of the starting material, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3×15 mL). The organic phases were combined, washed with brine, and diluted with Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD column, 30×150 mm, 5 um; Mobile phase: acetonitrile in water (NH 4 HCO 3 and 0.1% NH 4OH), gradient 28% to 58% in 10 min; detector: UV 254 nm. Obtained the title compound (11 mg, 5%). 1 H NMR (300 MHz, d6-DMSO) δ 13.21 (s, 1H), 8.33-7.98 (m, 5H), 7.65-7.43 (m, 3H), 3.70-3.61 (m, 4H), 3.41-3.32 (m, 4H). LC-MS (M+H) + = 477.2.

[0113] Example 2: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxyphenyl)nicotinamide [ka] Step 1: Benzyl 4-chloronicotinate [ka] A solution of 4-chloronicotinic acid (0.993 g, 6.3 mmol) in N,N-dimethylformamide (20 mL) was added with (bromomethyl)benzene (1.2 g, 7.0 mmol) and K 2 CO 3 (1.8 g, 12.7 mmol) was added. The reaction mixture was stirred at 60° C. for 15 min under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified on silica gel by CombiFlash (eluted with ethyl acetate in petroleum ether (10%, v / v)) to give the title compound (1.377 g, 88%). LC-MS (M+H) + = 248.0.

[0114] Step 2: Benzyl 4-(2-methoxyphenyl)nicotinate [ka] To a solution of benzyl 4-chloronicotinate (500 mg, 2.019 mmol) and (2-methoxyphenyl)boronic acid (613 mg, 4.037 mmol) in dioxane (18 mL) and water (3.6 mL) was added Pd(PPh 3 ) 4 (233 mg, 0.2019 mmol) and K 2 CO 3 (561 mg, 4.037 mmol) was added. The mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 mL). The solution was washed with brine (30 mL), dried over sodium sulfate, decanted and concentrated under reduced pressure. The residue was purified on silica gel by Combiflash, eluting with ethyl acetate in petroleum ether (20%, v / v) to give the title compound (353 mg, 55%). LC-MS (M+H) + = 320.1.

[0115] Step 3: 4-(2-Methoxyphenyl)nicotinic acid [ka] To a mixture of benzyl 4-(2-methoxyphenyl)nicotinate (353 mg, 1.106 mmol) in methanol (10 mL) was added 10 wt.% Pd / C (60 mg). The mixture was stirred at room temperature under 1 atm of hydrogen for 18 h. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give the title compound (200 mg, 79%). LC-MS (M+H) + = 230.1.

[0116] Step 4: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxyphenyl)nicotinamide A solution of 4-(2-methoxyphenyl)nicotinic acid (100 mg, 0.437 mmol) and 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine (100 mg, 0.383 mmol) in pyridine (3 mL) was added to POCl 3(110 mg, 0.874 mmol) was added at -10 °C under nitrogen atmosphere. The mixture was stirred at 25 °C under nitrogen for 20 min. Saturated NaHCO 3 (5 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (10 mL). The organic phase was washed with brine (10 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on silica gel by Combiflash, eluting with methanol in dichloromethane (5%, v / v) to give the title compound (11.9 mg, 7%). 1 H NMR (400 MHz, d6-DMSO) δ: 8.90 (s, 1H), 8.71 (s, 1H), 8.15 (d, J = 8.5 Hz, 2H), 8.06-8.00 (m, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.38 (dd, J 7.07 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 3.53 (s, 3H). LC-MS (M+H) + = 473.1.

[0117] Example 3: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-3-(2-methoxyphenyl)isonicotinamide [ka] Step 1: Methyl 3-(2-methoxyphenyl)isonicotinate [ka] The title compound (1.1 g, 97%) was prepared from methyl 3-bromoisonicotinate and (2-methoxyphenyl)boronic acid in a manner similar to Example 2, Step 2. 1H NMR (400 MHz, d6-DMSO) δ 8.70 (d, J = 5.0 Hz, 1H), 8.59 (s, 1H), 7.65 (d, J = 5.0 Hz, 1H), 7.41 (td, J = 7.9, 1.6 Hz, 1H), 7.33 (dd, J = 7.4, 1.4 Hz, 1H), 7.07 (t, J = 7.6 Hz, 2H), 3.66 (s, 3H), 3.66 (s, 3H). LC-MS (M+H) + = 244.1.

[0118] Step 2: 3-(2-Methoxyphenyl)isonicotinic acid [ka] The title compound (700 mg, 67%) was prepared from methyl 3-(2-methoxyphenyl)isonicotinate (1.1 g, 4.53 mmol) in a manner similar to Example 1, Step 3. 1 H NMR (400 MHz, d6-DMSO) δ 13.10 (s, 1H), 8.66 (d, J = 5.0 Hz, 1H), 8.53 (s, 1H), 7.63 (d, J = 5.0 Hz, 1H), 7.50 - 7.32 (m, 1H), 7.29 (dd, J = 7.5, 1.4 Hz, 1H), 7.04 (t, J = 7.5 Hz, 2H), 3.67 (s, 3H). LC-MS (M+H) + = 230.0.

[0119] Step 3: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-3-(2-methoxyphenyl)isonicotinamide A reaction mixture of 3-(2-methoxyphenyl)isonicotinic acid (50 mg, 0.22 mmol), 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine (57 mg, 0.22 mmol), PyBOP (114 mg, 0.22 mmol), and N,N-diisopropylethylamine (56 mg, 0.44 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 14 h. The solvent was evaporated and the residue was purified by preparative TLC (ethyl acetate as eluent) to give the title compound (13 mg, 12%). 1 H NMR (400 MHz, d6-DMSO) δ 13.08 (s, 1H), 8.76 (d, J = 4.9 Hz, 1H), 8.66 (s, 1H), 8.28 - 8.06 (m, 4H), 7.71 (d, J = 4.9 Hz, 1H), 7.57 (d, LC-MS (M+H) + = 473.0.

[0120] Example 4: 6-Cyano-2-morpholino-N-(5-(p-tolyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: 5-(p-tolyl)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (53 mg, 26%) was prepared from 5-bromothiazolo[5,4-b]pyridin-2-amine and p-tolylboronic acid in a manner similar to step 5 of example 1. LC-MS (M+H) + = 242.3.

[0121] Step 2: 6-cyano-2-morpholino-N-(5-(p-tolyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide To a solution of 5-(p-tolyl)thiazolo[5,4-b]pyridin-2-amine (42 mg, 0.17 mmol) and 6-cyano-2-morpholinonicotinic acid (42 mg, 0.18 mmol) in THF (2 mL) was added 1-methylimidazole (58 mg, 0.71 mmol) and TCFH (148 mg, 0.53 mmol) in portions at 0° C. The resulting mixture was stirred at 70° C. under nitrogen atmosphere for 16 hours, then cooled to room temperature and concentrated. The residue was purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD column, 30×150 mm, 5 um; Mobile phase: Methanol in water (NH at 10 mmol / L). 4 HCO 3 and 0.1% NH 4 OH), gradient 20% to 50% in 8 min; detector: UV 254 nm. Obtained the title compound (8 mg, 10%). 1 H-NMR (400 MHz, d6-DMSO) δ 8.00 (d, J = 6.8 Hz, 2H), 8.00 - 7.80 (m, 3H), 7.38 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 3.70 - 3.60 (m, 4H), 3.45 - 3.30 (m, 4H), 2.36 (s, 3H).

[0122] Example 5: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-morpholinonicotinamide [ka] Step 1: tert-Butyl (5-(4-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (1.8 g, 91%) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and (4-aminophenyl)boronic acid in a similar manner to step 5 of example 1. LC-MS (M+H) + = 343.1.

[0123] Step 2: tert-Butyl (5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] Acetyl chloride (50 mg, 0.6 mmol) was added dropwise to a solution of tert-butyl (5-(4-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (100 mg, 0.3 mmol) and N,N-diisopropylethylamine (200 mg, 1.6 mmol) in dichloromethane (5 mL) at 0° C. The mixture was stirred at 0° C. for 15 min. The mixture was diluted with water and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified on silica gel by CombiFlash (eluted with ethyl acetate in petroleum ether (50%, v / v)) to give the title compound (100 mg, 87%). LC-MS (M+H) + = 385.1.

[0124] Step 3: N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide [ka] The title compound (100 mg, crude) was prepared from tert-butyl (5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 285.1.

[0125] Step 4: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-morpholinonicotinamide The title compound (7 mg, 29%) was prepared from 6-cyano-2-morpholinonicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide in a similar manner to step 2 of example 4. 1H NMR (300 MHz, d6-DMSO) δ 13.10 (brs, 1H), 10.11 (s, 1H), 8.20-7.98 (m, 5H), 7.73 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 7.5 Hz, 1H), 3.70-3.61 (m, 4H), 3.41-3.32 (m, 4H), 2.09 (s, 3H). LC-MS (M+H) + = 500.2.

[0126] Example 6: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-(2-methoxyphenyl)nicotinamide [ka] Step 1: Methyl 6-cyano-2-(2-methoxyphenyl)nicotinate [ka] The title compound (1040 mg, 81%) was prepared from methyl 2-chloro-6-cyanicotinate and (2-methoxyphenyl)boronic acid in a manner similar to step 2 of example 2. LC-MS (M+H) + = 269.0.

[0127] Step 2: 6-Cyano-2-(2-methoxyphenyl)nicotinic acid [ka] The title compound (300 mg, 33%) was prepared from methyl 6-cyano-2-(2-methoxyphenyl)nicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + =255.1.

[0128] Step 3: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-(2-methoxyphenyl)nicotinamide The title compound (30 mg, 15%) was prepared from 6-cyano-2-(2-methoxyphenyl)nicotinic acid and 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to Example 4, Step 2. 1 H-NMR (400 MHz, d6-DMSO) δ 13.21 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.25-8.04 (m, 5H), 7.64-7.54 (m, 3H), 7.50-7.42 (m, 1H), 7.18-7.10 (m, 1H), 7.00 (d, J = 8.3 Hz, 1H), 3.52 (s, 3H). LC-MS (M+H) + = 498.1.

[0129] Example 7: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-(5-cyano-2-methoxyphenyl)nicotinamide [ka] Step 1: Methyl 6-cyano-2-(5-cyano-2-methoxyphenyl)nicotinate [ka] The title compound (275 mg, 54%) was prepared from methyl 2-chloro-6-cyanicotinate and (5-cyano-2-methoxyphenyl)boronic acid in a manner similar to step 2 of example 2. LC-MS (M+H) + = 294.0.

[0130] Step 2: 6-cyano-2-(5-cyano-2-methoxyphenyl)nicotinic acid [ka] The title compound (169 mg, 77%) was prepared from methyl 6-cyano-2-(5-cyano-2-methoxyphenyl)nicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 280.2.

[0131] Step 3: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-(5-cyano-2-methoxyphenyl)nicotinamide The title compound (37 mg, 14%) was prepared from 6-cyano-2-(5-cyano-2-methoxyphenyl)nicotinic acid and 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to Example 4, Step 2. 1 H NMR (300 MHz, d6-DMSO) δ 13.28 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.23-8.12 (m, 3H), 8.09 (d, J = 8.6 Hz, 1H), 8.05-7.92 (m, 2H), 7.62-7.51 (m, 2H), 7.21 (d, J = 8.7 Hz, 1H), 3.61 (s, 3H). LC-MS (M+H) + = 523.1.

[0132] Example 8: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: Methyl 4-chloro-6-methylnicotinate [ka] The title compound (3.7 g, 37%) was prepared from 4-chloro-6-methylnicotinic acid and iodomethane in a manner similar to Example 2, Step 1. 1 H NMR (400 MHz, d6-DMSO) δ 8.86 (s, 1H), 7.60 (s, 1H), 3.88 (s, 3H), 2.53 (s, 3H). LC-MS (M+H) + = 186.0.

[0133] Step 2: Methyl 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinate [ka] The title compound (2.7 g, 88.6%) was prepared from methyl 4-chloro-6-methylnicotinate and (5-cyano-2-methoxyphenyl)boronic acid in a manner similar to that of Example 2, Step 2. 1 H NMR (400 MHz, d6-DMSO) δ 8.82 (s, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.80 (s, 1H), 7.34 (s, 1H), 7.25 (d, J = 8.6 Hz, 1H), 3.75 (s, 3H), 3.65 (s, 3H), 2.56 (s, 3H). LC-MS (M+H) + = 283.1.

[0134] Step 3: 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid [ka] The title compound (2.2 g, 85.7%) was prepared from methyl 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinate in a similar manner to Example 1, Step 3. 1H NMR (400 MHz, d6-DMSO) δ 12.91 (s, 1H), 8.84 (s, 1H), 7.90 (dd, J = 8.6, 2.0 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J = 8.7 Hz, 1H), 3.76 (s, 3H), 2.55 (s, 3H). LC-MS (M+H) + = 269.1.

[0135] Step 4: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide The title compound (25 mg, 27%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to that described in step 3 of Example 3. 1 H-NMR (400 MHz, d6-DMSO) δ 13.05 (s, 1H), 8.81 (s, 1H), 8.23 ​​- 8.09 (m, 4H), 7.95 - 7.90 (m, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.47 (s, 1H), 7.19 (d, J = 9.2 Hz, 1H), 3.60 (s, 3H), 2.61 (s, 3H). LC-MS (M+H) + = 512.1.

[0136] Example 9: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: N,N-Dimethylpyridazine-4-carboxamide [ka] HATU (9 g, 24 mmol) was dissolved in pyridazine-4-carboxylic acid (2.5 g, 20 mmol) and dimethylamine hydrochloride (3.2 g, 40 mmol) in Et 3 A solution of N (10 mL) and N,N-dimethylformamide (30 mL) was added. The mixture was stirred at room temperature for 15 h. The mixture was concentrated under vacuum. The residue was purified on silica gel by Combiflash (eluting with methanol in dichloromethane (1% to 2%, v / v)) to give the title compound (2.0 g, 66%). LC-MS (M+H) + = 152.1.

[0137] Step 2: 5-(2-Methoxyphenyl)-N,N-dimethylpyridazine-4-carboxamide [ka] (2-Methoxyphenyl)magnesium bromide (16 ml, 16 mmol) was added dropwise to a solution of N,N-dimethylpyridazine-4-carboxamide (2.0 g, 13.2 mmol) in anhydrous THF (30 mL) at 0° C. The mixture was stirred at room temperature for 15 hours. The mixture was concentrated under vacuum. The residue was diluted with ethyl acetate (100 mL). To the mixture was added iodobenzene diacetate (7.4 g, 23 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with NaHSO 3 The mixture was quenched with ethyl acetate (2×50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by Combiflash eluting with methanol in dichloromethane (1%→5%, v / v) to give the title compound (2.0 g, 59%). LC-MS (M+H) + = 258.1.

[0138] Step 3: 5-(2-Methoxyphenyl)pyridazine-4-carboxylic acid [ka] To a solution of 5-(2-methoxyphenyl)-N,N-dimethylpyridazine-4-carboxamide (2.0 g, 7.8 mmol) in EtOH (20 mL) was added a solution of KOH (2.2 g, 39 mmol) in water (20 mL). The mixture was stirred at 100° C. for 3 days. The mixture was cooled and acidified to pH=2 with 2M aqueous HCl. The mixture was concentrated under vacuum to remove most of the solvent. The residue was cooled and filtered. The filter cake was dried under vacuum to give the title compound (1.0 g, 55%). LC-MS (M+H) + = 231.0.

[0139] Step 4: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide Oxalyl dichloride (200 mg, 1.6 mmol) was added dropwise to a suspension of 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid (50 mg, 0.22 mmol) in dichloromethane (1 mL) at 0° C. A drop of N,N-dimethylformamide was added to the mixture and the resulting mixture was stirred at 0° C. for 30 min and then concentrated under vacuum. To the residue at 0° C. was added a solution of 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine (57 mg, 0.22 mmol) in pyridine (1 mL). The mixture was stirred at room temperature for 3 h and then quenched with water. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were washed with brine and concentrated under vacuum. 2 SO 4 The mixture was dried at 40° C., filtered, and then concentrated in vacuo. The residue was purified by preparative TLC using ethyl acetate as the eluent to give the title compound (30 mg, 29%). 1 H NMR (400 MHz, d6-DMSO) δ 13.32 (s, 1H), 9.50 (s, 1H), 9.42 (s, 1H), 8.25 - 8.15 (m, 3H), 8.12 (d, J = 8.7 Hz, 1H), 7.62 - 7.45 (m, 4H), 7.19 - 7.12 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 3.56 (s, 3H). LC-MS (M+H)+ = 474.0, 476.0.

[0140] Example 10: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-(2-fluoro-6-methoxyphenyl)nicotinamide [ka] Step 1: Methyl 6-cyano-2-(2-fluoro-6-methoxyphenyl)nicotinate [ka] The title compound (200 mg, 40%) was prepared from methyl 2-chloro-6-cyanicotinate and (2-fluoro-6-methoxyphenyl)boronic acid in a manner similar to step 2 of example 2. LC-MS (M+H) + = 287.1.

[0141] Step 2: 6-cyano-2-(2-fluoro-6-methoxyphenyl)nicotinic acid [ka] The title compound (116 mg, 82%) was prepared from methyl 6-cyano-2-(2-fluoro-6-methoxyphenyl)nicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 273.0.

[0142] Step 3: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-(2-fluoro-6-methoxyphenyl)nicotinamide The title compound (51 mg, 28%) was prepared from 6-cyano-2-(2-fluoro-6-methoxyphenyl)nicotinic acid and 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to step 2 of example 4. 1H NMR (400 MHz, d6-DMSO) δ 13.36 (brs, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.25-8.09 (m, 4H), 7.61-7.54 (m, 2H), 7.52-7.42 (m, 1H), 7.01-6.86 (m, 2H), 3.58 (s, 3H). LC-MS (M+H) + = 516.0.

[0143] Example 11: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-3-(5-cyano-2-methoxyphenyl)isonicotinamide [ka] Step 1: Methyl 3-(5-cyano-2-methoxyphenyl)isonicotinate [ka] The title compound (670 mg, 94%) was prepared in a similar manner to Example 2, Step 2 from methyl 3-bromoisonicotinate (570 g, 2.64 mmol) and (5-cyano-2-methoxyphenyl)boronic acid (560 mg, 3.61 mmol). 1 H NMR (400 MHz, d6-DMSO) δ 8.77 (d, J = 5.0 Hz, 1H), 8.65 (s, 1H), 7.93 (dd, J = 8.6, 2.0 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 3.76 (s, 3H), 3.68 (s, 3H). LC-MS (M+H) + = 269.1.

[0144] Step 2: 3-(5-cyano-2-methoxyphenyl)isonicotinic acid [ka] The title compound (470 mg, 74%) was prepared from methyl 3-(5-cyano-2-methoxyphenyl)isonicotinate (670 mg, 2.5 mmol) in a manner similar to Example 1, Step 3. 1 H NMR (400 MHz, d6-DMSO) δ 13.32 (s, 1H), 8.73 (d, J = 5.0 Hz, 1H), 8.58 (s, 1H), 7.89 (dd, J = 8.6, 2.1 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.72 - 7.65 (m, 1H), 7.25 (d, J = 8.7 Hz, 1H), 3.74 (d, J = 12.0 Hz, 3H). LC-MS (M+H) + = 255.0.

[0145] Step 3: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-3-(5-cyano-2-methoxyphenyl)isonicotinamide 3-(5-cyano-2-methoxyphenyl)isonicotinic acid (50 mg, 0.2 mmol), 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine (50 mg, 0.2 mmol), T 3 A reaction mixture of P (50% in ethyl acetate, 1.5 mL) and pyridine (1.5 mL) was stirred at 60° C. under nitrogen for 14 h. The solvent was evaporated and the residue was dissolved in NaHCO 3 The mixture was extracted with ethyl acetate (2×10 mL). The organic layers were combined, washed with brine and 2 SO 4 The residue was purified by preparative TLC (using ethyl acetate as eluent) and preparative HPLC (eluent: acetonitrile (0.1% formic acid) / water (0.1% FA): 50%-80%, v / v) to give the title compound (27 mg, 27%). 1H NMR (400 MHz, d6-DMSO) δ 13.16 (s, 1H), 8.83 (d, J = 4.9 Hz, 1H), 8.72 (s, 1H), 8.36 - 8.05 (m, 4H), 8.00 - 7.88 (m, 2H), 7.77 (d, J = 7.57 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 1H), 3.60 (s, 3H). LC-MS (M+H) + = 498.1.

[0146] Example 12: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide [ka] Step 1: Ethyl 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylate [ka] 2-Methoxyaniline (1.3 g, 10 mmol), ethyl 2-oxoacetate (50% in water, 2.04 g, 10 mmol), and Na 2 SO 4 A reaction mixture of (7.1 g, 50 mmol) in toluene (30 mL) was stirred at 120° C. for 2 h. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated. The residue was dissolved in ethanol and then K 2 CO 3 (916 mg, 6.6 mmol) and tosylmethyl isocyanide (975 mg, 5 mmol) were added. The mixture was stirred at 50° C. for 14 h. The solvent was evaporated and the residue was purified on silica gel by Combiflash (eluted with ethyl acetate in petroleum ether (50%, v / v)) to give the title compound (620 mg, 25%). LC-MS (M+H) + = 247.1.

[0147] Step 2: 1-(2-Methoxyphenyl)-1H-imidazole-5-carboxylic acid [ka] The title compound (280 mg, 45%) was prepared from ethyl 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylate in a manner similar to Example 1, Step 3. 1 H NMR (400 MHz, d6-DMSO) δ 12.82 (s, 1H), 8.02 (s, 1H), 7.75 (s, 1H), 7.66 (dd, J = 7.8, 1.3 Hz, 1H), 7.61 - 7.47 (m, 3H). LC-MS (M+H) + =219.0.

[0148] Step 3: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide The title compound (21 mg, 13%) was prepared in a similar manner to step 3 of example 11 from 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine and 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylic acid. 1H NMR (400 MHz, d6-DMSO) δ 13.11 (s, 1H), 8.30 - 8.10 (m, 5H), 8.04 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 7.0 Hz, 1H), 7.43 (d, J = 6.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H) 7.10 (t, J =7.0 Hz, 1H), 3.70 (s, 3H). LC-MS (M+H) + = 462.1.

[0149] Example 13: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-(3-oxopiperazin-1-yl)nicotinamide [ka] Step 1: 2-Chloro-N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyanonicotinamide [ka] The title compound (274 mg, 79%) was prepared from 2-chloro-6-cyanonicotinic acid and 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to step 2 of example 4. LC-MS (M+H) + = 426.0.

[0150] Step 2: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-2-(3-oxopiperazin-1-yl)nicotinamide To a stirred solution of 2-chloro-N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyanonicotinamide (215 mg, 0.506 mmol) and piperazin-2-one (102 mg, 1.019 mmol) in dioxane (10 mL) was added N,N-diisopropylethylamine (262 mg, 2.027 mmol) at room temperature. The resulting mixture was stirred at 80° C. for 16 hours under nitrogen atmosphere. After consumption of the starting material, the resulting mixture was filtered and the filter cake was washed with dichloromethane (2×6 mL). The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD column, 30×150 mm, 5 um; Mobile phase: Acetonitrile in water (NH at 10 mmol / L). 4 HCO 3 and 0.1% NH 4OH), gradient 20% → 50% in 8 min; detector: UV 254 nm. Obtained the title compound (9 mg, 4%). 1H NMR (300 MHz, d6-DMSO) δ 13.17 (brs, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.25-8.16 (m, 3H), 8.16-8.07 (m, 2H), 7.64-7.50 (m, 3H), 3.87 (s, 2H), 3.64 (t, J = 4.0 Hz, 2H), 3.30 - 3.20 (m, 2H). LC-MS (M+H) + = 490.1.

[0151] Example 14: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: Benzyl 4-chloro-6-methylnicotinate [ka] The title compound (4.0 g, 94%) was prepared from 4-chloro-6-methylnicotinic acid and benzyl bromide in a similar manner to step 1 of example 2. LC-MS (M+H) + = 262.1.

[0152] Step 2: 4-(2-Methoxyphenyl)-6-methylnicotinic acid [ka] To a mixture of benzyl 4-chloro-6-methylnicotinate (4.0 g, 15.3 mmol) and (2-methoxyphenyl)boronic acid (2.8 g, 18.4 mmol) in dioxane (50 mL) and water (10 mL) was added K 2 CO 3(6.3 g, 18.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (600 mg, 0.8 mmol) were added. The mixture was stirred at 80° C. under nitrogen atmosphere for 14 h. The reaction was cooled to room temperature and diluted with water (30 mL). The mixture was then extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified to pH=2 with 2N HCl solution and then filtered. The filter cake was dried under vacuum to give the title compound (300 mg, 8%). LC-MS (M+H) + = 244.1.

[0153] Step 3: N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxyphenyl)-6-methylnicotinamide The title compound (15 mg, 15%) was prepared from 4-(2-methoxyphenyl)-6-methylnicotinic acid and 5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to step 3 of example 11. 1 H-NMR (400 MHz, d6-DMSO) δ 12.98 (s, 1H), 8.74 (s, 1H), 8.25 - 8.06 (m, 4H), 7.57 (d, J = 7.2 Hz, 2H), 7.45 - 7.30 (m, 3H), 7.14 - 7.07 (m, 1H), 6.99 (d, J = 8.8 Hz, 1H), 3.51 (s, 3H), 2.59 (s, 3H). LC-MS (M+H) + = 487.1, 489.0.

[0154] Example 15: 6-Cyano-N-(5-(1-methyl-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-yl)-2-morpholinonicotinamide [ka] Step 1: 5-(1-methyl-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (110 mg, 23%) was prepared from 5-bromothiazolo[5,4-b]pyridin-2-amine and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a manner similar to step 5 of example 1. LC-MS (M+H) + = 232.0.

[0155] Step 2: 6-cyano-N-(5-(1-methyl-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-yl)-2-morpholinonicotinamide The title compound (14 mg, 6%) was prepared from 5-(1-methyl-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-amine and 6-cyano-2-morpholinonicotinic acid in a manner similar to step 2 of example 4. 1 H-NMR (300 MHz, d6-DMSO) δ 13.23 (brs, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.55-7.47 (m, 2H), 6.86 (s, 1H), 4.21-4.15 (m, 3H), 3.68-3.59 (m, 4H), 3.44-3.32 (m, 4H).LC-MS (M+H) + = 447.1.

[0156] Example 16: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] The title compound (15 mg, 30%) was prepared from 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide in a manner similar to step 3 of example 11. 1H NMR (400 MHz, d6-DMSO) δ 13.24 (brs, 1H), 10.11 (s, 1H), 9.49 (s, 1H), 9.39 (s, 1H), 8.20 - 7.96 (m, 4H), 7.72 (d, J = 8.7 Hz, 2H), 7.57 - 7.44 (m, 2H), 7.17 - 7.11 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 3.56 (s, 3H), 2.08 (s, 3H). LC-MS (M+H) + = 497.2.

[0157] Example 17: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide [ka] The title compound (30 mg, 31%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide in a manner similar to step 3 of example 11. 1 H NMR (400 MHz, d6-DMSO) δ 12.96 (brs, 1H), 10.11 (s, 1H), 8.80 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.6 Hz, 1H), 7.95 - 7.88 (m, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.43 (s, 1H), 7.18 (d, J = 8.5 Hz, 1H), 3.60 (s, 3H), 2.60 (s, 3H), 2.08 (s, 3H). LC-MS (M+H) + = 535.2.

[0158] Example 18: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(methylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: tert-Butyl (5-(4-(methylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] To a mixture of tert-butyl (5-(4-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (50 mg, 0.15 mmol) in dichloromethane (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (100 mg, 0.77 mmol) and methanesulfonic anhydride (50 mg, 0.3 mmol). The mixture was stirred at room temperature for 14 h. The mixture was diluted with water and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified on silica gel by CombiFlash eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound (50 mg, 79%). LC-MS (M+H) + = 421.1.

[0159] Step 2: N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)methanesulfonamide [ka] The title compound (40 mg, crude) was prepared from tert-butyl (5-(4-(methylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 321.1.

[0160] Step 3: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(methylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (10 mg, 10%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)methanesulfonamide in a manner similar to step 3 of example 11. 1 H NMR (400 MHz, d6-DMSO) δ 12.94 (brs, 1H), 9.98 (s, 1H), 8.80 (s, 1H), 8.15 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 8.6 Hz, 2H), 8.02 (d, J = 8.5 Hz, 1H), 7.93 - 7.88 (m, 2H), 7.43 (s, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 3.60 (s, 3H), 3.06 (s, 3H), 2.60 (s, 3H). LC-MS (M+H) + = 571.3.

[0161] Example 19: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: tert-Butyl (5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (270 mg, 77%) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and (4-cyanophenyl)boronic acid in a similar manner to step 5 of example 1. LC-MS (M+H) + = 353.1.

[0162] Step 2: 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile [ka] The title compound (150 mg, 77%) was prepared from tert-butyl (5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 253.1.

[0163] Step 3: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (55 mg, 54%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1 H-NMR (400 MHz, d6-DMSO) δ 13.08 (s, 1H), 8.82 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.22 (s, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.94 - 7.85 (m, 2H), 7.43 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 3.60 (s, 3H), 2.60 (s, 3H). LC-MS (M+H) + = 503.1.

[0164] Example 20: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyclopropylphenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: tert-Butyl (5-(4-cyclopropylphenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (140 mg, 52%) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and (4-cyclopropylphenyl)boronic acid in a similar manner to step 5 of example 1. LC-MS (M+H) + = 368.0.

[0165] Step 2: 5-(4-cyclopropylphenyl)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (100 mg, 72%) was prepared from tert-butyl (5-(4-cyclopropylphenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 268.1.

[0166] Step 3: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyclopropylphenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (15 mg, 16%) was prepared from 5-(4-cyclopropylphenyl)thiazolo[5,4-b]pyridin-2-amine and 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid in a manner similar to step 3 of example 11. 1H-NMR (400 MHz, d6-DMSO) δ 12.96 (s, 1H), 8.81 (s, 1H), 8.14 (d, J = 9.1 Hz, 1H), 8.08 - 7.97 (m, 3H), 7.96 - 7.84 (m, 2H), 7.43 (s, 1H), 7.19 (t, J = 8.4 Hz, 3H), 3.60 (s, 3H), 2.60 (s, 3H), 2.07 - 1.85 (m, 1H), 1.01 (dd, J = 8.3, 2.0 Hz, 2H), 0.81 - 0.66 (m, 2H). LC-MS (M+H) + = 518.2.

[0167] Example 21: N-(5-(4-carbamoylphenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide [ka] The title compound (120 mg, 48%) was prepared from 5-bromothiazolo[5,4-b]pyridin-2-amine and 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid in a manner similar to step 3 of example 11. LC-MS (M+H) + = 480.0, 482.0.

[0168] Step 2: N-(5-(4-carbamoylphenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide The title compound (2 mg, 2%) was prepared in a manner similar to step 5 of example 1 from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide and (4-carbamoylphenyl)boronic acid. 1 H-NMR (400 MHz, d6-DMSO) δ 8.87 (s, 1H), 8.32 - 8.15 (m, 2H), 8.06 (s, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.5 Hz, 1H), 7.83 (s, 1H), 7.45 - 7.25 (m, 2H), 7.17 (d, J = 8.7 Hz, 1H), 3.60 (s, 3H), 2.56 (s, 3H). LC-MS (M+H) + = 521.2.

[0169] Example 22: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-3-(5-cyano-2-methoxyphenyl)isonicotinamide [ka] The title compound (17 mg, 18%) was prepared from 3-(5-cyano-2-methoxyphenyl)isonicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide in a manner similar to step 3 of example 11. 1 H-NMR (400 MHz, d6-DMSO) δ 13.07 (s, 1H), 10.12 (s, 1H), 8.82 (d, J = 4.9 Hz, 1H), 8.71 (s, 1H), 8.24 - 8.13 (m, 1H), 8.05 (dd, J = LC-MS (M+H) + = 521.2.

[0170] Example 23: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(5-cyano-2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: 5-(5-cyano-2-methoxyphenyl)pyridazine-4-carboxylic acid [ka] A mixture of 3-bromo-4-methoxybenzonitrile (200 mg, 1 mmol) and pyridazine-4-carboxylic acid (100 mg, 1 mmol) in N,N-dimethylformamide (5 mL) was added to the solution of Cs 2 CO 3 (900 mg, 3 mmol), Pd(OAc) 2 (20 mg, 0.1 mmol), and di(1-adamantyl)-n-butylphosphine hydroiodide (50 mg, 0.1 mmol) were added. The mixture was stirred at 150° C. under nitrogen atmosphere for 15 h. The mixture was cooled to room temperature and diluted with water (20 mL). The resulting solution was washed with ethyl acetate (2×20 mL). The aqueous layer was acidified to pH=2 with 2N HCl and then extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated in vacuo. The residue was purified on silica gel by CombiFlash eluting with methanol in dichloromethane (7%, v / v) to give the title compound (20 mg, 8%). LC-MS (M+H) + = 256.1.

[0171] Step 2: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(5-cyano-2-methoxyphenyl)pyridazine-4-carboxamide The title compound (2 mg, 5%) was prepared from 5-(5-cyano-2-methoxyphenyl)pyridazine-4-carboxylic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide in a manner similar to step 3 of example 11. 1 H NMR (400 MHz, d6-DMSO) δ 12.99 (brs, 1H), 10.06 (s, 1H), 9.57 (s, 1H), 9.27 (brs, 1H), 8.16 (s, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.96 - 7.80 (m, 3H), 7.68 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 9.0 Hz, 1H), 3.64 (s, 3H), 2.07 (s, 3H). LCMS (M+H) + = 522.3.

[0172] Example 24: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinamide [ka] Step 1: Methyl 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinate [ka] The title compound (0.6 g, 34%) was prepared from methyl 4-chloro-6-methylnicotinate and (2-methoxy-5-(trifluoromethyl)phenyl)boronic acid in a manner similar to step 2 of example 2. LC-MS (M+H) + = 326.1.

[0173] Step 2: 4-(2-Methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinic acid [ka] The title compound (0.45 g, 78%) was prepared from methyl 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 312.1.

[0174] Step 3: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinamide The title compound (12 mg, 12%) was prepared from 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 12.97 (s, 1H), 10.11 (s, 1H), 8.80 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.74 -7.71 (m, 3H), 7.43 (s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 3.60 (s, 3H), 2.61 (s, 3H), 2.08 (s, 3H). LC-MS (M+H) + = 578.2.

[0175] Example 25: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-fluoro-2-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: Methyl 4-(5-fluoro-2-methoxyphenyl)-6-methylnicotinate [ka] The title compound (550 mg, 100%) was prepared from methyl 4-chloro-6-methylnicotinate and (5-fluoro-2-methoxyphenyl)boronic acid in a manner similar to Example 2, Step 2. 1 H-NMR (400 MHz, d6-DMSO) δ 8.77 (s, 1H), 7.32 - 7.25 (m, 1H), 7.21 (dt, J = 9.2, 3.1 Hz, 2H), 7.04 (dd, J = 8.9, 4.5 Hz, 1H), 3.64 (s, 3H), 2.55 (s, 3H). LC-MS (M+H) + = 276.1.

[0176] Step 2: 4-(5-fluoro-2-methoxyphenyl)-6-methylnicotinic acid [ka] The title compound (320 mg, 61%) was prepared from methyl 4-(5-fluoro-2-methoxyphenyl)-6-methylnicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 262.2.

[0177] Step 3: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-fluoro-2-methoxyphenyl)-6-methylnicotinamide A reaction mixture of 4-(5-fluoro-2-methoxyphenyl)-6-methylnicotinic acid (55 mg, 0.21 mmol) and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide (50 mg, 0.18 mmol), EDCI (172 mg, 0.9 mmol), HOBt (122 mg, 0.9 mmol) and pyridine (5 mL) was stirred at 80 °C for 14 h. The solvent was evaporated and the residue was treated with water. The precipitate was filtered and dried. The crude product was purified by preparative HPLC (elution: acetonitrile (0.1% formic acid) / water (0.1% formic acid): 50% to 80%, v / v) to give the title compound (41 mg, 43%). 1H-NMR (400 MHz, d6-DMSO) δ 12.91 (s, 1H), 10.11 (s, 1H), 8.76 (s, 1H), 8.26 - 7.93 (m, 4H), 7.72 (d, J = 8.7 Hz, 2H), 7.38 (s, 1H), 7.33 - 7.20 (m, 2H), 6.99 (dd, J = 9.1, 4.4 Hz, 1H), 3.50 (s, 3H), 2.59 (s, 3H), 2.08 (s, 3H). LC-MS (M+H) + = 528.2.

[0178] Example 26: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-carbamoyl-2-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: 4-(5-carbamoyl-2-methoxyphenyl)-6-methylnicotinic acid [ka] 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid (150 mg, 0.6 mmol) was dissolved in H 2 SO 4 (80%, 1 mL). The reaction mixture was stirred at 40° C. for 15 h, then cooled to room temperature and diluted with water (10 mL). The mixture was filtered and the filter cake was dried under vacuum to give the crude title compound (150 mg). LC-MS (M+H) + = 287.1.

[0179] Step 2: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-carbamoyl-2-methoxyphenyl)-6-methylnicotinamide The title compound (30 mg, 31%) was prepared from 4-(5-carbamoyl-2-methoxyphenyl)-6-methylnicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide in a manner similar to step 3 of example 25. 1 H NMR (400 MHz, d6-DMSO) δ 12.93 (brs, 1H), 10.11 (s, 1H), 8.77 (s, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 8.7 Hz, 2H), 8.04 - 7.91 (m, 4H), 7.71 (d, J = 8.7 Hz, 2H), 7.40 (s, 1H), 7.31 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 3.56 (s, 3H), 2.61 (s, 3H), 2.08 (s, 3H). LC-MS (M+H) + = 553.3.

[0180] Example 27: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-4-(2-methoxyphenyl)nicotinamide [ka] Step 1: Benzyl 6-bromo-4-chloronicotinate [ka] The title compound (4.023 g, 97%) was prepared from 6-bromo-4-chloronicotinic acid and benzyl bromide in a similar manner to step 1 of example 2. LC-MS (M+H) + = 326.0, 327.9.

[0181] Step 2: Benzyl 4-chloro-6-cyanonicotinate [ka] The title compound (4.023 g, 97%) was prepared from benzyl 6-bromo-4-chloronicotinate in a similar manner to step 2 of example 1. LC-MS (M+H) + = 273.1.

[0182] Step 3: Benzyl 6-cyano-4-(2-methoxyphenyl)nicotinate [ka] The title compound (456 mg, 90%) was prepared from benzyl 4-chloro-6-cyanonicotinate and (2-methoxyphenyl)boronic acid in a manner similar to step 2 of example 2. LC-MS (M+H) + =345.1.

[0183] Step 4: 6-Cyano-4-(2-methoxyphenyl)nicotinic acid [ka] The title compound (98 mg, 29%) was prepared from benzyl 6-cyano-4-(2-methoxyphenyl)nicotinate in a similar manner to step 3 of example 2. LC-MS (M+H) + = 255.0.

[0184] Step 5: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-4-(2-methoxyphenyl)nicotinamide The title compound (34 mg, 47%) was prepared from 6-cyano-4-(2-methoxyphenyl)nicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide in a manner similar to step 3 of example 25. 1H-NMR (400 MHz, d6-DMSO) δ: 13.20 (s, 1H), 10.11 (s, 1H), 9.04 (s, 1H), 8.21 - 8.13 (m, 2H), 8.08 (d, J = 8.7 Hz, 2H), 8.03 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.47 (dd, J = 15.5, 7.5 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 3.54 (s, 3H), 2.08 (s, 3H). LC-MS (M+H) + = 521.2.

[0185] Example 28: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxy-5-(methoxymethyl)phenyl)-6-methylnicotinamide [ka] Step 1: 2-Bromo-1-methoxy-4-(methoxymethyl)benzene [ka] To a solution of (3-bromo-4-methoxyphenyl)methanol (2.17 g, 10 mmol) in anhydrous THF (30 mL) was added NaH (0.48 g, 60%, 12 mmol) slowly at 0° C., followed by iodomethane (1.7 g, 12 mmol). The resulting mixture was stirred at room temperature for 1 h and then quenched with water (20 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified on silica gel by CombiFlash eluting with ethyl acetate in petroleum ether (10%, v / v) to give the title compound (1.8 g, 78%). 1H-NMR (400 MHz, d6-DMSO) δ 7.51 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 8.4, 1.9 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 4.33 (s, 2H), 3.84 (s, 3H), 3.25 (s, 3H). LC-MS (M+H) + =230.9, 232.9.

[0186] Step 2: 2-(2-methoxy-5-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a mixture of 2-bromo-1-methoxy-4-(methoxymethyl)benzene (1.8 g, 7.8 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.37 g, 9.35 mmol) in dioxane (50 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (570 mg, 0.78 mmol) and KOAc (1.53 g, 15.6 mmol). The reaction mixture was stirred at 100° C. under nitrogen for 15 h, then cooled to room temperature and diluted with ethyl acetate (50 mL). The organic layer was separated from the aqueous layer, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel by Combiflash eluting with ethyl acetate in petroleum ether (16%, v / v) to give the title compound (1.6 g, 74%). LC-MS (M+H) + =279.0.

[0187] Step 3: Methyl 4-(2-methoxy-5-(methoxymethyl)phenyl)-6-methylnicotinate [ka] The title compound (1.2 g, 77%) was prepared from methyl 4-chloro-6-methylnicotinate and 2-(2-methoxy-5-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to step 2 of example 2. LC-MS (M+H) + = 302.1.

[0188] Step 4: 4-(2-Methoxy-5-(methoxymethyl)phenyl)-6-methylnicotinic acid [ka] The title compound (0.92 g, 80%) was prepared from methyl 4-(2-methoxy-5-(methoxymethyl)phenyl)-6-methylnicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 288.1.

[0189] Step 5: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxy-5-(methoxymethyl)phenyl)-6-methylnicotinamide The title compound (6 mg, 6%) was prepared from 4-(2-methoxy-5-(methoxymethyl)phenyl)-6-methylnicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 12.90 (s, 1H), 10.10 (s, 1H), 8.74 (s, 1H), 8.11 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 8.8 Hz, 2H), 8.00 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.39 - 7.29 (m, 3H), 6.96 (d, J = 9.0 Hz, 1H), 4.41 (s, 2H), 3.51 (s, 3H), 3.30 (s, 3H), 2.59 (s, 3H), 2.08 (s, 3H). LC-MS (M+H)+ = 554.1.

[0190] Example 29: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(1-cyanocyclopropyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: tert-Butyl (5-(4-(1-cyanocyclopropyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (crude) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and (4-(1-cyanocyclopropyl)phenyl)boronic acid in a manner similar to step 5 of example 1. LC-MS (M+H) + = 393.1.

[0191] Step 2: 1-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carbonitrile [ka] The title compound (220 mg, 75% for 2 steps) was prepared from tert-butyl (5-(4-(1-cyanocyclopropyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 293.1.

[0192] Step 3: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(1-cyanocyclopropyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (15 mg, 14%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 1-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carbonitrile in a manner similar to step 3 of example 11. 1 H NMR (400 MHz, d6-DMSO) δ 12.99 (s, 1H), 8.80 (s, 1H), 8.24 - 8.05 (m, 4H), 7.98 - 7.76 (m, 2H), 7.46 (d, J = 8.8 Hz, 3H), 7.18 (d, J = LC-MS (M+H) + = 543.3.

[0193] Example 30: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-fluorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: tert-Butyl (5-(4-fluorophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (crude) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and (4-fluorophenyl)boronic acid in a similar manner to step 5 of example 1. LC-MS (M+H) + = 346.1.

[0194] Step 2: 5-(4-fluorophenyl)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (200 mg, 81% for two steps) was prepared from tert-butyl (5-(4-fluorophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 246.0.

[0195] Step 3: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-fluorophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (10 mg, 8%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 5-(4-fluorophenyl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to step 3 of example 11. 1 H NMR (400 MHz, d6-DMSO) δ 12.97 (s, 1H), 8.82 (s, 1H), 8.17 (dt, J = 14.7, 7.4 Hz, 3H), 8.05 (d, J = 8.6 Hz, 1H), 7.91 (dd, J = 11.2, 2.6 Hz, 2H), 7.42 (s, 1H), 7.33 (t, J = 8.8 Hz, 2H), 7.18 (d, J = 8.6 Hz, 1H), 3.60 (s, 3H), 2.60 (s, 3H). LC-MS (M+H) + = 496.2.

[0196] Example 31: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-3-(2-fluoro-6-methoxyphenyl)isonicotinamide [ka] Step 1: 2-(2-fluoro-6-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 2-bromo-1-fluoro-3-methoxybenzene (1 g, 4.9 mmol) in THF (20 mL) under nitrogen atmosphere, nBuLi (3 mL, 2.5 M, 7.5 mmol) was added at -78°C and stirred for 1 h. Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.3 g, 12.25 mmol) was added and the reaction mixture was stirred at room temperature for 14 h. The reaction was quenched with water and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried at 70° C., then filtered and evaporated. The residue was purified on silica gel by CombiFlash (eluted with ethyl acetate in petroleum ether (50%, v / v)) to give the title compound (740 mg, 60%). LC-MS (M+H) + = 253.2.

[0197] Step 2: Methyl 3-(2-fluoro-6-methoxyphenyl)isonicotinate [ka] The title compound (365 mg, 47%) was prepared from 2-(2-fluoro-6-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and methyl 3-bromoisonicotinate in a manner similar to step 2 of example 2. LC-MS (M+H) + = 262.1.

[0198] Step 3: 3-(2-fluoro-6-methoxyphenyl)isonicotinic acid [ka] The title compound (190 mg, 77%) was prepared from methyl 3-(2-fluoro-6-methoxyphenyl)isonicotinate in a manner similar to Example 1, Step 3. 1H-NMR (400 MHz, d6-DMSO) δ 13.26 (s, 1H), 8.71 (d, J = 5.0 Hz, 1H), 8.55 (s, 1H), 7.77 (d, J = 5.0 Hz, 1H), 7.41 (dd, J = 15.4, 8.3 Hz, 1H), 7.04 - 6.79 (m, 2H), 3.70 (s, 3H). LC-MS (M+H) + = 248.0.

[0199] Step 4: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-3-(2-fluoro-6-methoxyphenyl)isonicotinamide The title compound (32 mg, 24%) was prepared from 3-(2-fluoro-6-methoxyphenyl)isonicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 13.15 (s, 1H), 10.11 (s, 1H), 8.79 (d, J = 5.0 Hz, 1H), 8.66 (d, J = 1.5 Hz, 1H), 8.16 (t, J = 8.4 Hz, 1H), 8.05 (dd, J = 19.5, 8.6 Hz, 3H), 7.81 (d, J = 5.0 Hz, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.42 (dd, J = 15.3, 8.2 Hz, 1H), 7.10 - 6.79 (m, 2H), 3.59 (s, 3H), 2.08 (s, 3H). LC-MS (M+H) + = 514.3.

[0200] Example 32: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(N-methylmethylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)-N-methylmethanesulfonamide [ka] N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)methanesulfonamide (80 mg, 0.25 mmol) and K 2 CO 3 To a mixture of (70 mg, 0.5 mmol) in N,N-dimethylformamide (2 mL) was added iodomethane (50 mg, 0.35 mmol). The mixture was stirred at room temperature for 3 h and then diluted with water. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 It was dried over rt, filtered and concentrated in vacuo to give the title compound (80 mg, crude). LC-MS (M+H) + = 335.1.

[0201] Step 2: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(N-methylmethylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (25 mg, 19%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)-N-methylmethanesulfonamide in a manner similar to step 3 of example 25. 1 H NMR (400 MHz, d6-DMSO) δ 12.99 (brs, 1H), 8.81 (s, 1H), 8.22 - 8.13 (m, 3H), 8.09 (d, J = 8.2 Hz, 1H), 7.94 - 7.88 (m, 2H), 7.54 (d, J = LC-MS (M+H) += 585.3.

[0202] Example 33: 6-chloro-4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: Ethyl 6-chloro-4-(5-cyano-2-methoxyphenyl)nicotinate [ka] Ethyl 4,6-dichloronicotinate (5 g, 22.83 mmol), (5-cyano-2-methoxyphenyl)boronic acid (4.04 g, 22.83 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.67 g, 0.228 mmol), and K 2 CO 3 The reaction mixture of (6.3 g, 45.66 mmol) in 1,4-dioxane / water (100 mL / 14 mL) under nitrogen was stirred at 90° C. for 14 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified on silica gel by Combiflash (eluted with ethyl acetate in petroleum ether (50%, v / v)) to give the title compound (3.2 g, 44.4%). 1 H-NMR (400 MHz, d6-DMSO) δ 8.78 (s, 1H), 7.96 (dd, J = 8.6, 1.5 Hz, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.27 (d, J = 8.7 Hz, 1H), 4.11 (dd, J = 14.1, 7.0 Hz, 2H), 3.77 (s, 3H), 1.04 (t, J = 7.1 Hz, 3H). LC-MS (M+H) + = 317.2.

[0203] Step 2: 6-Chloro-4-(5-cyano-2-methoxyphenyl)nicotinic acid [ka] The title compound (100 mg, 74%) was prepared from ethyl 6-chloro-4-(5-cyano-2-methoxyphenyl)nicotinate in a similar manner to Step 3 of Example 1. LC-MS (M+H) + = 289.2.

[0204] Step 3: 6-chloro-4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (15 mg, 14%) was prepared from 6-chloro-4-(5-cyano-2-methoxyphenyl)nicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1 H-NMR (400 MHz, d6-DMSO) δ 13.23 (s, 1H), 8.81 (s, 1H), 8.35 (d, J = 8.4 Hz, 2H), 8.28 - 8.22 (m, 2H), 8.01 - 7.94 (m, 4H), 7.77 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 3.61 (s, 3H).LC-MS (M+H) + = 523.2.

[0205] Example 34: 4-(5-cyano-2-methoxyphenyl)-6-(cyanomethyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: Ethyl 6-(2-(tert-butoxy)-1-cyano-2-oxoethyl)-4-(5-cyano-2-methoxyphenyl)nicotinate [ka] Ethyl 6-chloro-4-(5-cyano-2-methoxyphenyl)nicotinate (0.65 g, 2 mmol), tert-butyl 2-cyanoacetate (0.7 g, 5 mmol), tetrabutylammonium bromide (64 mg, 0.2 mmol), and K 2 CO 3 The reaction mixture of (1.38 g, 10 mmol) in DMSO (10 mL) under nitrogen was stirred at 90° C. for 3 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified on silica gel by Combiflash (eluted with ethyl acetate in petroleum ether (0-50%, v / v)) to give the title compound (0.88 g, 100%). LC-MS (M+H) + = 422.5.

[0206] Step 2: Ethyl 4-(5-cyano-2-methoxyphenyl)-6-(cyanomethyl)nicotinate [ka] To a solution of ethyl 6-(2-(tert-butoxy)-1-cyano-2-oxoethyl)-4-(5-cyano-2-methoxyphenyl)nicotinate (0.88 g, 2 mmol) in toluene (10 mL) was added p-toluenesulfonic acid (34 mg, 0.2 mmol). The reaction mixture was stirred at 110° C. for 14 h, then cooled to room temperature and concentrated. The residue was purified on silica gel by CombiFlash (eluted with ethyl acetate in petroleum ether (0-50%, v / v)) to give the title compound (0.61 g, 95%). LC-MS (M+H) + = 322.3.

[0207] Step 3: 4-(5-cyano-2-methoxyphenyl)-6-(cyanomethyl)nicotinic acid [ka] The title compound (190 mg, 65%) was prepared from ethyl 4-(5-cyano-2-methoxyphenyl)-6-(cyanomethyl)nicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 294.1.

[0208] Step 4: 4-(5-cyano-2-methoxyphenyl)-6-(cyanomethyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (1.5 mg, 1.4%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-(cyanomethyl)nicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1 H-NMR (400 MHz, d6-DMSO) δ 13.18 (s, 1H), 8.94 (s, 1H), 8.35 (d, J = 8.5 Hz, 2H), 8.25 (q, J = 8.7 Hz, 2H), 7.96 (dd, J = 13.5, 8.4 Hz, 4H), 7.59 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 4.37 (s, 2H), 3.61 (s, 3H). LC-MS (M+H) + = 528.3.

[0209] Example 35: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(ethylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: tert-Butyl (5-(4-(ethylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] To a mixture of tert-butyl (5-(4-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (300 mg, 0.88 mmol) in pyridine (10 mL) was added ethanesulfonyl chloride (150 mg, 1.2 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 1 h and then quenched with water. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine and extracted with Na 2 SO 4 Drying at 40° C., filtration and concentration in vacuo afforded the title compound (280 mg, crude). LC-MS (M+H) + = 435.1.

[0210] Step 2: N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)ethanesulfonamide [ka] The title compound (180 mg, crude) was prepared from tert-butyl (5-(4-(ethylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a manner similar to that described in step 6 of Example 1. LC-MS (M+H) + = 335.1.

[0211] Step 3: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(ethylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (50 mg, 28%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)ethanesulfonamide in a manner similar to that described in step 3 of example 25. 1H NMR (400 MHz, d6-DMSO) δ 12.96 (s, 1H), 10.03 (s, 1H), 8.80 (s, 1H), 8.17 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 8.7 Hz, 1H), 7.95 - 7.87 (m, 2H), 7.44 (s, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 9.3 Hz, 1H), 3.60 (s, 3H), 3.16 (q, J = 7.3 Hz, 2H), 2.60 (s, 3H), 1.21 (t, J = 7.3 Hz, 3H). LC-MS (M+H) + = 585.3.

[0212] Example 36: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-4-(5-cyano-2-methoxyphenyl)nicotinamide [ka] Step 1: Benzyl 6-cyano-4-(5-cyano-2-methoxyphenyl)nicotinate [ka] The title compound (530 mg, 90%) was prepared from benzyl 4-chloro-6-cyanonicotinate and (5-cyano-2-methoxyphenyl)boronic acid in a manner similar to that described in step 2 of Example 2. LC-MS (M+H) + =370.1.

[0213] Step 2: 6-cyano-4-(5-cyano-2-methoxyphenyl)nicotinic acid [ka] The title compound (143 mg, 36%) was prepared from benzyl 6-cyano-4-(5-cyano-2-methoxyphenyl)nicotinate in a manner similar to that described in step 3 of Example 2. LC-MS (M+H) + = 280.2.

[0214] Step 3: N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-4-(5-cyano-2-methoxyphenyl)nicotinamide The title compound (31 mg, 41%) was prepared from 6-cyano-4-(5-cyano-2-methoxyphenyl)nicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)acetamide in a manner similar to that described in step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ: 13.26 (s, 1H), 10.11 (s, 1H), 9.11 (s, 1H), 8.29 (s, 1H), 8.21 - 8.00 (m, 5H), 7.97 (dd, J = 8.6, 1.9 Hz, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 1H), 3.61 (s, 3H), 2.08 (s, 3H). LC-MS (M+H) + = 546.3.

[0215] Example 37: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-(trifluoromethyl)nicotinamide [ka] Step 1: Methyl 4-(5-cyano-2-methoxyphenyl)-6-(trifluoromethyl)nicotinate [ka] The title compound (0.53 g, 79%) was prepared from methyl 4-chloro-6-(trifluoromethyl)nicotinate and (5-cyano-2-methoxyphenyl)boronic acid in a manner similar to step 2 of example 2. LC-MS (M+H) + = 337.1.

[0216] Step 2: 4-(5-cyano-2-methoxyphenyl)-6-(trifluoromethyl)nicotinic acid [ka] The title compound (0.35 g, 66%) was prepared from methyl 4-(5-cyano-2-methoxyphenyl)-6-(trifluoromethyl)nicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 323.1.

[0217] Step 3: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-(trifluoromethyl)nicotinamide The title compound (25 mg, 27%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-(trifluoromethyl)nicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 13.34 (s, 1H), 9.14 (s, 1H), 8.35 (d, J = 8.4 Hz, 2H), 8.27 - 8.23 ​​(m, 2H), 8.15 - 8.08 (m, 2H), 8.02 - 7.92 (m, 3H), 7.22 (d, J = 8.8 Hz, 1H), 3.62 (s, 3H). LC-MS (M+H) + = 557.2.

[0218] Example 38: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: Ethyl 4-(5-cyano-2-methoxyphenyl)nicotinate [ka] A solution of ethyl 6-chloro-4-(5-cyano-2-methoxyphenyl)nicotinate (0.15 g, 0.5 mmol) in methanol (5 mL) was diluted with NaHCO 3 (42 mg, 0.5 mmol) and 10 wt.% Pd / C (15 mg) were added and the reaction mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 2 h. The mixture was filtered through a short pad of diatomaceous earth. The filtrate was concentrated to give the title compound (0.13 g, crude), which was used in the next step without further purification. LC-MS (M+H) + = 283.2.

[0219] Step 2: 4-(5-cyano-2-methoxyphenyl)nicotinic acid [ka] The title compound (90 mg, 71%, 2 steps) was prepared from ethyl 4-(5-cyano-2-methoxyphenyl)nicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 255.3.

[0220] Step 3: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (20 mg, 20%) was prepared from 4-(5-cyano-2-methoxyphenyl)nicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1H-NMR (400 MHz, d6-DMSO) δ 13.12 (s, 1H), 8.96 (s, 1H), 8.82 (d, J = 5.4 Hz, 1H), 8.34 (d, J = 8.3 Hz, 2H), 8.23-8.15 (m, 2H), 8.01 - 7.83 (m, 4H), 7.56 - 7.51 (m, 1H), 7.19 (d, J = 8.6 Hz, 1H), 3.61 (s, 3H). LC-MS (M+H) + = 489.2.

[0221] Example 39: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-fluoronicotinamide [ka] Step 1: Ethyl 4-(5-cyano-2-methoxyphenyl)-6-fluoronicotinate [ka] To a solution of ethyl 6-chloro-4-(5-cyano-2-methoxyphenyl)nicotinate (0.32 g, 1 mmol) in DMSO (5 mL) was added CsF (0.38 g, 2.5 mmol) and the reaction mixture was stirred at 80° C. for 14 h and then cooled to room temperature. The mixture was purified on silica gel by CombiFlash (eluted with ethyl acetate in petroleum ether (0%→30%, v / v)) to give the title compound (0.25 g, 83%). LC-MS (M+H) + = 301.1.

[0222] Step 2: 4-(5-cyano-2-methoxyphenyl)-6-fluoronicotinic acid [ka] The title compound (220 mg, 97%) was prepared from ethyl 4-(5-cyano-2-methoxyphenyl)-6-fluoronicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) += 273.2.

[0223] Step 3: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-fluoronicotinamide The title compound (20 mg, 19.8%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-fluoronicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1 H-NMR (400 MHz, d6-DMSO) δ 13.20 (s, 1H), 8.68 (s, 1H), 8.35 (d, J = 8.5 Hz, 2H), 8.24 (q, J = 8.5 Hz, 2H), 7.99 - 7.95 (m, 4H), 7.46 (s, 1H), 7.21 (d, J = 8.7 Hz, 1H), 3.61 (s, 3H). LC-MS (M+H) + = 507.2.

[0224] Example 40: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(trifluoromethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: tert-Butyl (5-(4-(trifluoromethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (600 mg, 100%) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and (4-(trifluoromethyl)phenyl)boronic acid in a manner similar to step 2 of example 2. LC-MS (M+H) + = 396.1.

[0225] Step 2: 5-(4-(trifluoromethyl)phenyl)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (220 mg, 50%) was prepared from tert-butyl (5-(4-(trifluoromethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 296.1.

[0226] Step 3: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(trifluoromethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (50 mg, 31%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 5-(4-(trifluoromethyl)phenyl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 13.07 (s, 1H), 8.81 (s, 1H), 8.36 (d, J = 8.2 Hz, 2H), 8.25 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.95 - 7.90 (m, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.45 (s, 1H), 7.18 (d, J = 9.2 Hz, 1H), 3.60 (s, 3H), 2.61 (s, 3H). LC-MS (M+H) + = 546.2.

[0227] Example 41: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-propionamidophenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: tert-Butyl (5-(4-propionamidophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] To a solution of tert-butyl (5-(4-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (342 mg, 1 mmol) in THF (20 mL) at 0° C. was added N,N-diisopropylethylamine (258 mg, 2 mmol) and propionyl chloride (140 mg, 1.5 mmol). The reaction solution was stirred at room temperature for 1 h and then diluted with ethyl acetate (30 mL). The solution was washed with water, brine and Na 2 SO 4 Drying at 40° C., filtration and evaporation gave the crude product (390 mg). LC-MS (M+H) + = 399.1.

[0228] Step 2: N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)propionamide [ka] Crude tert-butyl (5-(4-propionamidophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (390 mg) was dissolved in dichloromethane (3 mL) and cooled to 0° C. Trifluoroacetic acid (3 mL) was added and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was dissolved in dichloromethane. This solution was diluted with water, saturated NaHCO 3 Wash with aqueous solution of Na 2 SO 4 The mixture was dried at 77° C., filtered and evaporated. The crude product (250 mg, 83% for two steps) was used in the next step without further purification. LC-MS (M+H) + = 299.1.

[0229] Step 3: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-propionamidophenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (61 mg, 50%) was prepared from N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)propionamide and 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 12.95 (s, 1H), 10.04 (s, 1H), 8.80 (s, 1H), 8.08 (td, J = 23.4, 8.5 Hz, 4H), 7.96 - 7.88 (m, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.43 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 3.60 (s, 3H), 2.60 (s, 3H), 2.36 (q, J = 7.5 Hz, 2H), 1.10 (t, J = 7.5 Hz, 3H).LC-MS (M+H) + = 549.3.

[0230] Example 42: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(2-hydroxyacetamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: 2-((4-(2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridin-5-yl)phenyl)amino)-2-oxoethyl acetate [ka] To a solution of tert-butyl (5-(4-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (342 mg, 1 mmol) in THF (20 mL) at 0° C. was added N,N-diisopropylethylamine (258 mg, 2 mmol) and 2-chloro-2-oxoethyl acetate (204 mg, 1.5 mmol). The reaction solution was stirred at room temperature for 1 h and then diluted with ethyl acetate (30 mL). The mixture was washed with water, brine, and then Na2 SO 4 Drying at 40° C., filtration and evaporation gave the crude product without further purification. LC-MS (M+H) + = 443.1.

[0231] Step 2: 2-((4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)amino)-2-oxoethyl acetate [ka] The crude 2-((4-(2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridin-5-yl)phenyl)amino)-2-oxoethyl acetate was dissolved in dichloromethane (3 mL). The solution was cooled to 0° C., then trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 2 h and then concentrated. The residue was dissolved in dichloromethane and washed with water, saturated NaHCO 3 The mixture was washed with aqueous solution, then dried over sodium sulfate, filtered and concentrated. The crude product (200 mg, 58% for two steps) was used in the next step without further purification. LC-MS (M+H) + = 343.1.

[0232] Step 3: 2-((4-(2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamido)thiazolo[5,4-b]pyridin-5-yl)phenyl)amino)-2-oxoethyl acetate [ka] The title compound was prepared from 2-((4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)amino)-2-oxoethyl acetate and 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid in a similar manner to step 3 of example 25. The crude product was used in the next step without further purification. LC-MS (M+H) + = 593.2.

[0233] Step 4: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(2-hydroxyacetamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide To a solution of crude 2-((4-(2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamido)thiazolo[5,4-b]pyridin-5-yl)phenyl)amino)-2-oxoethyl acetate in THF (20 mL) was added an aqueous solution of LiOH (49 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for 14 h, then cooled to 0° C. and acidified to pH=2 with 1M HCl. The mixture was concentrated to remove THF and precipitation of a solid was observed. The solid was filtered and purified by preparative HPLC (elution: acetonitrile (0.1% formic acid) / water (0.1% formic acid): 50%-80%, v / v) to give the title compound (115 mg, 36%). 1 H-NMR (400 MHz, d6-DMSO) δ 12.95 (s, 1H), 9.84 (s, 1H), 8.80 (s, 1H), 8.26 - 8.00 (m, 4H), 7.97 - 7.69 (m, 4H), 7.44 (s, 1H), 7.18 (d, J = 8.9 Hz, 1H), 5.68 (t, J = 6.0 Hz, 1H), 4.03 (d, J = 6.0 Hz, 2H), 3.60 (s, 3H), 2.60 (s, 3H). LC-MS (M+H) + = 551.3.

[0234] Example 43: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(2-oxooxazolidin-3-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: tert-Butyl (5-(4-(((2-chloroethoxy)carbonyl)amino)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] To a solution of tert-butyl (5-(4-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (342 mg, 1 mmol) in MeCN (20 mL) at 0 °C, 2 CO 3 (276 mg, 2 mmol) and 2-chloroethyl carbonochloridate (286 mg, 2 mmol) were added. The reaction mixture was stirred at room temperature for 14 h and then diluted with ethyl acetate (30 mL). The mixture was washed with water, brine and then Na 2 SO 4 The mixture was dried at 70° C., filtered and evaporated. The residue was purified on silica gel by CombiFlash eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound (300 mg, 67%). LC-MS (M+H) + = 449.1.

[0235] Step 2: tert-Butyl (5-(4-(2-oxooxazolidin-3-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] To a solution of tert-butyl (5-(4-(((2-chloroethoxy)carbonyl)amino)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (300 mg, 0.67 mmol) in N,N-dimethylformamide (6 mL) under nitrogen was added NaH (80 mg, 2.01 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 14 h and then cooled to 0° C. Water was added to quench the reaction and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine and Na 2 SO 4 The mixture was dried at 75° C., filtered and evaporated. The residue was purified on silica gel by CombiFlash (eluted with ethyl acetate) to give the title compound (140 mg, 51%). LC-MS (M+H) + = 413.0.

[0236] Step 3: 3-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)oxazolidin-2-one [ka] The title compound (90 mg, 84%) was prepared from tert-butyl (5-(4-(2-oxooxazolidin-3-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 313.1.

[0237] Step 4: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(2-oxooxazolidin-3-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (65 mg, 40%) was prepared from 3-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)oxazolidin-2-one and 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 12.95 (s, 1H), 8.82 (s, 1H), 8.15 (t, J = 10.8 Hz, 3H), 8.05 (d, J = 8.5 Hz, 1H), 7.91 (dd, J = 11.1, 2.5 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.18 (d, J = 8.6 Hz, 1H), 4.57 - 4.38 (m, 2H), 4.13 (t, J = 8.0 Hz, 2H), 3.60 (s, 3H), 2.60 (s, 3H). LC-MS (M+H) + = 563.3.

[0238] Example 44: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(hydroxymethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: tert-Butyl (5-(4-(hydroxymethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (840 mg, 52%) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and (4-(hydroxymethyl)phenyl)boronic acid in a manner similar to step 5 of example 1. LC-MS (M+H) + = 358.1.

[0239] Step 2: tert-Butyl (5-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] tert-Butyl (5-(4-(hydroxymethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (840 mg, 2.35 mmol) and Et 3 To a solution of N (475 mg, 4.7 mmol) in THF (50 mL) at 0° C. was added tert-butyldimethylsilyl chloride (711 mg, 4.7 mmol). The reaction solution was stirred at room temperature for 14 h and then diluted with ethyl acetate (90 mL). The solution was washed with water, brine, and then Na 2 SO 4 The mixture was dried at 70° C., filtered and evaporated. The residue was purified on silica gel by Combiflash eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound (300 mg, 27%). 1H-NMR (400 MHz, d6-DMSO) δ 11.97 (s, 1H), 8.09 (dd, J = 8.4, 2.1 Hz, 3H), 8.01 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 4.78 (s, 2H), 1.53 (s, 10H), 0.92 (s, 10H), 0.10 (s, 6H). LC-MS (M+H) + = 472.2.

[0240] Step 3: 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)thiazolo[5,4-b]pyridin-2-amine [ka] To a solution of tert-butyl (5-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (300 mg, 0.64 mmol) in dichloromethane (30 mL) was added zinc chloride (1.43 g, 6.4 mmol) and the resulting mixture was stirred at room temperature for 14 h and then diluted with dichloromethane. The reaction solution was washed with water and brine, then dried over sodium sulfate, filtered and evaporated to give the crude product (150 mg, 63%). LC-MS (M+H) + = 372.2.

[0241] Step 4: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(hydroxymethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (10 mg, 10%) was prepared from 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)thiazolo[5,4-b]pyridin-2-amine and 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid in a manner similar to step 3 of example 25. 1H-NMR (400 MHz, d6-DMSO) δ 12.94 (s, 1H), 8.82 (s, 1H), 8.17 - 7.99 (m, 4H), 7.98 - 7.78 (m, 2H), 7.61 - 7.29 (m, 3H), 7.18 (d, J = 8.6 Hz, 1H), 5.26 (s, 1H), 4.57 (s, 2H), 3.60 (s, 3H), 2.59 (s, 3H). LC-MS (M+H) + = 508.3.

[0242] Example 45: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: tert-Butyl (5-(4-(4-chlorobutanamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (370 mg, 83%) was prepared from tert-butyl (5-(4-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate and 4-chlorobutanoyl chloride in a similar manner to step 1 of example 43. LC-MS (M+H) + = 447.1 Step 2: tert-Butyl (5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (crude) was prepared from tert-butyl (5-(4-(4-chlorobutanamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 2 of Example 43. LC-MS (M+H) + = 411.1.

[0243] Step 3: 1-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)pyrrolidin-2-one [ka] The title compound (210 mg, 81% for 2 steps) was prepared from tert-butyl (5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 311.1.

[0244] Step 4: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (36 mg, 20%) was prepared from 1-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)pyrrolidin-2-one and 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 12.94 (s, 1H), 8.81 (s, 1H), 8.21 - 8.09 (m, 3H), 8.05 (d, J = 8.6 Hz, 1H), 7.91 (dd, J = 10.7, 2.0 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.18 (d, J = 8.5 Hz, 1H), 3.90 (t, J = 7.0 Hz, 2H), 3.60 (s, 3H), 2.60 (s, 3H), 2.54 (t, J = 7.0 Hz, 2H), 2.18 - 1.95 (m, 2H) LC-MS (M+H) + = 561.3.

[0245] Example 46: 5-((5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamoyl)-4-(2-methoxyphenyl)picolinic acid [ka] To a solution of N-(5-(4-acetamidophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-cyano-4-(2-methoxyphenyl)nicotinamide (24 mg, 0.046 mmol) in EtOH (2 mL) was added aqueous NaOH (10%, 2 mL). The mixture was stirred under nitrogen at 90° C. for 2 h. The reaction mixture was concentrated in vacuo. THF (2 mL) was added followed by acetyl chloride (36 mg, 0.46 mmol). The resulting mixture was stirred at room temperature for 18 h after which water was added. Then 2N HCl solution was added until pH=3. The aqueous layer was separated from the organic layer and extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel by CombiFlash, eluting with methanol in dichloromethane (10%, v / v) to give the title compound (9.7 mg, 39%). 1 H-NMR (400 MHz, d6-DMSO) δ: 13.12 (s, 1H), 10.12 (s, 1H), 8.98 (s, 1H), 8.17 (d, J = 8.6 Hz, 1H), 8.12 - 7.99 (m, 4H), 7.72 (d, J = 8.7 Hz, 2H), 7.46 (dd, J = 13.1, 7.0 Hz, 2H), 7.13 (t, J = 7.3 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 3.55 (s, 3H), 2.08 (s, 3H). LC-MS (M+H) + = 540.3.

[0246] Example 47: N-(5-(1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-amine [ka] To a stirred mixture of 5-bromothiazolo[5,4-b]pyridin-2-amine (475 mg, 2.064 mmol) and 1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1149 mg, 4.128 mmol) in toluene (10 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (404 mg, 0.619 mmol) and K 3 PO 4 (2191 mg, 10.320 mmol) was added at room temperature. The reaction mixture was irradiated in a microwave at 100° C. for 2 h, then cooled to room temperature and concentrated. The residue was purified on silica gel by Combiflash (eluted with methanol in dichloromethane (7%, v / v)) to give the title compound (194 mg, 31%). LC-MS (M+H) + = 302.2.

[0247] Step 2: 5-(2-Methoxyphenyl)-N-(5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide [ka] The title compound (28 mg, 17%) was prepared from 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-amine and 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid in a manner similar to step 2 of example 4. LC-MS (M+H) + =514.3.

[0248] Step 3: N-(5-(1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide To 5-(2-methoxyphenyl)-N-(5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide (28 mg, 0.055 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) under nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h and then saturated NaHCO 3 The residue was purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD column, 30×150 mm, 5 um; Mobile phase: Acetonitrile in water (10 mmol / L NH 4 HCO 3 and 0.1% NH 4 OH), gradient 8% to 36% in 9 min; detector: UV 254 nm. Obtained the title compound (2 mg, 10%). 1H NMR (300 MHz, d6-DMSO) δ 13.05 (brs, 1H), 9.47 (s, 1H), 9.32 (s, 1H), 8.05-7.99 (m, 2H), 7.88-7.62 (brs,1H), 7.52-7.40 (m, 2H), 7.17-7.02 (m, 2H), 6.90-6.83 (m, 1H), 3.58 (s, 3H). LC-MS (M+H) + = 429.9.

[0249] Example 48: 5-(2-Methoxyphenyl)-N-(5-(4-(methylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide [ka] Step 1: tert-Butyl (5-(4-(methylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] To a mixture of tert-butyl (5-(4-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (50 mg, 0.15 mmol) in dichloromethane (5 mL) was added N,N-diisopropylethylamine (100 mg, 0.77 mmol) and methanesulfonic anhydride (50 mg, 0.3 mmol). The mixture was stirred at room temperature for 14 h and then diluted with water. The mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified on silica gel by preparative TLC using ethyl acetate in petroleum ether (50%, v / v) as eluent to give the title compound (50 mg, 79%). LC-MS (M+H) + = 421.1.

[0250] Step 2: N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)methanesulfonamide [ka] The title compound (40 mg, crude) was prepared from tert-butyl (5-(4-(methylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a manner similar to that described in step 6 of Example 1. LC-MS (M+H) + = 321.1.

[0251] Step 3: 5-(2-Methoxyphenyl)-N-(5-(4-(methylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide The title compound (10 mg, 9%) was prepared from 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)methanesulfonamide in a manner similar to that described in step 3 of example 25. 1 H NMR (400 MHz, d6-DMSO) δ 13.25 (brs, 1H), 9.99 (s, 1H), 9.49 (s, 1H), 9.42 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.6 Hz, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.58 - 7.44 (m, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.18 - 7.12 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 3.56 (s, 3H), 3.06 (s, 3H). LC-MS (M+H) + = 533.2.

[0252] Example 49: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2,5-dimethoxyphenyl)-6-methylnicotinamide [ka] Step 1: Methyl 4-(2,5-dimethoxyphenyl)-6-methylnicotinate [ka] The title compound (50 mg, 31%) was prepared from methyl 4-chloro-6-methylnicotinate and (2,5-dimethoxyphenyl)boronic acid in a manner similar to step 2 of example 2. LC-MS (M+H) + = 288.2.

[0253] Step 2: 4-(2,5-dimethoxyphenyl)-6-methylnicotinic acid [ka] The title compound (50 mg, 31%) was prepared from methyl 4-(2,5-dimethoxyphenyl)-6-methylnicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 274.2.

[0254] Step 3: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2,5-dimethoxyphenyl)-6-methylnicotinamide The title compound (35 mg, 19%) was prepared from 4-(2,5-dimethoxyphenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 12.99 (s, 1H), 8.74 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.26 - 8.17 (m, 2H), 7.98 (s, 1H), 7.96 (s, 1H), 7.38 (s, 1H), 7.02 - 6.94 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 3.78 (s, 3H), 3.46 (s, 3H), 2.59 (s, 3H).LC-MS (M+H) + = 508.2.

[0255] Example 50: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-isobutyramidophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: tert-Butyl (5-(4-isobutylamidophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (400 mg, 96%) was prepared from tert-butyl (5-(4-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 2 of example 5. LC-MS (M+H) + = 413.1.

[0256] Step 2: N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)isobutyramide [ka] The title compound (250 mg, 82.6%) was prepared from tert-butyl (5-(4-isobutylamidophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 313.1.

[0257] Step 3: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-isobutyramidophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (62 mg, 34%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)isobutyramide in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 12.94 (s, 1H), 9.99 (s, 1H), 8.81 (s, 1H), 8.18 - 7.98 (m, 4H), 7.91 (dd, J = 10.6, 2.0 Hz, 2H), 7.75 (d, J = LC-MS (M+H) + = 563.3.

[0258] Example 51: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-isobutyramido-3-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: tert-Butyl (5-(4-amino-3-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (105 mg, 70%) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and (4-amino-3-methylphenyl)boronic acid in a similar manner to step 5 of example 1. LC-MS (M+H) + = 357.1.

[0259] Step 2: tert-Butyl (5-(4-isobutylamido-3-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (200 mg, 41%) was prepared from tert-butyl (5-(4-amino-3-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 2 of example 5. LC-MS (M+H) + = 427.2.

[0260] Step 3: N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)-2-methylphenyl)isobutyramide [ka] The title compound (110 mg, 71%) was prepared from tert-butyl (5-(4-isobutylamido-3-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 327.1.

[0261] Step 4: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-isobutyramido-3-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (30 mg, 15%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)-2-methylphenyl)isobutyramide in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 12.94 (s, 1H), 9.25 (s, 1H), 8.81 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7.96 - 7.85 (m, 3H), 7.55 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.18 (d, J = 8.5 Hz, 1H), 3.60 (s, 3H), 2.71 (dt, J = 13.6, 6.8 Hz, 1H), 2.60 (s, 3H), 2.30 (s, 3H), 1.15 (d, J = 6.9 Hz, 6H). LC-MS (M+H) + = 577.4.

[0262] Example 52: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxy-5-(methylsulfonyl)phenyl)-6-methylnicotinamide [ka] Step 1: 2-Bromo-4-(methylsulfonyl)phenol [ka] To a solution of 4-(methylsulfonyl)phenol (2.4 g, 13.94 mmol) in dichloromethane (14 mL) and methanol (14 mL) was added tetrabutylammonium tribromide (4.94 g, 15.33 mmol) and the solution was stirred at room temperature for 18 h. Most of the solvent was removed under reduced pressure, ethyl acetate was added and the resulting mixture was washed with water, saturated Na 2 SO 3 The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (3.85 g, crude). LC-MS (M+H) + = 250.9, 253.0.

[0263] Step 2: 2-Bromo-1-methoxy-4-(methylsulfonyl)benzene [ka] 2-Bromo-4-(methylsulfonyl)phenol (3.85 g, 15.33 mmol) and Cs 2 CO 3 To a mixture of (7.5 g, 23 mmol) in N,N-dimethylformamide (40 mL) was added iodomethane (2.4 g, 16.9 mmol). The reaction mixture was stirred under nitrogen at 25° C. for 18 h and then diluted with ethyl acetate (50 mL). The organic solution was washed with water and brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel by CombiFlash eluting with ethyl acetate in petroleum ether (33%, v / v) to give the title compound (2 g, 49%). LC-MS (M+H) + =265.1, 267.1.

[0264] Step 3: 2-(2-Methoxy-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] The title compound (800 mg, 68%) was prepared from 2-bromo-1-methoxy-4-(methylsulfonyl)benzene in a similar manner to step 2 of Example 28. LC-MS (M+H) + =313.1.

[0265] Step 4: Methyl 4-(2-methoxy-5-(methylsulfonyl)phenyl)-6-methylnicotinate [ka] The title compound (380 mg, 99%) was prepared from methyl 4-chloro-6-methylnicotinate and 2-(2-methoxy-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to step 2 of example 2. LC-MS (M+H) + =336.1.

[0266] Step 5: 4-(2-Methoxy-5-(methylsulfonyl)phenyl)-6-methylnicotinic acid [ka] The title compound (190 mg, 52%) was prepared from methyl 4-(2-methoxy-5-(methylsulfonyl)phenyl)-6-methylnicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 322.0.

[0267] Step 6: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxy-5-(methylsulfonyl)phenyl)-6-methylnicotinamide The title compound (4.7 mg, 5%) was prepared from 4-(2-methoxy-5-(methylsulfonyl)phenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1H-NMR (400 MHz, d6-DMSO) δ: 13.13 (s, 1H), 8.81 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.24 (q, J = 8.6 Hz, 2H), 8.01 - 7.91 (m, 4H), 7.49 (s, 1H), 7.24 (d, J = 8.7 Hz, 1H), 3.62 (s, 3H), 3.27 (s, 3H), 2.63 (s, 3H). LC-MS (M+H) + = 556.3.

[0268] Example 53: 4-(2-cyanophenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: Methyl 4-(2-cyanophenyl)-6-methylnicotinate [ka] The title compound (250 mg, 37%) was prepared from methyl 4-chloro-6-methylnicotinate and (2-cyanophenyl)boronic acid in a manner similar to step 2 of example 2. LC-MS (M+H) + = 253.1.

[0269] Step 2: 4-(2-cyanophenyl)-6-methylnicotinic acid [ka] The title compound (200 mg, 85%) was prepared from methyl 4-(2-cyanophenyl)-6-methylnicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 239.1.

[0270] Step 3: 4-(2-cyanophenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (20 mg, 18%) was prepared from 4-(2-cyanophenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1 H-NMR (400 MHz, d6-DMSO) δ 13.39 (s, 1H), 9.03 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.28 - 8.17 (m, 2H), 8.02 - 7.91 (m, 3H), 7.79 (t, J = 7.1 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.57 - 7.44 (m, 2H), 2.64 (s, 3H). LC-MS (M+H) + = 473.2.

[0271] Example 54: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-1,6'-dimethyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-3'-carboxamide [ka] Step 1: Methyl 1,6'-dimethyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-3'-carboxylate [ka] To a solution of methyl 4-chloro-6-methylnicotinate (195 mg, 1.06 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (299 mg, 1.27 mmol) in dioxane (10 mL) and water (2 mL) was added Pd(PPh 3 ) 4 (122 mg, 0.106 mmol) and K 2 CO 3(294 mg, 2.12 mmol) was added. The mixture was stirred under nitrogen at 80° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel by Combiflash, eluting with ethyl acetate in petroleum ether (20%, v / v) to give the title compound (230 mg, 84%). LC-MS (M+H) + =259.0.

[0272] Step 2: 1,6'-Dimethyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-3'-carboxylic acid [ka] The title compound (134 mg, 61%) was prepared from methyl 1,6'-dimethyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-3'-carboxylate in a manner similar to step 3 of example 1. LC-MS (M+H) + = 245.0.

[0273] Step 3: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-1,6'-dimethyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-3'-carboxamide The title compound (4.5 mg, 6%) was prepared from 1,6'-dimethyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-3'-carboxylic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1H-NMR (400 MHz, d6-DMSO) δ: 13.15 (s, 1H), 8.76 (s, 1H), 8.36 (d, J = 8.5 Hz, 2H), 8.28 - 8.18 (m, 2H), 8.03 (d, J = 2.6 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.45 (s, 1H), 7.37 (dd, J = 9.4, 2.7 Hz, 1H), 6.39 (d, J = 9.4 Hz, 1H), 3.48 (s, 3H), 2.58 (s, 3H). LC-MS (M+H) + = 479.2.

[0274] Example 55: N-(5-(5-chloropyridin-2-yl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: 5-(5-chloropyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine [ka] To a stirred solution of 5-bromothiazolo[5,4-b]pyridin-2-amine (196 mg, 0.597 mmol) in N,N-dimethylformamide (6 mL) was added 5-chloro-2-(tributylstannyl)pyridine (240 mg, 0.597 mmol) and bis(triphenylphosphine)palladium(II) dichloride (42 mg, 0.060 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110° C. under nitrogen atmosphere for 18 hours, then cooled to room temperature and quenched by the addition of water (40 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with brine and diluted with Na 2 SO 4 The mixture was dried at 70° C., then filtered and concentrated. The residue was purified on silica gel by CombiFlash (eluted with ethyl acetate in petroleum ether (0% to 25%, v / v)) to give the title compound (92 mg, 58%). LC-MS (M+H)+ = 263.0.

[0275] Step 2: N-(5-(5-chloropyridin-2-yl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide The title compound (3 mg, 2%) was prepared from 5-(5-chloropyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine and 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid in a similar manner to step 7 of example 1. 1H NMR (300 MHz, d6-DMSO) δ 13.36 (brs, 1H), 9.50 (d, J = 1.1 Hz, 1H), 9.37 (s, 1H), 8.77-8.70 (m, 1H), 8.49-8.39 (m, 2H), 8.22-8.01 (m, 2H), 7.56-7.42 (m, 2H), 7.19-7.02 (m, 2H), 3.57 (s, 3H). LC-MS (M+H) + = 475.0.

[0276] Example 56: 5-(2-Methoxyphenyl)-N-(5-(4-(N-methylacetamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide [ka] Step 1: N-Methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [ka] To a solution of N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (500 mg, 1.915 mmol) in THF (7 mL) was added NaH (114 mg, 2.873 mmol, 60%) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 15 min under nitrogen atmosphere, after which iodomethane (2175 mg, 15.320 mmol) was added. The resulting mixture was stirred at room temperature for an additional 10 h, after which it was quenched by the addition of water (20 mL). The resulting mixture was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine and Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated. The residue was purified on silica gel by CombiFlash (eluted with ethyl acetate in petroleum ether (0%→50%, v / v)) to give the title compound (284 mg, 53%). LC-MS (M+H) + = 276.1.

[0277] Step 2: N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)-N-methylacetamide [ka] The title compound (166 mg, 93%) was prepared from N-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide and 5-bromothiazolo[5,4-b]pyridin-2-amine in a manner similar to step 5 of example 1. LC-MS (M+H) + =299.2.

[0278] Step 3: 5-(2-Methoxyphenyl)-N-(5-(4-(N-methylacetamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide The title compound (15 mg, 13%) was prepared from N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)-N-methylacetamide and 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid in a similar manner to step 2 of example 4. 1H NMR (300 MHz, d6-DMSO) δ 13.32 (brs, 1H), 9.51 (s, 1H), 9.42 (s, 1H), 8.26-8.06 (m, 4H), 7.63-7.39 (m, 4H), 7.21-7.04 (m, 2H), 3.57 (s, 3H), 3.22 (s, 3H), 1.88 (s, 3H). LC-MS (M+H) + = 511.0.

[0279] Example 57: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyclopropyl-2-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: 4-Bromo-2-chloro-1-methoxybenzene [ka] NaH (500 mg, 12.7 mmol) was added to a solution of 4-bromo-2-chlorophenol (1.8 g, 8.7 mmol) in N,N-dimethylformamide (20 mL) at 0° C. The mixture was stirred at room temperature for 30 min, then iodomethane (1.8 g, 12.7 mmol) was added. The reaction mixture was stirred at room temperature for 14 h, then quenched with water (50 mL). The mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL) and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo The residue was purified on silica gel by CombiFlash (eluting with petroleum ether) to give the title compound (1.6 g, 83%). 1H-NMR (400 MHz, d6-DMSO) δ 7.66 (d, J = 2.5 Hz, 1H), 7.50 (dd, J = 8.8, 2.4 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 3.85 (s, 3H).

[0280] Step 2: 2-Chloro-4-cyclopropyl-1-methoxybenzene [ka] A mixture of 4-bromo-2-chloro-1-methoxybenzene (3.1 g, 14 mmol) and cyclopropylboronic acid (1.8 g, 21 mmol) in toluene (80 mL) and water (15 mL) was added with K 3 PO 4 (8.9 g, 42 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (600 mg, 0.7 mmol) were added. The mixture was stirred at 100° C. under nitrogen for 14 h, then cooled to room temperature and diluted with water (20 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo The residue was purified on silica gel by CombiFlash (eluting with petroleum ether) to give the title compound (1.8 g, 70%). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.08 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.5, 2.2 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 1.87 - 1.78 (m, 1H), 0.95 - 0.88 (m, 2H), 0.65 - 0.58 (m, 2H).

[0281] Step 3: 2-(5-cyclopropyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 2-chloro-4-cyclopropyl-1-methoxybenzene (1.8 g, 10 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.8 g, 15 mmol) in dioxane (30 mL) was added KOAc (2.9 g, 30 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (390 mg, 0.5 mmol). The mixture was stirred at 80° C. under nitrogen for 14 h, then cooled to room temperature and diluted with water (20 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified on silica gel by CombiFlash (eluted with petroleum ether) to give the title compound (0.5 g, 18%). LC-MS (M+H) + = 275.2.

[0282] Step 4: Methyl 4-(5-cyclopropyl-2-methoxyphenyl)-6-methylnicotinate [ka] The title compound (370 mg, 95%) was prepared from 2-(5-cyclopropyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and methyl 4-chloro-6-methylnicotinate in a manner similar to step 2 of example 2. LC-MS (M+H) + = 298.2.

[0283] Step 5: 4-(5-cyclopropyl-2-methoxyphenyl)-6-methylnicotinic acid [ka] The title compound (200 mg, 70%) was prepared from methyl 4-(5-cyclopropyl-2-methoxyphenyl)-6-methylnicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 284.2.

[0284] Step 6: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyclopropyl-2-methoxyphenyl)-6-methylnicotinamide The title compound (15 mg, 14%) was prepared from 4-(5-cyclopropyl-2-methoxyphenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1 H-NMR (400 MHz, d6-DMSO) δ 12.98 (s, 1H), 8.72 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.26 - 8.18 (m, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.35 (s, 1H), 7.12 - 7.07 (m, 2H), 6.86 (d, J = 9.1 Hz, 1H), 3.47 (s, 3H), 2.59 (s, 3H), 1.99 - 1.90 (m, 1H), 0.98 - 0.88 (m, 2H), 0.74 - 0.64 (m, 2H). LC-MS (M+H) + = 518.3.

[0285] Example 58: 6-chloro-4-(5-cyano-2-methoxyphenyl)-N-(5-(4-morpholinophenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: tert-Butyl (5-(4-morpholinophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] tert-Butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate (0.66 g, 2 mmol), (4-morpholinophenyl)boronic acid (0.5 g, 2.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.16 g, 0.2 mmol), and K 2 CO 3 A reaction mixture of (0.69 g, 5 mmol) in dioxane (7 mL) was stirred at 100° C. under nitrogen for 14 h and then cooled to room temperature. The mixture was filtered and the filtrate was evaporated. The residue was purified on silica gel by Combiflash (eluted with ethyl acetate in petroleum ether (50%, v / v)) to give the title compound (0.5 g, 61%). LC-MS (M+H) + = 413.2.

[0286] Step 2: 5-(4-morpholinophenyl)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (260 mg, 63%) was prepared from tert-butyl (5-(4-morpholinophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a manner similar to Example 1, Step 6.

[0287] Step 3: 6-chloro-4-(5-cyano-2-methoxyphenyl)-N-(5-(4-morpholinophenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (20 mg, 15.6%) was prepared from 6-chloro-4-(5-cyano-2-methoxyphenyl)nicotinic acid and 5-(4-morpholinophenyl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to step 3 of example 11. 1H-NMR (400 MHz, d6-DMSO) δ 13.06 (s, 1H), 8.79 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 - 7.93 (m, 5H), 7.76 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 3.76 (t, J = 4.6 Hz, 4H), 3.61 (s, 3H), 3.21 (t, J = 4.8 Hz, 4H). LC-MS (M+H) + = 583.3.

[0288] Example 59: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-morpholinophenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] The title compound (25 mg, 17%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 5-(4-morpholinophenyl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to step 3 of example 11. 1 H-NMR (400 MHz, d6-DMSO) δ 12.89 (s, 1H), 8.80 (s, 1H), 8.07 - 7.90 (m, 6H), 7.42 (s, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 3.76 (t, J = 4.6 Hz, 4H), 3.60 (s, 3H), 3.21 (t, J = 4.6 Hz, 4H), 2.60 (s, 3H). LC-MS (M+H) + = 563.3.

[0289] Example 60: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-morpholinothiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: tert-Butyl (5-morpholinothiazolo[5,4-b]pyridin-2-yl)carbamate [ka] A reaction mixture of tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate (0.33 g, 1 mmol), morpholine (0.13 g, 1.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (92 mg, 0.1 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (116 mg, 0.2 mmol), and sodium tert-butoxide (190 mg, 2 mmol) in toluene / t-BuOH (3 mL, v / v 2 / 1) was stirred at 100° C. for 14 h under nitrogen atmosphere and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified on silica gel by CombiFlash eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound (0.13 g, 39%). LC-MS (M+H) + = 337.2.

[0290] Step 2: 5-Morpholinothiazolo[5,4-b]pyridin-2-amine [ka] The title compound (130 mg, crude) was prepared from tert-butyl (5-morpholinothiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 237.2.

[0291] Step 3: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-morpholinothiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (3 mg, 3.1%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 5-morpholinothiazolo[5,4-b]pyridin-2-amine in a manner similar to step 3 of example 11. 1H-NMR (400 MHz, d6-DMSO) δ 12.63 (s, 1H), 8.75 (s, 1H), 7.92 - 7.85 (m, 3H), 7.40 (s, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 9.1 Hz, 1H), 3.72 (t, J = 4.6 Hz, 4H), 3.58 (s, 3H), 3.47 (t, J = 4.6 Hz, 4H), 2.58 (s, 3H). LC-MS (M+H) + = 487.3.

[0292] Example 61: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(1H-indazol-4-yl)-6-methylnicotinamide [ka] Step 1: 4-chloro-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] The title compound (210 mg, 65%) was prepared from 4-chloro-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 4 of example 2. LC-MS (M+H) + = 406.0.

[0293] Step 2: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(1H-indazol-4-yl)-6-methylnicotinamide The title compound (16 mg, 22%) was prepared from 4-chloro-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide and (1H-indazol-4-yl)boronic acid in a manner similar to step 2 of example 2. 1H-NMR (400 MHz, d6-DMSO) δ: 13.23 (s, 1H), 13.17 (s, 1H), 8.87 (s, 1H), 8.32 (d, J = 8.4 Hz, 2H), 8.19 (s, 2H), 7.96 (d, J = 8.4 Hz, 3H), 7.61 - 7.53 (m, 2H), 7.44 - 7.36 (m, 1H), 7.11 (d, J = 7.0 Hz, 1H), 2.64 (s, 3H). LC-MS (M+H) + = 488.2.

[0294] Example 62: N-(5-(4-chlorophenethyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: tert-Butyl (5-((4-chlorophenyl)ethynyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] A solution of tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate (605 mg, 1.830 mmol) and 1-chloro-4-ethynylbenzene (250 mg, 1.830 mmol) in acetonitrile (16 mL) and methanol (8 mL) was treated with N,N-diisopropylethylamine (525 mg, 4.063 mmol), triphenylphosphine (105 mg, 0.403 mmol), CuI (38 mg, 0.201 mmol), and Pd(OAc) 2 (45 mg, 0.201 mmol) was added at room temperature. The resulting mixture was stirred at 80° C. for 16 h under nitrogen atmosphere and then cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with dichloromethane (3×10 mL). The filtrate was concentrated under reduced pressure and the residue was purified on silica gel by Combiflash (eluted with ethyl acetate in petroleum ether (0%→50%, v / v)) to give the title compound (268 mg, 38%). LC-MS (M+H)+ = 386.0.

[0295] Step 2: tert-Butyl (5-(4-chlorophenethyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] To a solution of tert-butyl (5-((4-chlorophenyl)ethynyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (270 mg, 0.7 mmol) in methanol (2 mL) was added 10 wt.% Pd / C (0.15 g, 0.14 mmol) under nitrogen atmosphere. The mixture was hydrogenated under hydrogen atmosphere at room temperature for 2 h using a hydrogen balloon. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel by Combiflash (eluted with ethyl acetate in petroleum ether (0%→50%, v / v)) to give the title compound (254 mg, 93%). LC-MS (M+H) + =390.0.

[0296] Step 3: 5-(4-chlorophenethyl)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (105 mg, 55%) was prepared from tert-butyl (5-(4-chlorophenethyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + =290.0.

[0297] Step 4: N-(5-(4-chlorophenethyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide The title compound (8 mg, 19%) was prepared in a similar manner to Example 4, Step 2 from 5-(4-chlorophenethyl)thiazolo[5,4-b]pyridin-2-amine and 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid. 1H NMR (400 MHz, d6-DMSO) δ 13.18 (brs, 1H), 9.47 (s, 1H), 9.40 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.55-7.44 (m, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.34-7.24 (m, 4H), 7.18-7.01 (m, 2H), 3.55 (s, 3H), 3.18-3.09 (m, 2H), 3.09-2.99 (m, 2H). LC-MS (M+H) + = 502.0.

[0298] Example 63: N-(5-((4-chlorophenyl)ethynyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: 5-((4-chlorophenyl)ethynyl)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (166 mg, 92%) was prepared from tert-butyl (5-((4-chlorophenyl)ethynyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + =285.9.

[0299] Step 2: N-(5-((4-chlorophenyl)ethynyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide The title compound (21 mg, 16%) was prepared from 5-((4-chlorophenyl)ethynyl)thiazolo[5,4-b]pyridin-2-amine and 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid in a manner similar to step 7 of example 1. 1H NMR (300 MHz, d6-DMSO) δ 13.42 (brs, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.73-7.62 (m, 2H), 7.60-7.44 (m, 4H), 7.21-7.02 (m, 2H), 3.56 (s, 3H). LC-MS (M+H) + = 498.0.

[0300] Example 64: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-(hydroxymethyl)phenyl)-6-methylnicotinamide [ka] Step 1: 2-((2-bromobenzyl)oxy)tetrahydro-2H-pyran [ka] 4-Methylbenzenesulfonic acid (78 mg, 0.41 mmol) was added to a solution of (2-bromophenyl)methanol (1.54 g, 8.2 mmol) and 3,4-dihydro-2H-pyran (827 mg, 9.85 mmol) in dichloromethane (50 mL). The resulting solution was stirred at room temperature for 14 hours. The reaction solution was washed with water (10 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by preparative TLC using ethyl acetate (17%) in petroleum ether as eluent to give the title compound (2.22 g, 99%).

[0301] Step 2: 4,4,5,5-Tetramethyl-2-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-1,3,2-dioxaborolane [ka] The title compound (2.06 g, 79%) was prepared from 2-((2-bromobenzyl)oxy)tetrahydro-2H-pyran in a manner similar to Example 28, Step 2.

[0302] Step 3: Methyl 6-methyl-4-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)nicotinate [ka] The title compound (123 mg, 27%) was prepared from methyl 4-chloro-6-methylnicotinate and 4,4,5,5-tetramethyl-2-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-1,3,2-dioxaborolane in a manner similar to step 2 of example 2. LC-MS (M+H) + = 342.3.

[0303] Step 4: 6-Methyl-4-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)nicotinic acid [ka] The title compound (100 mg, 85%) was prepared from methyl 6-methyl-4-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)nicotinate in a manner similar to step 3 of example 1. LC-MS (M+H) + = 328.1.

[0304] Step 5: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methyl-4-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)nicotinamide [ka] The title compound (62 mg, 36%) was prepared from 6-methyl-4-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)nicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to that described in step 3 of Example 11. LC-MS (M+H) + = 562.2.

[0305] Step 6: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-(hydroxymethyl)phenyl)-6-methylnicotinamide To a solution of N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methyl-4-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)nicotinamide (62 mg, 0.11 mmol) in methanol (5 mL) and dichloromethane (5 mL) was added 4-methylbenzenesulfonic acid (2.1 mg, 0.01 mmol). The resulting solution was stirred at room temperature for 14 h and then washed with water (5 mL). The aqueous layer was extracted with dichloromethane (3×5 mL). The combined dichloromethane layers were dried, filtered and concentrated. The residue was purified by preparative TLC using methanol in dichloromethane (5%, v / v) to give the title compound (40 mg, 75%). 1 H-NMR (400 MHz, d6-DMSO) δ 12.90 (s, 1H), 8.84 (s, 1H), 8.33 (d, J = 8.3 Hz, 2H), 8.27 - 8.15 (m, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.33 (s, 1H), 7.28 (t, J = 7.3 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 5.43 (s, 1H), 4.39 (s, 2H), 2.59 (s, 3H). LC-MS (M+H) + = 478.4.

[0306] Example 65: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(2-morpholinoethoxy)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: tert-Butyl (5-(2-morpholinoethoxy)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] To a solution of 2-morpholinoethan-1-ol (330 mg, 1 mmol) in anhydrous N,N-dimethylformamide (50 mL) was added NaH (88 mg, 60%, 2.2 mmol) slowly at 0° C., followed by tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate. The resulting mixture was stirred at 100° C. for 16 h, then cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated. The residue was purified on silica gel by CombiFlash eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound (50 mg, 13%). LC-MS (M+H) + = 381.1.

[0307] Step 2: 5-(2-morpholinoethoxy)thiazolo[5,4-b]pyridin-2-amine [ka] To a reaction solution of tert-butyl (5-(2-morpholinoethoxy)thiazolo[5,4-b]pyridin-2-yl)carbamate (50 mg, 0.13 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL), and the reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in saturated NaHCO 3Worked up with aqueous solution. The precipitate was filtered, washed with water and dried to give the title compound (36 mg, crude), which was used directly in the next step without further purification. LC-MS (M+H) + = 281.1.

[0308] Step 3: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(2-morpholinoethoxy)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (1.5 mg, 2%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 5-(2-morpholinoethoxy)thiazolo[5,4-b]pyridin-2-amine in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 8.74 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.81 - 7.78 (m, 2H), 7.42 (s, 1H), 7.12 (d, J = 9.3 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 4.52 (t, J = 5.6 Hz, 2H), 3.75 - 3.69 (m, 4H), 3.67 (s, 3H), 2.84 (t, J = 5.6 Hz, 2H), 2.67 (s, 3H), 2.65 - 2.57 (m, 4H).LC-MS (M+H) + = 531.1.

[0309] Example 66: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxy-5-(methoxymethyl)phenyl)-6-methylnicotinamide [ka] The title compound (11 mg, 7%) was prepared from 4-(2-methoxy-5-(methoxymethyl)phenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 25. 1H-NMR (400 MHz, d6-DMSO) δ 13.03 (s, 1H), 8.74 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.27 - 8.18 (m, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.35 - 7.34 (m, 3H), 6.96 (d, J = 9.0 Hz, 1H), 4.42 (s, 2H), 3.51 (s, 3H), 3.30 (s, 3H), 2.59 (s, 3H). LC-MS (M+H) + = 522.2.

[0310] Example 67: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydro-2H-pyran-4-yl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: tert-Butyl (5-(3,6-dihydro-2H-pyran-4-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (200 mg, 79%) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to step 2 of example 2. LC-MS (M+H) + = 334.1.

[0311] Step 2: tert-Butyl (5-(tetrahydro-2H-pyran-4-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] To a mixture of tert-butyl (5-(3,6-dihydro-2H-pyran-4-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate (200 mg, 0.6 mmol) in EtOH (60 mL) was added 10 wt.% Pd / C (360 mg). The mixture was stirred at room temperature under 1 atm of hydrogen for 18 h. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel by Combiflash (eluted with methanol in dichloromethane (5%, v / v)) to give the title compound (125 mg, 62%). LC-MS (M+H) + = 336.2.

[0312] Step 3: 5-(tetrahydro-2H-pyran-4-yl)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (110 mg, crude) was prepared from tert-butyl (5-(tetrahydro-2H-pyran-4-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 236.1.

[0313] Step 4: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydro-2H-pyran-4-yl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (32 mg, 38%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid (55 mg, 0.2 mmol) and 5-(tetrahydro-2H-pyran-4-yl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to step 3 of example 25. 1H-NMR (400 MHz, d6-DMSO) δ: 12.86 (s, 1H), 8.78 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.93 - 7.85 (m, 2H), 7.41 (d, J = 8.9 Hz, 2H), 7.17 (d, J = 8.5 Hz, 1H), 3.99-3.55 (m, 2H), 3.58 (s, 3H), 3.52 - 3.41 (m, 2H), 3.09-3.01 (m, 1H), 2.59 (s, 3H), 1.83-1.77 (m, 4H).LC-MS (M+H) + = 486.1.

[0314] Example 68: 4-(benzo[d][1,3]dioxol-4-yl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: 2-(benzo[d][1,3]dioxol-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] The title compound (410 mg, 83%) was prepared from 4-bromobenzo[d][1,3]dioxole in a similar manner to step 2 of example 28. LC-MS (M+H) + = 249.1.

[0315] Step 2: Methyl 4-(benzo[d][1,3]dioxol-4-yl)-6-methylnicotinate [ka] The title compound (352 mg, 81%) was prepared from 2-(benzo[d][1,3]dioxol-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and methyl 4-chloro-6-methylnicotinate in a manner similar to step 2 of example 2. LC-MS (M+H)+ = 272.1.

[0316] Step 3: 4-(benzo[d][1,3]dioxol-4-yl)-6-methylnicotinic acid [ka] The title compound (206 mg, 90%) was prepared from methyl 4-(benzo[d][1,3]dioxol-4-yl)-6-methylnicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 258.1.

[0317] Step 4: 4-(benzo[d][1,3]dioxol-4-yl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (2.5 mg, 2.5%) was prepared from 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile and 4-(benzo[d][1,3]dioxol-4-yl)-6-methylnicotinic acid in a manner similar to step 3 of example 11. 1 H-NMR (400 MHz, d6-DMSO) δ: 13.16 (s, 1H), 8.82 (s, 1H), 8.40 - 8.32 (m, 2H), 8.26 - 8.21 (m, 2H), 8.02 - 7.95 (m, 2H), 7.50 (s, 1H), 7.03 - 6.94 (m, 3H), 5.84 (s, 2H), 2.61 (s, 3H).LC-MS (M+H) + = 492.1.

[0318] Example 69: N-(5-(4-chlorobenzyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: 5-(4-chlorobenzyl)thiazolo[5,4-b]pyridin-2-amine [ka] To a mixture of Zn (825 mg, 12.627 mmol) in THF (5 mL), 3 SiCl (7 uL, 0.066mmol) was added dropwise at room temperature under nitrogen atmosphere. To the above mixture, 1-(bromomethyl)-4-chlorobenzene (1.22g, 5.905mmol) in THF (5mL) was added dropwise over 5 minutes at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 10 minutes. This mixture was added to a solution of tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate (500mg, 1.514mmol) in THF (5mL) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour and then concentrated. The residue was purified on silica gel by Combiflash (eluted with ethyl acetate in petroleum ether (0%→25%, v / v)) to give the title compound (100mg, 23%). LC-MS (M+H) + = 276.0.

[0319] Step 2: 2-Bromo-5-(4-chlorobenzyl)thiazolo[5,4-b]pyridine [ka] 5-(4-chlorobenzyl)thiazolo[5,4-b]pyridin-2-amine (100 mg, 0.362 mmol) and t-BuNO 2 (50 mg, 0.435 mmol) in MeCN (6 ml) was treated with TsOH (75 mg, 0.435 mmol) and CuBr 2 (1 mg, 0.003 mmol) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h and then concentrated. The residue was purified on silica gel by Combiflash (eluted with ethyl acetate in petroleum ether (0%→10%, v / v)) to give the title compound (60 mg, 48%). LC-MS (M+H) + = 388.8.

[0320] Step 3: 5-(2-Methoxyphenyl)pyridazine-4-carboxamide [ka] To a mixture of 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid (291 mg, 1.269 mmol) and HATU (724 mg, 1.903 mmol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (492 mg, 3.807 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. The above mixture was added with NH 4 Cl (102 mg, 1.903 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 16 h and then concentrated. The residue was purified on silica gel by Combiflash (eluted with methanol in dichloromethane (0%→5%, v / v)) to give the title compound (190 mg, 65%). LC-MS (M+H) + = 230.2.

[0321] Step 4: N-(5-(4-chlorobenzyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide A solution of 2-bromo-5-(4-chlorobenzyl)thiazolo[5,4-b]pyridine (30 mg, 0.088 mmol) and 5-(2-methoxyphenyl)pyridazine-4-carboxamide (20 mg, 0.087 mmol) in dioxane (4 mL) was added to Pd 2 (dba) 3 (8 mg, 0.009 mmol), XantPhos (16 mg, 0.026 mmol), and Cs 2 CO 3 (60 mg, 0.174 mmol) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 16 h under nitrogen atmosphere, then cooled to room temperature and concentrated. The residue was purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD column, 30×150 mm, 5 um; Mobile phase: Acetonitrile in water (NH at 10 mmol / L). 4 HCO 3 and 0.1% NH 4OH), gradient 20% to 50% in 8 min; detector: UV 254 nm. Obtained the title compound (8 mg, 19%). 1H NMR (400 MHz, d6-DMSO) δ 13.19 (brs, 1H), 9.47 (s, 1H), 9.41 (s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.56-7.30 (m, 7H), 7.18-7.10 (m, 1H), 7.08-7.01 (m, 1H), 4.20 (s, 2H), 3.34 (s, 3H). LC-MS (M+H) + = 488.0.

[0322] Example 70: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methyl-4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)nicotinamide [ka] Step 1: 8-Bromo-2H-benzo[b][1,4]oxazin-3(4H)-one [ka] A solution of 2-amino-6-bromophenol (2.0 g, 10.7 mmol) in acetonitrile (25 mL) was 2 CO 3 (3.0 g, 21.4 mmol) and 3-chloropropanoyl chloride (2.0 g, 16.1 mmol) were added. The reaction mixture was stirred at 80° C. for 14 h, then cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.5 g, 62%), which was used in the next step without further purification. LC-MS (M+H) + = 227.8.

[0323] Step 2: 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one [ka] The title compound (820 mg, 64%) was prepared from 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one in a similar manner to step 2 of example 28. LC-MS (M+H) + = 276.1.

[0324] Step 3: Methyl 6-methyl-4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)nicotinate [ka] The title compound (360 mg, 66%) was prepared from 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one and methyl 4-chloro-6-methylnicotinate in a manner similar to that described in Example 2, Step 2. LC-MS (M+H) + = 299.1.

[0325] Step 4: 6-Methyl-4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)nicotinic acid [ka] The title compound (160 mg, 83%) was prepared from methyl 6-methyl-4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)nicotinate in a manner similar to that described in step 3 of Example 1. LC-MS (M+H) + = 285.1.

[0326] Step 5: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methyl-4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)nicotinamide The title compound (15 mg, 14%) was prepared from 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile and 6-methyl-4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)nicotinic acid in a manner similar to that described in step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ: 13.18 (s, 1H), 10.80 (s, 1H), 8.81 (s, 1H), 8.38 - 8.30 (m, 2H), 8.29 - 8.19 (m, 2H), 8.01 - 7.92 (m, LC-MS (M+H) + = 519.1.

[0327] Example 71: N-(5-(4-(cyclopropanecarboxamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide [ka] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (910 mg, 4.150 mmol) in dichloromethane (15 mL) was added triethylamine (630 mg, 6.225 mmol) and cyclopropanecarbonyl chloride (475 mg, 4.565 mmol) under nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours and then concentrated. The residue was treated with water (50 mL) and the resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and extracted with Na 2 SO4 The mixture was dried at 70° C., filtered and concentrated. The residue was purified on silica gel by CombiFlash (eluted with ethyl acetate in petroleum ether (0% to 25%, v / v)) to give the title compound (768 mg, 64%). LC-MS (M+H) + = 287.9.

[0328] Step 2: N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)cyclopropanecarboxamide [ka] The title compound (142 mg, 51%) was prepared from N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide and 5-bromothiazolo[5,4-b]pyridin-2-amine in a manner similar to step 5 of example 1. LC-MS (M+H) + =311.0.

[0329] Step 3: N-(5-(4-(cyclopropanecarboxamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide The title compound (12 mg, 21%) was prepared in a similar manner to Example 4, Step 2 from N-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)phenyl)cyclopropanecarboxamide and 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid. 1H NMR (300 MHz, Methanol-d4) δ 13.27 (brs, 1H), 10.66 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 8.12-7.97 (m, 2H), 7.93 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.58-7.44 (m, 2H), 7.23-7.02 (m, 2H), 3.65 (s, 3H), 1.93-1.65 (m, 1H), 1.03-0.83 (m, 4H). LC-MS (M+H) + = 523.0.

[0330] Example 72: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxyphenyl)-6-methylnicotinamide [ka] The title compound (25 mg, 8%) was prepared from 4-(2-methoxyphenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to that described in step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 12.98 (s, 1H), 8.75 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.26 - 8.14 (m, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.45 - 7.36 (m, 2H), 7.33 (s, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 3.52 (s, 3H), 2.59 (s, 3H). LC-MS (M+H) + = 478.6.

[0331] Example 73: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(ethylcarbamoyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: Methyl 4-(2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridin-5-yl)benzoate [ka] The title compound (4.2 g, 74%) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and (4-(methoxycarbonyl)phenyl)boronic acid in a similar manner to step 5 of example 1. LC-MS (M+H) + = 386.4.

[0332] Step 2: Methyl 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzoate [ka] The title compound (2.1 g, 68%) was prepared from methyl 4-(2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridin-5-yl)benzoate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 286.6.

[0333] Step 3: Methyl 4-(2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamido)thiazolo[5,4-b]pyridin-5-yl)benzoate [ka] The title compound (1.7 g, 92%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and methyl 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzoate in a similar manner to step 3 of example 11. LC-MS (M+H) + = 536.2.

[0334] Step 4: 4-(2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid [ka] The title compound (1.6 g, 97%) was prepared from methyl 4-(2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamido)thiazolo[5,4-b]pyridin-5-yl)benzoate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 522.3.

[0335] Step 5: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(ethylcarbamoyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide To a solution of 4-(2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid (100 mg, 0.2 mmol) in N,N-dimethylformamide (5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.11 g, 0.3 mmol) and N,N-diisopropylethylamine (52 mg, 0.4 mmol). The reaction mixture was stirred for 10 min and then diluted with 30% EtNH in EtOH. 2 (18 mg, 0.4 mmol) was added. The resulting mixture was stirred at room temperature for 14 h. The mixture was purified by preparative HPLC (elution: acetonitrile (0.1% formic acid) / water (0.1% formic acid): 50%-80%, v / v) to give the title compound (50 mg, 46%). 1 H-NMR (400 MHz, d6-DMSO) δ 13.01 (s, 1H), 8.81 (s, 1H), 8.56 (t, J = 5.5 Hz, 1H), 8.23 ​​- 8.13 (m, 4H), 8.03 - 7.86 (m, 4H), 7.44 (s, 1H), 7.18 (d, J = 9.3 Hz, 1H), 3.60 (s, 3H), 3.35 - 3.28 (m, 2H), 2.61 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H). LC-MS (M+H) + = 549.4.

[0336] Example 74: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(isopropylcarbamoyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] The title compound (1 mg, 9%) was prepared in a similar manner to step 5 of example 73 from 4-(2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid and isopropylamine. 1 H-NMR (400 MHz, d6-DMSO) δ 12.99 (s, 1H), 8.85 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.21 - 8.12 (m, 4H), 7.97 (d, J = 8.4 Hz, 2H), 7.93 - 7.82 (m, 2H), 7.39 (s, 1H), 7.18 (d, J = 8.7 Hz, 1H), 4.17 - 4.09 (m, 1H), 3.60 (s, 3H), 2.59 (s, 3H), 1.19 (d, J = 6.6 Hz, 6H). LC-MS (M+H) + = 563.3.

[0337] Example 75: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(3-fluoro-2-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: Methyl 4-(3-fluoro-2-methoxyphenyl)-6-methylnicotinate [ka] The title compound (400 mg, 90%) was prepared from methyl 4-chloro-6-methylnicotinate and (3-fluoro-2-methoxyphenyl)boronic acid in a manner similar to step 2 of example 2. LC-MS (M+H) + = 276.1.

[0338] Step 2: 4-(3-fluoro-2-methoxyphenyl)-6-methylnicotinic acid [ka] The title compound (300 mg, 90%) was prepared from methyl 4-(3-fluoro-2-methoxyphenyl)-6-methylnicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 262.0.

[0339] Step 3: 4-(3-fluoro-2-methoxyphenyl)-6-methylnicotinamide [ka] The title compound (87 mg, 88%) was prepared by the reaction of 4-(3-fluoro-2-methoxyphenyl)-6-methylnicotinic acid and NH 4 Prepared from Cl. LC-MS (M+H) + =261.0.

[0340] Step 4: 4-(2-bromothiazolo[5,4-b]pyridin-5-yl)benzonitrile [ka] The title compound (65 mg, 59%) was prepared from 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 2 of example 69. LC-MS (M+H) + = 316.1.

[0341] Step 5: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(3-fluoro-2-methoxyphenyl)-6-methylnicotinamide The title compound (10 mg, 27%) was prepared in a similar manner to step 4 of example 69 from 4-(2-bromothiazolo[5,4-b]pyridin-5-yl)benzonitrile and 4-(3-fluoro-2-methoxyphenyl)-6-methylnicotinamide. 1 H NMR (400 MHz, d6-DMSO) δ 13.19 (brs, 1H), 8.86 (s, 1H), 8.37-8.18 (m, 4H), 8.00-7.93 (m, 2H), 7.46-7.29 (m, 2H), 7.27-7.17 (m, 2H), 3.63-3.58 (m, 3H), 2.61 (s, 3H). LC-MS (M+H) + = 496.1.

[0342] Example 76: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxy-5-nitrophenyl)-6-methylnicotinamide [ka] Step 1: Methyl 4-(2-methoxy-5-nitrophenyl)-6-methylnicotinate [ka] The title compound (260 mg, 66%) was prepared from (2-methoxy-5-nitrophenyl)boronic acid and methyl 4-chloro-6-methylnicotinate in a manner similar to that described in step 2 of Example 2. LC-MS (M+H) + = 303.1.

[0343] Step 2: 4-(2-Methoxy-5-nitrophenyl)-6-methylnicotinic acid [ka] The title compound (200 mg, 83%) was prepared from methyl 4-(2-methoxy-5-nitrophenyl)-6-methylnicotinate in a manner similar to that described in step 3 of Example 1. LC-MS (M+H) += 289.1.

[0344] Step 3: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxy-5-nitrophenyl)-6-methylnicotinamide The title compound (50 mg, 39%) was prepared from 4-(2-methoxy-5-nitrophenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to that described in step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 13.09 (s, 1H), 8.84 (s, 1H), 8.38 - 8.31 (m, 3H), 8.29 (d, J = 2.8 Hz, 1H), 8.27 - 8.20 (m, 2H), 7.97 (d, J = 7.50 (s, 1H), 7.24 (d, J = 9.1 Hz, 1H), 3.67 (s, 3H), 2.63 (s, 3H). LC-MS (M+H) + = 523.5.

[0345] Example 77: 4-(5-cyano-2-methoxyphenyl)-N-(5-(2-methoxyethoxy)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: tert-Butyl (5-(2-methoxyethoxy)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (150 mg, 46%) was prepared from 2-methoxyethan-1-ol and tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate in a manner similar to step 1 of example 65. LC-MS (M+H) + = 326.1.

[0346] Step 2: 5-(2-Methoxyethoxy)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (48 mg, 46%) was prepared from tert-butyl (5-(2-methoxyethoxy)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 226.1.

[0347] Step 3: 4-(5-cyano-2-methoxyphenyl)-N-(5-(2-methoxyethoxy)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (6 mg, 6%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 5-(2-methoxyethoxy)thiazolo[5,4-b]pyridin-2-amine in a manner similar to step 3 of example 25. 1 H-NMR (400 MHz, d6-DMSO) δ 12.77 (s, 1H), 8.78 (s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.91 - 7.86 (m, 2H), 7.40 (s, 1H), 7.17 (d, J = 8.7 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.51 - 4.30 (m, 2H), 3.74 - 3.63 (m, 2H), 3.58 (s, 3H), 3.31 (s, 3H), 2.59 (s, 3H). LC-MS (M+H) + = 476.5.

[0348] Example 78: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(3-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: 1-(4-bromo-2-methylphenyl)pyrrolidin-2-one [ka] 4-Bromo-2-methylaniline (0.37 g, 2 mmol), Et 3 To a solution of N (0.4 g, 4 mmol) in dichloromethane (10 mL) was added 4-chlorobutanoyl chloride (0.42 g, 3 mmol) carefully. It was stirred at room temperature for 14 h. The mixture was diluted with dichloromethane, washed with brine, the organic phase was dried and evaporated. The residue was used directly without purification. It was dissolved in N,N-dimethylformamide (3 mL) and NaH (0.16 g, 4 mmol) was added. The mixture was stirred for 2 h. Some ice chips were added, extracted with ethyl acetate, washed with brine, dried and evaporated. The crude product was purified by column chromatography (eluted with ethyl acetate in petroleum ether (50%, v / v)) to give the title compound (0.48 g, 96%). LC-MS (M+H) + = 254.2.

[0349] Step 2: 1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one [ka] The title compound (0.34 g, 59%) was prepared from 1-(4-bromo-2-methylphenyl)pyrrolidin-2-one and bis(pinacolato)diboron in a similar manner to step 2 of example 28. LC-MS (M+H) + = 302.4.

[0350] Step 3: tert-Butyl (5-(3-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] tert-Butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate (0.16 g, 0.5 mmol), 1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (0.18 g, 0.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (41 mg, 0.05 mmol), and K 2 CO 3 The reaction mixture of (0.14 g, 1 mmol) in dioxane / water (10 mL, 10:1 v / v) under nitrogen was stirred at 100° C. for 14 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound (85 mg, 40%). LC-MS (M+H) + = 425.3.

[0351] Step 4: 1-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)-2-methylphenyl)pyrrolidin-2-one [ka] The title compound (45 mg, 69%) was prepared from tert-butyl (5-(3-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 325.3.

[0352] Step 5: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(3-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (8 mg, 10%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 1-(4-(2-aminothiazolo[5,4-b]pyridin-5-yl)-2-methylphenyl)pyrrolidin-2-one in a manner similar to step 3 of example 25. 1H NMR (400 MHz, d6-DMSO) δ 12.98 (s, 1H), 8.80 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.12 - 8.03 (m, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 7.0 Hz, 2H), 7.44 (s, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 9.4 Hz, 1H), 3.73 (t, J = 6.9 Hz, 2H), 3.60 (s, 3H), 2.60 (s, 3H), 2.44 (t, J = 7.9 Hz, 2H), 2.25 (s, 3H), 2.19 - 2.12 (m, 2H). LC-MS (M+H) + = 575.4.

[0353] Example 79: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(methoxymethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] The title compound (18 mg, 28%) was prepared from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide and (4-(methoxymethyl)phenyl)boronic acid in a manner similar to step 3 of example 78. 1 H NMR (400 MHz, d6-DMSO) δ: 12.97 (s, 1H), 8.81 (s, 1H), 8.21 - 8.04 (m, 4H), 7.94 - 7.87 (m, 2H), 7.48 - 7.42 (m, 3H), 7.18 (d, J = 8.5 Hz, 1H), 4.48 (s, 2H), 3.60 (s, 3H), 3.33 (s, 3H), 2.60 (s, 3H). LC-MS (M+H) + = 522.5.

[0354] Example 80: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(2-hydroxypropan-2-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] The title compound (19 mg, 28%) was prepared from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide and (4-(2-hydroxypropan-2-yl)phenyl)boronic acid in a manner similar to step 3 of example 78. 1 H NMR (400 MHz, d6-DMSO) δ: 12.96 (s, 1H), 8.80 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.4 Hz, 3H), 7.96 - 7.86 (m, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.44 (s, 1H), 7.18 (d, J = 9.2 Hz, 1H), 5.08 (s, 1H), 3.60 (s, 3H), 2.60 (s, 3H), 1.47 (s, 6H). LC-MS (M+H) + = 536.3.

[0355] Example 81: 5-(2-Methoxyphenyl)-N-(5-(4-(methylsulfonyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide [ka] Step 1: 5-(4-(methylsulfonyl)phenyl)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (100 mg, 36%) was prepared from 5-bromothiazolo[5,4-b]pyridin-2-amine and (4-(methylsulfonyl)phenyl)boronic acid in a manner similar to step 3 of example 78. LC-MS (M+H)+ = 306.0.

[0356] Step 2: 5-(2-Methoxyphenyl)-N-(5-(4-(methylsulfonyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide To a solution of 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid (39 mg, 0.170 mmol) and N,N-diisopropylethylamine (76 mg, 0.590 mmol) in N,N-dimethylformamide (1 mL) was added BTFFH (75 mg, 0.236 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 0.5 h under nitrogen atmosphere. To the above mixture was added 5-(4-(methylsulfonyl)phenyl)thiazolo[5,4-b]pyridin-2-amine (40 mg, 0.131 mmol) at room temperature. The resulting mixture was stirred at 80° C. for another 16 h. After consumption of starting material, the resulting mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD column, 30×150 mm, 5 um; Mobile phase: Acetonitrile in water (NH at 10 mmol / L). 4 HCO 3 and 0.1% NH 4 OH), gradient 16% to 46% in 8 min; detector: UV 254 nm. Obtained the title compound (20 mg, 29%). 1H NMR (400 MHz, d6-DMSO) δ 13.39 (brs, 1H), 9.52-9.47 (m, 1H), 9.38 (s, 1H), 8.44-8.36 (m, 2H), 8.19 (s, 2H), 8.07-8.02 (m, 2H), 7.55-7.43 (m, 2H), 7.17-7.03 (m, 2H), 3.57 (s, 3H), 3.28 (s, 3H). LC-MS (M+H) + = 518.0.

[0357] Example 82: 4-(3-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: Methyl 4-(3-cyano-2-methoxyphenyl)-6-methylnicotinate [ka] The title compound (77 mg, 54%) was prepared from 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile and methyl 4-chloro-6-methylnicotinate in a manner similar to step 2 of example 2. LC-MS (M+H) + = 283.1.

[0358] Step 2: 4-(3-cyano-2-methoxyphenyl)-6-methylnicotinic acid [ka] The title compound (45 mg, 61%) was prepared from methyl 4-(3-cyano-2-methoxyphenyl)-6-methylnicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 269.2.

[0359] Step 3: 4-(3-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (11 mg, 16%) was prepared from 4-(3-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 2 of example 81. 1H NMR (300 MHz, d6-DMSO) δ 13.24 (brs, 1H), 8.92 (s, 1H), 8.39-8.17 (m, 4H), 8.01-7.93 (m, 2H), 7.92-7.82 (m, 1H), 7.77-7.68 (m, 1H), 7.47-7.36 (m, 2H), 3.61 (s, 3H), 2.62 (s, 3H). LC-MS (M+H)+ = 503.2.

[0360] Example 83: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] The title compound (15 mg, 7%) was prepared from 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1H NMR (400 MHz, d6-DMSO) δ 13.35 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 8.35 (d, J = 8.5 Hz, 2H), 8.31 - 8.21 (m, 2H), 7.98 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 7.7 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.19 - 7.12 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 3.56 (s, 3H). LC-MS (M+H) + = 465.4.

[0361] Example 84: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(morpholine-4-carbonyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] The title compound (60 mg, 50%) was prepared from 4-(2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid and morpholine in a manner similar to step 5 of example 73. 1H NMR (400 MHz, d6-DMSO) δ 13.02 (s, 1H), 8.81 (s, 1H), 8.23 ​​- 8.12 (m, 4H), 7.98 - 7.88 (m, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.45 (s, 1H), 7.19 (d, J = 9.4 Hz, 1H), 3.69 - 3.55 (m, 8H), 3.37 (s, 3H), 2.61 (s, 3H). LC-MS (M+H) + = 591.4.

[0362] Example 85: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(4-(pyrrolidine-1-carbonyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] The title compound (23.9 mg, 22%) was prepared from 4-(2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid and pyrrolidine in a manner similar to step 5 of example 73. 1 H NMR (400 MHz, d6-DMSO) δ: 13.02 (s, 1H), 8.81 (s, 1H), 8.24 - 8.08 (s, 4H), 7.93 - 7.87 (m, 2H), 7.70 - 7.62 (m, 2H), 7.46 (s, 1H), 7.24 - 7.15 (m, 1H), 3.61 (s, 3H), 3.53 - 3.34 (m, 4H), 2.49 (s, 3H), 1.90 - 1.80 (s, 4H). LC-MS (M+H) + = 575.1.

[0363] Example 86: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(dimethylcarbamoyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] The title compound (18.7 mg, 18%) was prepared from 4-(2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid and dimethylamine in a manner similar to that described in step 5 of example 73. 1H NMR (400 MHz, d6-DMSO) δ: 13.01 (s, 1H), 8.81 (s, 1H), 8.24 - 8.08 (s, 4H), 7.93 - 7.87 (m, 2H), 7.70 - 7.62 (m, 2H), 7.46 (s, 1H), 7.24 - 7.15 (m, 1H), 3.61 (s, 3H), 3.05 - 2.90 (m, 6H), 2.61 (s, 3H). LC-MS (M+H) + = 549.1.

[0364] Example 87: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxy-6-methylphenyl)-6-methylnicotinamide [ka] Step 1: 2-Bromo-1-methoxy-3-methylbenzene [ka] A solution of 2-bromo-3-methylphenol (2.0 g, 10.6 mmol) in acetonitrile (25 mL) was diluted with KOH (898 mg, 16.0 mmol), CH 3 I (7.6 g, 53.5 mmol) was added. The reaction mixture was stirred at 25° C. for 14 h. The mixture was diluted with ethyl acetate (50 mL), washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether (50%, v / v)) to give the title compound (1.8 g, 83%).

[0365] Step 2: 2-(2-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 2-bromo-1-methoxy-3-methylbenzene (1.0 g, 5.0 mmol) in THF (25 mL) was added n-BuLi (2.8 mL, 7.5 mmol, 2.5 M). The reaction mixture was stirred at −75° C. under nitrogen atmosphere for 0.5 h, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.3 g, 12.5 mmol) was added. The reaction mixture was stirred at room temperature for 14 h, then diluted with ethyl acetate (50 mL). The solution was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether (50%, v / v)) to give the title compound (1.0 g, 82%).

[0366] Step 3: Methyl 4-(2-methoxy-6-methylphenyl)-6-methylnicotinate [ka] A solution of 2-(2-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (400 mg, 1.6 mmol) and methyl 4-chloro-6-methylnicotinate (249 mg, 1.3 mmol) in dioxane (8 mL) and water (2 mL) was added with 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (98 mg, 0.13 mmol) and K 2 CO 3 (370 mg, 2.7 mmol) was added. The mixture was stirred under nitrogen at 90° C. for 14 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether (50%, v / v)) to give the title compound (285 mg, 81%). LC-MS (M+H)+ = 272.1.

[0367] Step 4: 4-(2-Methoxy-6-methylphenyl)-6-methylnicotinic acid [ka] To a solution of methyl 4-(2-methoxy-6-methylphenyl)-6-methylnicotinate (240 mg, 0.89 mmol) in THF (2 mL), methanol (2 mL), and water (2 mL) was added LiOH (84 mg, 3.5 mmol). The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with chloroform and isopropyl alcohol (40 mL), washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give compound 1-4 (206 mg, 90%). LC-MS (M+H) + = 258.1.

[0368] Step 5: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-methoxy-6-methylphenyl)-6-methylnicotinamide The title compound (10.5 mg, 11%) was prepared from 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile and 4-(2-methoxy-6-methylphenyl)-6-methylnicotinic acid in a manner similar to step 3 of example 11. 1H NMR (400 MHz, d6-DMSO) δ: 13.00 (s, 1H), 8.85 (s, 1H), 8.35 - 8.28 (m, 2H), 8.26 - 8.21 (m, 2H), 8.02 - 7.89 (m, 2H), 7.15 - 7.22 (s, 2H), 6.97 - 6.85 (m, 2H), 3.53 (s, 3H), 2.49 (s, 3H), 2.09 (s, 3H). LC-MS (M+H) + = 492.1.

[0369] Example 88: 5-(2-Methoxyphenyl)-N-(5-(4-(pyrrolidine-1-carbonyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide [ka] Step 1: Methyl 4-(2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoate [ka] The title compound (1.54 g, 66%) was prepared from 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid and methyl 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzoate in a similar manner to step 3 of example 25. LC-MS (M+H) + = 498.1.

[0370] Step 2: 4-(2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid [ka] The title compound (0.4 g, 95%) was prepared from methyl 4-(2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 484.1.

[0371] Step 3: 5-(2-Methoxyphenyl)-N-(5-(4-(pyrrolidine-1-carbonyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide The title compound (1.1 g, 97%) was prepared from 4-(2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid and pyrrolidine in a manner similar to step 5 of example 73. 1H NMR (400 MHz, DMSO- d6) δ 13.30 (s, 1H), 9.50 (d, J = 0.6 Hz, 1H), 9.41 (s, 1H), 8.28 - 8.07 (m, 4H), 7.65 (d, J = 8.3 Hz, 2H), 7.57 - 7.44 (m, 2H), 7.15 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 3.57 (s, 3H), 3.49 (t, J = 6.8 Hz, 2H), 3.44 (t, J = 6.2 Hz, 2H), 1.95 - 1.78 (m, 4H).LC-MS (M+H) + = 537.4.

[0372] Example 89: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(3-methyl-4-(N-methylmethylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide [ka] Step 1: N-Methyl-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide [ka] The title compound (560 mg, 99%) was prepared from N-(4-bromo-2-methylphenyl)-N-methylmethanesulfonamide and bis(pinacolato)diboron in a manner similar to step 2 of Example 28. LC-MS (M+H) + = 326.2.

[0373] Step 2: 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(3-methyl-4-(N-methylmethylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide The title compound (26 mg, 42%) was prepared from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide and N-methyl-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide in a manner similar to step 3 of example 78. 1H NMR (400 MHz, d6-DMSO) δ: 12.99 (s, 1H), 8.80 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.12 - 8.05 (m, 2H), 8.00 (d, J = 8.5 Hz, 1H), 7.95 - 7.87 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J = 9.1 Hz, 1H), 3.60 (s, 3H), 3.19 (s, 3H), 3.10 (s, 3H), 2.60 (s, 3H), 2.41 (s, 3H).LC-MS (M+H) + = 599.5.

[0374] Example 90: 4-(5-cyano-2-methoxyphenyl)-N-(5-(3-fluoro-4-(methylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide [ka] The title compound (550 mg, 99%) was prepared from N-(4-bromo-2-fluorophenyl)methanesulfonamide and bis(pinacolato)diboron in a manner similar to step 2 of example 28. LC-MS (M+H) + = 316.1.

[0375] Step 2: 4-(5-cyano-2-methoxyphenyl)-N-(5-(3-fluoro-4-(methylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (24 mg, 38%) was prepared from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide and N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide in a manner similar to step 3 of example 78. 1H NMR (400 MHz, d6-DMSO) δ: 13.01 (s, 1H), 9.79 (s, 1H), 8.80 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.06 - 7.96 (m, 2H), 7.94 - 7.87 (m, 2H), 7.53 (t, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J = 9.3 Hz, 1H), 3.60 (s, 3H), 3.10 (s, 3H), 2.60 (s, 3H).LC-MS (M+H) + = 589.2.

[0376] Example 91: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2,6-dimethoxyphenyl)-6-methylnicotinamide [ka] Step 1: Methyl 4-(2,6-dimethoxyphenyl)-6-methylnicotinate [ka] The title compound (289 mg, 80%) was prepared from methyl 4-chloro-6-methylnicotinate and 2-(2,6-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to that described in step 2 of Example 2. LC-MS (M+H) + = 288.1 Step 2: 4-(2,6-dimethoxyphenyl)-6-methylnicotinic acid [ka] The title compound (253 mg, 89%) was prepared from methyl 4-(2,6-dimethoxyphenyl)-6-methylnicotinate in a manner similar to that described in step 3 of Example 1. LC-MS (M+H) + = 274.1 Step 3: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2,6-dimethoxyphenyl)-6-methylnicotinamide The title compound (9.0 mg, 3.8%) was prepared from 4-(2,6-dimethoxyphenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to that described in step 3 of Example 11. 1H NMR (400 MHz, d6-DMSO) δ: 12.98 (s, 1H), 8.85 (s, 1H), 8.35 - 8.28 (m, 2H), 8.26 - 8.21 (m, 2H), 8.02 - 7.89 (m, 2H), 7.36 - 7.20 (s, 2H), 6.75 - 6.65 (m, 2H), 3.61 (s, 6H), 2.49 (s, 3H). LC-MS (M+H) + = 508.1.

[0377] Example 92: N-(5-(4-(dimethylcarbamoyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] The title compound (50 mg, 47%) was prepared from 4-(2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid and dimethylamine in a manner similar to step 5 of example 73. 1H NMR (400 MHz, DMSO- d6) δ 13.30 (s, 1H), 9.50 (d, J = 0.7 Hz, 1H), 9.43 (s, 1H), 8.30 - 8.09 (m, 4H), 7.60 - 7.44 (m, 4H), 7.16 (t, LC-MS (M+H) + = 511.5.

[0378] Example 93: 5-(2-Methoxyphenyl)-N-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide [ka] The title compound (43 mg, 36%) was prepared from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one in a manner similar to step 3 of example 78. 1H NMR (300 MHz, d6-DMSO) δ 9.9.49 (s, 1H), 9.43 (s, 1H), 8.25-8.02 (m, 4H), 7.86-7.77 (m, 2H), 7.59-7.44 (m, 2H), 7.21-7.02 (m, 2H), 3.90 (t, J = 7.0 Hz, 2H), 3.55 (s, 3H), 2.59-2.51 (m, 2H), 2.17-2.04 (m, 2H). LC-MS (M+H) + = 523.1.

[0379] Example 94: N-Ethyl-2-(5-(2-methoxyphenyl)pyridazine-4-carboxamide)thiazolo[5,4-b]pyridine-5-carboxamide [ka] Step 1: Methyl 2-bromothiazolo[5,4-b]pyridine-5-carboxylate [ka] The title compound (252 mg, 74%) was prepared from methyl 2-aminothiazolo[5,4-b]pyridine-5-carboxylate in a similar manner to step 2 of example 69. LC-MS (M+H) + = 272.8.

[0380] Step 2: Methyl 2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridine-5-carboxylate [ka] The title compound (274 mg, 73%) was prepared from methyl 2-bromothiazolo[5,4-b]pyridine-5-carboxylate and 5-(2-methoxyphenyl)pyridazine-4-carboxamide in a manner similar to step 4 of example 69. LC-MS (M+H) + = 421.9.

[0381] Step 3: 2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridine-5-carboxylic acid [ka] The title compound (163 mg, 61%) was prepared from methyl 2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridine-5-carboxylate in a manner similar to step 3 of example 1. LC-MS (M+H) + = 408.0.

[0382] Step 5: N-Ethyl-2-(5-(2-methoxyphenyl)pyridazine-4-carboxamide)thiazolo[5,4-b]pyridine-5-carboxamide The title compound (25 mg, 79%) was prepared in a similar manner to step 5 of example 73 from 2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridine-5-carboxylic acid and ethylamine hydrochloride. 1H NMR (400 MHz, d6-DMSO) δ 13.46 (brs, 1H), 9.50 (s, 1H), 9.42 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.28-8.11 (m, 2H), 7.58-7.40 (m, 2H), 7.20-7.03 (m, 2H), 3.55 (s, 3H), 3.38-3.29 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H). LC-MS (M+H) + = 435.0.

[0383] Example 95: N-(5-ethoxythiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: 2-Aminothiazolo[5,4-b]pyridin-5-ol [ka] A mixture of 5-methoxythiazolo[5,4-b]pyridin-2-amine (285 mg, 1.573 mmol) in HBr (30.00 mL, 48%) in water was stirred at 100° C. for 16 h under nitrogen atmosphere. After the starting material was consumed, the mixture was diluted with saturated NaHCO 3 Basified with aqueous solution to pH 8. The precipitated solid was collected by filtration and washed with water (2×5 mL) to give the title compound (198 mg, 75%). LC-MS (M+H) + = 168.2.

[0384] Step 2: 5-Ethoxythiazolo[5,4-b]pyridin-2-amine [ka] To a mixture of 2-aminothiazolo[5,4-b]pyridin-5-ol (148 mg, 0.886 mmol) and ethyl iodide (165 mg, 1.063 mmol) in N,N-dimethylformamide (3 mL) was added CsF (538 mg, 3.544 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. After consumption of the starting material, the reaction was then quenched by adding water (10 mL) at room temperature. The resulting solution was extracted with dichloromethane (3×10 mL). The organic phases were combined, washed with brine and diluted with Na 2 SO 4 The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 40% gradient) to give the title compound (37 mg, 21%). LC-MS (M+H) + = 196.2.

[0385] Step 3: N-(5-ethoxythiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide The title compound (21 mg, 36%) was prepared in a similar manner to step 2 of example 81 from 5-ethoxythiazolo[5,4-b]pyridin-2-amine and 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid. 1 H NMR (300 MHz, d6-DMSO) δ 13.06 (brs, 1H), 9.47 (d, J = 1.2 Hz, 1H), 9.40 (s, 1H), 8.06 (m, 12.0 Hz, 1H), 7.55-7.41 (m, 2H), 7.18-7.00 (m, 2H), 6.94-6.85 (m, 1H), 4.33 (q, J = 7.0 Hz, 2H), 3.53 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H). LC-MS (M+H) += 408.0.

[0386] Example 96: N-(5-(4-chloro-2-methoxyphenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] 5-(2-Methoxyphenyl)pyridazine-4-carboxylic acid (1 g, 4.35 mmol), 5-bromothiazolo[5,4-b]pyridin-2-amine (1 g, 4.35 mmol), T 3 The reaction mixture of P (10 mL) in pyridine (10 mL) under nitrogen was stirred at 80° C. for 14 h. The solvent was evaporated under vacuum. Water (30 mL) was added. The residue was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine and diluted with Na 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo gave the crude product (1.6 g, 83%). LC-MS (M+H) + = 441.9, 443.9.

[0387] Step 2: N-(5-(4-chloro-2-methoxyphenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide (50 mg, 0.113 mmol), (4-chloro-2-methoxyphenyl)boronic acid (21 mg, 0.17 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.01 mmol), and K 2 CO 3A reaction mixture of (31 mg, 0.226 mmol) in 1,4-dioxane / water (10 mL / 1 mL) under nitrogen was stirred at 90° C. for 14 h. The mixture was filtered and the filtrate was evaporated. The residue was purified using preparative HPLC to give the title compound (18 mg, 34%). 1 H NMR (400 MHz, d6-DMSO) δ 13.26 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.19 - 7.12 (m, 2H), 7.07 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H), 3.56 (s, 3H). LC-MS (M+H) + = 504.1.

[0388] Example 97: N-(5-(4-chloro-2-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] The title compound (32 mg, 14%) was prepared from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide and (4-chloro-2-methylphenyl)boronic acid in a manner similar to steps 1-2. 1H NMR (400 MHz, d6-DMSO) δ 13.28 (s, 1H), 9.53 - 9.47 (m, 1H), 9.43 (s, 1H), 8.23 ​​(d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.54 (dd, J = 7.6, 1.5 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.44 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.3, 2.2 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 3.57 (s, 3H), 2.37 (s, 3H). LC-MS (M+H) + = 488.1.

[0389] Example 98: N-(5-(4-chlorophenoxy)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: 2-Chloro-6-(4-chlorophenoxy)-3-nitropyridine and 6-chloro-2-(4-chlorophenoxy)-3-nitropyridine [ka] A mixture of 2,6-dichloro-3-nitropyridine (1 g, 5.182 mmol) and 4-chlorophenol (0.67 g, 5.182 mmol) in DMSO (30 mL) was added to the solution of Cs 2 CO 3(1.69 g, 5.182 mmol) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After the starting material was consumed, the reaction was then quenched by adding water (35 mL) at room temperature. The resulting solution was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with brine and diluted with Na 2 SO 4 The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with dichloromethane in petroleum ether (gradient from 0% to 60%) to give a mixture of 2-chloro-6-(4-chlorophenoxy)-3-nitropyridine and 6-chloro-2-(4-chlorophenoxy)-3-nitropyridine (748 mg, 50%). LC-MS (M+H) + = 284.9.

[0390] Step 2: 2-Chloro-6-(4-chlorophenoxy)pyridin-3-amine [ka] To the above mixture of 2-chloro-6-(4-chlorophenoxy)-3-nitropyridine and 6-chloro-2-(4-chlorophenoxy)-3-nitropyridine (740 mg, 2.596 mmol) in methanol (24 mL) / water (8 mL) was added Fe (49 mg, 0.875 mmol) and NH 4 Cl (694 mg, 12.980 mmol) was added at room temperature. The resulting mixture was stirred at 80° C. for 3 h. After consumption of the starting material, the resulting mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with dichloromethane in petroleum ether (0%→50% gradient) to give the title compound (247 mg, 37%). 1H NMR (300 MHz, d6-DMSO) δ 7.35-7.24 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 6.98-6.87 (m, 2H), 6.76 (d, J = 8.4 Hz, 1H), 5.25 (s, 2H).

[0391] Step 3: N-((2-chloro-6-(4-chlorophenoxy)pyridin-3-yl)carbamothioyl)benzamide [ka] A mixture of 2-chloro-6-(4-chlorophenoxy)pyridin-3-amine (178 mg, 0.713 mmol) and benzoyl isothiocyanate (114 mg, 0.713 mmol) in acetone (5.0 mL) was stirred at room temperature under nitrogen atmosphere for 16 hours. After consumption of the starting material, the resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with petroleum ether (3×5 mL) to give the title compound (208 mg, 71%). LC-MS (M+H) + = 417.9.

[0392] Step 4: 5-(4-chlorophenoxy)thiazolo[5,4-b]pyridin-2-amine [ka] A solution of N-((2-chloro-6-(4-chlorophenoxy)pyridin-3-yl)carbamothioyl)benzamide (196 mg, 0.469 mmol) in methanol (2.0 mL) was treated dropwise with NaOH (10 M) (250 uL, 0.070 mmol) at 0° C. The resulting mixture was stirred at 75° C. for 16 hours under nitrogen atmosphere. After consumption of the starting material, the resulting mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate in dichloromethane (gradient from 0% to 25%) to give the title compound (78 mg, 60%). LC-MS (M+H) + = 277.9.

[0393] Step 5: N-(5-(4-chlorophenoxy)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide The title compound (46 mg, 37%) was prepared from 5-(4-chlorophenoxy)thiazolo[5,4-b]pyridin-2-amine and 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid in a similar manner to step 2 of example 81. 1H NMR (300 MHz, d6-DMSO) δ 13.16 (brs, 1H), 9.46 (s, 1H), 9.41 (s, 1H), 8.28-8.19 (m, 1H), 7.56-7.41 (m, 4H), 7.29-7.10 (m, 4H), 7.09-7.00 (m, 1H), 3.53 (s, 3H). LC-MS (M+H) + = 490.0.

[0394] Example 99: N-(5-(4-chloro-2-(trifluoromethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] The title compound (117 mg, 52%) was prepared from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide and (4-chloro-2-(trifluoromethyl)phenyl)boronic acid in a manner similar to step 2 of example 96. 1H NMR (400 MHz, d6-DMSO) δ 13.35 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 8.3, 2.0 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 3.57 (s, 3H). LC-MS (M+H) + = 542.1.

[0395] Example 100: N-(5-(4-chloro-2-fluorophenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] The title compound (135 mg, 30%) was prepared in a similar manner to step 2 of example 96 from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide and (4-chloro-2-fluorophenyl)boronic acid. 1H NMR (400 MHz, d6-DMSO) δ 13.35 (s, 1H), 9.51 (s, 1H), 9.43 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.04 (t, J = 8.6 Hz, 1H), 7.92 (dd, J = 8.5, 1.8 Hz, 1H), 7.62 (dd, J = 11.2, 2.0 Hz, 1H), 7.55 (dd, J = 7.6, 1.5 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.16 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 3.56 (s, 3H). LC-MS (M+H) + = 492.1.

[0396] Example 101: N-(5-(4-chloro-2,6-dimethylphenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] The title compound (22 mg, 10%) was prepared in a manner similar to step 2 of example 96 from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide and (4-chloro-2,6-dimethylphenyl)boronic acid. 1H NMR (400 MHz, d6-DMSO) δ 13.28 (s, 1H), 9.49 (s, 1H), 9.41 (s, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.50 (dd, J = 17.7, 7.8 Hz, 2H), 7.43 (d, LC-MS (M+H) + = 502.1.

[0397] Example 102: N-(5-(4-(isopropylcarbamoyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] The title compound (50 mg, 45%) was prepared from 4-(2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid and propan-2-amine in a manner similar to step 5 of example 73. 1H NMR (400 MHz, d6-DMSO) δ 13.31 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 8.31 (d, J = 7.7 Hz, 1H), 8.28 - 8.16 (m, 4H), 7.98 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 7.6 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.19 - 7.13 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 4.18 - 4.08 (m, 1H), 3.56 (s, 3H), 1.19 (d, J = 6.6 Hz, 6H) LC-MS (M+H) + = 525.3.

[0398] Example 103: 5-(2-Methoxyphenyl)-N-(5-(4-(morpholine-4-carbonyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide [ka] The title compound (50 mg, 43%) was prepared from 4-(2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid and morpholine in a manner similar to step 5 of example 73. 1H NMR (400 MHz, dmso) δ 13.30 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 8.28 - 8.19 (m, 3H), 8.16 (d, J = 8.6 Hz, 1H), 7.57 - 7.52 (m, 3H), 7.52 - 7.46 (m, 1H), 7.18 - 7.13 (m, 1H), 7.07 (d, J = 8.2 Hz, 1H), 3.75 - 3.35 (m, 11H). LC-MS (M+H) + = 553.3.

[0399] Example 104: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: 2-(2-fluoro-6-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] The title compound (876 mg, 71%) was prepared from 2-bromo-1-fluoro-3-methoxybenzene in a manner similar to that described in Step 2 of Example 87.

[0400] Step 2: Methyl 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinate [ka] The title compound (341 mg, 78%) was prepared from methyl 4-chloro-6-methylnicotinate and 2-(2-fluoro-6-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to that described in step 2 of Example 2. LC-MS (M+H) + = 276.1.

[0401] Step 3: 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid [ka] The title compound (250 mg, 88%) was prepared from methyl 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinate in a manner similar to that described in step 3 of Example 1. LC-MS (M+H) + = 262.1.

[0402] Step 4: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinamide The title compound (24.5 mg, 11%) was prepared from 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to that described in step 3 of Example 11. 1 H NMR (400 MHz, d6-DMSO) δ: 13.14 (s, 1H), 8.88 (s, 1H), 8.35 - 8.28 (m, 2H), 8.26 - 8.21 (m, 2H), 8.02 - 7.89 (m, 2H), 7.50 - 7.35 (m, 2H), 6.97 - 6.85 (m, 2H), 3.53 (s, 3H), 2.49 (s, 3H). LC-MS (M+H) + = 496.1.

[0403] Example 105: 4-(5-cyano-2-ethoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: 3-Bromo-4-ethoxybenzonitrile [ka] 3-Bromo-4-hydroxybenzonitrile (1.98 g, 10 mmol), EtI (1.87 g, 12 mmol), and K 2 CO 3 A mixture of (2.07 g, 15 mmol) in N,N-dimethylformamide (20 mL) was stirred at 80° C. for 3 h. The mixture was diluted with ethyl acetate, washed with brine, and the organic phase was dried and evaporated. The residue was purified by column chromatography (eluted with ethyl acetate in petroleum ether (17%, v / v)) to give the title compound (2.3 g, 96%). LC-MS (M+H) + = 226.3.

[0404] Step 2: 4-Ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile [ka] The title compound (0.9 g, 33%) was prepared from 3-bromo-4-ethoxybenzonitrile and bis(pinacolato)diboron in a manner similar to Example 28, Step 2.

[0405] Step 3: Methyl 4-(5-cyano-2-ethoxyphenyl)-6-methylnicotinate [ka] The title compound (0.17 g, 60%) was prepared from 4-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile and methyl 4-chloro-6-methylnicotinate in a manner similar to step 2 of example 2. LC-MS (M+H) + = 297.4.

[0406] Step 4: 4-(5-cyano-2-ethoxyphenyl)-6-methylnicotinic acid [ka] The title compound (150 mg, 93%) was prepared from methyl 4-(5-cyano-2-ethoxyphenyl)-6-methylnicotinate in a similar manner to step 3 of example 1. LC-MS (M+H) + = 283.4.

[0407] Step 5: 4-(5-cyano-2-ethoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] The title compound (10 mg, 3.7%) was prepared from 4-(5-cyano-2-ethoxyphenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1H NMR (400 MHz, d6-DMSO) δ 13.08 (s, 1H), 8.84 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.24 (q, J = 8.6 Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 7.5 Hz, 2H), 7.42 (s, 1H), 7.16 (d, J = 9.2 Hz, 1H), 4.00 - 3.80 (m, 2H), 2.61 (s, 3H), 1.09 (t, J = 7.0 Hz, 3H). LC-MS (M+H) + = 517.4.

[0408] Example 106: 4-(5-cyano-2-methylphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] Step 1: Methyl 4-(5-cyano-2-methylphenyl)-6-methylnicotinate [ka] The title compound (290 mg, 40%) was prepared from (5-cyano-2-methylphenyl)boronic acid and methyl 4-chloro-6-methylnicotinate in a manner similar to step 2 of example 2. LC-MS (M+H) + = 267.4.

[0409] Step 2: 4-(5-cyano-2-methylphenyl)-6-methylnicotinic acid [ka] The title compound (150 mg, 93%) was prepared from methyl 4-(5-cyano-2-methylphenyl)-6-methylnicotinate (290 mg, 1.09 mmol) in a manner similar to step 3 of example 1. LC-MS (M+H) + = 253.6.

[0410] Step 3: 4-(5-cyano-2-methylphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide The title compound (50 mg, 21.4%) was prepared from 4-(5-cyano-2-methylphenyl)-6-methylnicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. 1H NMR (400 MHz, d6-DMSO) δ 13.17 (s, 1H), 8.96 (s, 1H), 8.32 (d, J = 8.4 Hz, 2H), 8.22 (q, J = 8.6 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.78 (dd, J = 7.9, 1.5 Hz, 1H), 7.65 (d, J = 1.3 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 2.62 (s, 3H), 2.16 (s, 3H). LC-MS (M+H) + = 487.4.

[0411] Example 107: N-(5-(4-chlorophenethyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide [ka] The title compound (0.5 g, 89%) was prepared from 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid and 5-bromothiazolo[5,4-b]pyridin-2-amine in a manner similar to step 3 of example 11. LC-MS (M+H) + = 480.4.

[0412] Step 2: N-(5-((4-chlorophenyl)ethynyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide [ka] N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide (0.2 g, 0.42 mmol), 1-chloro-4-ethynylbenzene (0.138 g, 1 mmol), Et 3 N (0.13 g, 1.26 mmol), Pd(PPh 3 ) 2 Cl 2 A reaction mixture of (15 mg, 0.021 mmol) and CuI (12 mg, 0.063 mmol) in acetonitrile (5 mL) under nitrogen was stirred at 80° C. for 14 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (eluted with ethyl acetate in petroleum ether (0-100%, v / v)) to give the title compound (0.13 g, 58%). LC-MS (M+H) + = 536.4.

[0413] Step 3: N-(5-(4-chlorophenethyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide N-(5-((4-chlorophenyl)ethynyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide (0.13 g, 0.24 mmol), 10 wt.% Pd / C (26 mg, 20%) in H 2The reaction mixture below in THF (5 mL) was stirred at room temperature for 14 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by preparative HPLC to give the title compound (40 mg, 31%). 1H NMR (400 MHz, d6-DMSO) δ 12.86 (s, 1H), 8.78 (s, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.96 - 7.81 (m, 2H), 7.42 (s, 1H), 7.31 (m, 5H), 7.17 (d, J = 8.6 Hz, 1H), 3.59 (s, 3H), 3.13 (dd, J = 9.0, 5.9 Hz, 2H), 3.03 (dd, J = 9.2, 6.1 Hz, 2H), 2.59 (s, 3H). LC-MS (M+H) + = 540.3.

[0414] Example 108: N-(5-(4-(ethylcarbamoyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] The title compound (60 mg, 56%) was prepared from 4-(2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid and ethylamine in a manner similar to step 5 of example 73. 1H NMR (400 MHz, d6-DMSO) δ 13.30 (s, 1H), 9.50 (s, 1H), 9.44 (s, 1H), 8.56 (t, J = 5.5 Hz, 1H), 8.31 - 8.15 (m, 4H), 7.98 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 7.5 Hz, 1H), 7.53 - 7.46 (m, 1H), 7.19 - 7.13 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 3.56 (s, 3H), 3.39 - 3.26 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H) LC-MS (M+H) + = 511.4.

[0415] Example 109: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-(hydroxymethyl)nicotinamide [ka] Step 1: Benzyl 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinate [ka] 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid (0.59 g, 2.2 mmol), BnBr (0.45 g, 2.64 mmol), and K 2 CO 3 A mixture of (0.76 g, 5.5 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate, washed with brine, and the organic phase was dried and evaporated. The residue was purified by column chromatography (eluted with ethyl acetate in petroleum ether (25%, v / v)) to give the title compound (0.78 g, 99%). LC-MS (M+H) + = 359.3.

[0416] Step 2: 5-((benzyloxy)carbonyl)-4-(5-cyano-2-methoxyphenyl)-2-methylpyridine 1-oxide [ka] 3-Chloroperbenzoic acid (0.56 g, 3.27 mmol) was added to a solution of benzyl 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinate (0.78 g, 2.18 mmol) in dichloromethane and stirred at room temperature for 14 h. The mixture was diluted with ethyl acetate, washed with brine, and the organic phase was dried and evaporated. The residue was purified by column chromatography (EA) to give the title compound (0.48 g, 59%). L LC-MS (M+H) + = 375.4.

[0417] Step 3: Benzyl 6-(acetoxymethyl)-4-(5-cyano-2-methoxyphenyl)nicotinate [ka] Acetic anhydride (0.26 g, 2.57 mmol) was added to a solution of 5-((benzyloxy)carbonyl)-4-(5-cyano-2-methoxyphenyl)-2-methylpyridine 1-oxide (0.48 g, 1.28 mmol) in acetonitrile (8 mL) under nitrogen and stirred at 80° C. for 14 h. The mixture was evaporated and the residue was purified by column chromatography (eluted with ethyl acetate in petroleum ether (0-100%, v / v)) to give the title compound (0.29 g, 55%). LC-MS (M+H) + = 417.3.

[0418] Step 4: 6-(acetoxymethyl)-4-(5-cyano-2-methoxyphenyl)nicotinic acid [ka] The title compound (0.2 g, 87.6%) was prepared from benzyl 6-(acetoxymethyl)-4-(5-cyano-2-methoxyphenyl)nicotinate and 10 wt.% Pd / C in a similar manner to step 3 of example 2. LC-MS (M+H) + = 327.2.

[0419] Step 5: (4-(5-cyano-2-methoxyphenyl)-5-((5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamoyl)pyridin-2-yl)methyl acetate [ka] The title compound (60 mg, 35%) was prepared from 6-(acetoxymethyl)-4-(5-cyano-2-methoxyphenyl)nicotinic acid and 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzonitrile in a manner similar to step 3 of example 11. LC-MS (M+H)+ = 561.3.

[0420] Step 6: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-6-(hydroxymethyl)nicotinamide The title compound (20 mg, 33%) was prepared in a similar manner to step 3 of example 1 from (4-(5-cyano-2-methoxyphenyl)-5-((5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamoyl)pyridin-2-yl)methyl acetate and LiOH. 1H NMR (400 MHz, d6-DMSO) δ 13.10 (s, 1H), 8.86 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.24 (q, J = 8.6 Hz, 2H), 8.01 - 7.86 (m, 4H), 7.55 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 5.60 (t, J = 5.9 Hz, 1H), 4.69 (d, J = 5.7 Hz, 2H), 3.61 (s, 3H). LC-MS (M+H) + = 519.3.

[0421] Example 110: N-(5-(4-carbamoyl-3-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: 4-Bromo-2-methylbenzamide [ka] Oxalyl chloride (1.4 g, 11 mmol) was added dropwise to a solution of 4-bromo-2-methylbenzoic acid (2.15 g, 10 mmol) in dichloromethane at 0° C. and stirred at 0° C. for 0.5 h, then a solution of 7N ammonia in methanol (2 mL) was added dropwise and stirred at room temperature for a further 1 h. The reaction was evaporated and the residue was purified by column chromatography (eluting with ethyl acetate in petroleum ether (0-100%, v / v)) to give the title compound (1.78 g, 84%). LC-MS (M+H) + = 214.3.

[0422] Step 2: 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] A reaction mixture of 4-bromo-2-methylbenzamide (1.78 g, 8.36 mmol), bis(pinacolato)diboron (2.33 g, 9.16 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.68 g, 0.836 mmol), and KOAc (2.46 g, 25 mmol) in 1,2-dimethoxyethane (20 mL) under nitrogen was stirred at 80° C. for 14 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (eluted with ethyl acetate in petroleum ether (0-100%, v / v)) to give the title compound (2.1 g, 96%). LC-MS (M+H) + = 262.3.

[0423] Step 3: tert-Butyl (5-(4-carbamoyl-3-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.31 g, 1.2 mmol), tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate (0.21 g, 1 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (82 mg, 0.1 mmol), and K 2 CO 3 The reaction mixture of (0.35 g, 2.5 mmol) in dioxane (5 mL) under nitrogen was stirred at 100° C. for 14 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (eluted with ethyl acetate in petroleum ether (0-100%, v / v)) to give the title compound (0.23 g, 60%). LC-MS (M+H) + = 385.4.

[0424] Step 4: 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)-2-methylbenzamide [ka] Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl (5-(4-carbamoyl-3-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (0.23 g, 0.6 mmol) in dichloromethane (6 mL). This was stirred at room temperature for 14 hours. The solvent was evaporated and the residue was dissolved in NaHCO 3 The crude product was purified by column chromatography (eluted with ethyl acetate in petroleum ether (0-100%, v / v)) to give the title compound (0.15 g, 65%). LC-MS (M+H) + = 285.2.

[0425] Step 5: N-(5-(4-carbamoyl-3-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide The title compound (30 mg, 50%) was prepared from 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)-2-methylbenzamide and 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid in a manner similar to step 3 of example 25. 1H NMR (400 MHz, d6-DMSO) δ 12.98 (s, 1H), 8.81 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 8.04 - 7.87 (m, 4H), 7.77 LC-MS (M+H) + = 535.3.

[0426] Example 111: N-(5-(4-(2-hydroxyacetamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: 2-oxo-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl acetate [ka] The title compound (634 mg, 71%) was prepared from 2-((4-bromophenyl)amino)-2-oxoethyl acetate in a similar manner to step 2 of example 28. LC-MS (M+H) + = 320.1.

[0427] Step 2: N-(5-(4-(2-hydroxyacetamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide The title compound (21 mg, 31%) was prepared from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide and 2-oxo-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl acetate in a manner similar to step 3 of example 78. 1H NMR (400 MHz, d6-DMSO) δ 13.24 (brs, 1H), 9.83 (s, 1H), 9.49 (s, 1H), 9.40 (s, 1H), 8.19-8.01 (m, 4H), 7.85 (d, J = 8.6 Hz, 2H), 7.56-7.40 (m, 2H), 7.18-7.10 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 5.67 (t, J = 6.0 Hz, 1H), 4.03 (d, J = 5.8 Hz, 2H), 3.57 (s, 3H). LC-MS (M+H) + = 513.0.

[0428] Example 112: N-(2-hydroxyethyl)-2-(5-(2-methoxyphenyl)pyridazine-4-carboxamide)thiazolo[5,4-b]pyridine-5-carboxamide [ka] The title compound (15 mg, 34%) was prepared from 2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridine-5-carboxylic acid and 2-aminoethan-1-ol in a manner similar to step 5 of example 73. 1H NMR (400 MHz, d6-DMSO) δ 13.47 (brs, 1H), 9.48 (s, 1H), 9.34 (s, 1H), 8.70 (t, J = 5.9 Hz, 1H), 8.17-7.98 (m, 2H), 7.52-7.42 (m, 2H), 7.16-6.95 (m, 2H), 4.80 (s, 1H), 3.57-3.52 (m, 4H), 3.44-3.35 (m, 3H). LC-MS (M+H) += 451.0.

[0429] Example 113: 2-(5-(2-methoxyphenyl)pyridazine-4-carboxamide)-N-(tetrahydro-2H-pyran-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide [ka] The title compound (47 mg, 77%) was prepared from 2-(5-(2-methoxyphenyl)pyridazine-4-carboxamido)thiazolo[5,4-b]pyridine-5-carboxylic acid and tetrahydro-2H-pyran-4-amine in a manner similar to step 5 of example 73. 1H NMR (300 MHz, d6-DMSO) δ 13.46 (brs, 1H), 9.50 (s, 1H), 9.42 (s, 1H), 8.78 (d, J = 8.4 Hz, 1H), 8.28-8.10 (m, 2H), 7.59-7.43 (m, LC-MS (M+H) + = 491.0.

[0430] Example 114: N-(5-(cyclopentyloxy)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: 5-(cyclopentyloxy)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (90 mg, 43%) was prepared from 2-aminothiazolo[5,4-b]pyridin-5-ol and iodocyclopentane in a manner similar to step 2 of example 95. LC-MS (M+H) += 236.0.

[0431] Step 2: N-(5-(cyclopentyloxy)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide The title compound (9 mg, 7%) was prepared from 5-(cyclopentyloxy)thiazolo[5,4-b]pyridin-2-amine and 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid in a manner similar to step 2 of example 81. 1H NMR (300 MHz, d6-DMSO) δ 9.42 (s, 1H), 9.12 (s, 1H), 7.74-7.65 (m, 1H), 7.45-7.30 (m, 2H), 7.10-6.96 (m, 2H), 6.67-6.58 (m, 1H), 5.40-5.28 (m, 1H), 3.60 (s, 3H),1.98-1.86 (m, 2H), 1.76-1.53 ​​(m, 6H). LC-MS (M+H) + = 448.0.

[0432] Example 115: N-(5-(4-(acetamidomethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide [ka] The title compound (23 mg, 22%) was prepared from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide and (4-(acetamidomethyl)phenyl)boronic acid in a manner similar to step 2 of example 96. 1H NMR (400 MHz, d6-DMSO) δ 12.96 (s, 1H), 8.81 (s, 1H), 8.39 (t, J = 6.0 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.06 (dd, J = 11.9, 8.5 Hz, 3H), 7.94 - 7.85 (m, 2H), 7.43 (s, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.6 Hz, 1H), 4.31 (d, J = 5.9 Hz, 2H), 3.60 (s, 3H), 2.60 (s, 3H), 1.90 (s, 3H). LC-MS (M+H) + = 549.1.

[0433] Example 116: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-(cyanomethyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide [ka] The title compound (23 mg, 22%) was prepared from N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide and (4-(cyanomethyl)phenyl)boronic acid in a manner similar to step 2 of example 96. 1 H NMR (400 MHz, d6-DMSO) δ 12.98 (s, 1H), 8.80 (s, 1H), 8.18 (dd, J = 11.3, 8.5 Hz, 3H), 8.09 (d, J = 8.6 Hz, 1H), 7.95 - 7.89 (m, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.44 (s, 1H), 7.18 (d, J = 9.2 Hz, 1H), 4.12 (s, 2H), 3.60 (s, 3H), 2.60 (s, 3H). LC-MS (M+H) + = 517.1.

[0434] Example 117: N-(5-(2,4-dichlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: tert-Butyl (5-(2,4-dichlorophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (150 mg, 81%) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and (2,4-dichlorophenyl)boronic acid in a similar manner to step 3 of example 78. LC-MS (M+H) + = 396.1.

[0435] Step 2: 5-(2,4-dichlorophenyl)thiazolo[5,4-b]pyridin-2-amine [ka] The title compound (139 mg, 86%) was prepared from tert-butyl (5-(2,4-dichlorophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 296.1.

[0436] Step 3: N-(5-(2,4-dichlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide The title compound (28 mg, 12%) was prepared from 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid and 5-(2,4-dichlorophenyl)thiazolo[5,4-b]pyridin-2-amine in a manner similar to step 3 of example 11. 1H NMR (400 MHz, d6-DMSO) δ 13.34 (s, 1H), 9.50 (s, 1H), 9.40 (s, 1H), 8.21 (d, J = 7.7 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.73 - 7.66 (m, 1H), 7.61 - 7.43 (m, 3H), 7.14 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 3.56 (s, 3H). LC-MS (M+H) + = 508.3.

[0437] Example 118: 5-(2-Methoxyphenyl)-N-(5-((tetrahydrofuran-2-yl)methoxy)thiazolo[5,4-b]pyridin-2-yl)pyridazine-4-carboxamide [ka] N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide (69.3 mg, 0.678 mmole) was dissolved in dry THF (5 mL). NaH (22.6 mg, 0.6565 mmole) was added at 0° C. under nitrogen atmosphere. (Tetrahydrofuran-2-yl)methanol (100 mg, 0.226 mmole) and CuI (200 mg, 1.05 mmol) were added and heated to 80° C. under nitrogen atmosphere for 14 hours. Water (10 mL) was added and extracted with ethyl acetate. The combined organic layers were washed with brine and Na 2 SO 4Drying at 4° C. The title compound (4 mg, 3.8%) was obtained by silica gel chromatography and purification by preparative HPLC. 1H NMR (400 MHz, d6-DMSO) δ 13.06 (s, 1H), 9.46 (s, 1H), 9.41 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.61 - 7.40 (m, 2H), 7.14 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.24 (tdd, J = 10.6, 8.8, 3.9 Hz, 3H), 3.79 (dd, J = 14.7, 6.8 Hz, 1H), 3.67 (dd, J = 13.9, 7.6 Hz, 1H), 3.54 (s, 3H), 2.00 (d, J = 8.3 Hz, 1H), 1.94 - 1.77 (m, 2H), 1.74 - 1.61 (m, 1H). LC-MS (M+H) + = 464.0.

[0438] Example 119: N-(5-(4-cyano-2-methoxyphenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka] Step 1: tert-Butyl (5-(4-cyano-2-methoxyphenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate [ka] The title compound (348 mg, 99%) was prepared from tert-butyl (5-bromothiazolo[5,4-b]pyridin-2-yl)carbamate and 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile in a manner similar to step 3 of example 78. LC-MS (M+H) + = 383.0.

[0439] Step 2: 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)-3-methoxybenzonitrile [ka] The title compound (101 mg, 39%) was prepared from tert-butyl (5-(4-cyano-2-methoxyphenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate in a similar manner to step 6 of example 1. LC-MS (M+H) + = 283.0.

[0440] Step 3: N-(5-(4-cyano-2-methoxyphenyl)thiazolo[5,4-b]pyridin-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide The title compound (60 mg, 22%) was prepared from 4-(2-aminothiazolo[5,4-b]pyridin-5-yl)-3-methoxybenzonitrile and 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid in a manner similar to that described in step 3 of Example 11. 1H NMR (400 MHz, d6-DMSO)δ 13.32 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 1.1 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.52 - 7.45 (m, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 3.93 (s, 3H), 3.56 (s, 3H). LC-MS (M+H) + = 495.0.

[0441] Example 120: N-(5-(4-cyanophenyl)thiazolo[5,4-b]pyridin-2-yl)-1,2,6'-trimethyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-3'-carboxamide [ka] Step 1: 5-Bromo-1,6-dimethylpyridin-2(1H)-one [ka] The title compound (651 mg, 59%) was prepared from 5-bromo-6-methylpyridin-2(1H)-one and iodomethane in a manner similar to that described in step 1 of Example 87. LC-MS (M+H) + = 202.0.

[0442] Step 2: 1,6-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one [ka] ...

Claims

1. Compounds of formula (I): 【Chemistry 506】 or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof. [In the formula, Ring CyA is a 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O, or S as ring member(s); R １ is -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, haloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR １ａ , -SO ２ R １ａ , -SO ２ N.R. １ａ R １ｂ , -P(O)R １ａ R １ｂ , -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -NR １ａ R １ｂ , -NR １ａ C.O.R. １ｂ , -NR １ａ CO ２ R １ｂ , -NR １ａ C.O.N.R. １ｂ R １ｃ or -NR １ａ SO ２ R １ｂ and said C １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R １ｄ is replaced by R １ａ , R １ｂ , and R １ｃ are each independently hydrogen, -C １－８ alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R １ｆ is replaced by, or (R １ａ and R １ｂ ), (R １ｂ and R １ｃ ), or (R １ａ and R １ｃ ) together with the atom(s) to which they are attached form a 3- to 12-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R １ｆ is replaced by R １ｄ and R １ｆ are each independently hydrogen, halogen, or -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR １ｇ , -SO ２ R １ｇ , -SO ２ N.R. １ｇ R １ｈ , -P(O)R １ｇ R １ｈ , -COR １ｇ , -CO ２ R １ｇ , -CONR １ｇ R １ｈ , -NO ２ , -NR １ｇ R １ｈ , -NR １ｇ C.O.R. １ｈ , -NR １ｇ CO ２ R １ｈ , -NR １ｇ C.O.N.R. １ｈ R １ｉ , or -NR １ｇ SO ２ R １ｈ and said -C １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R １ｊ is replaced by, or Two R's １ｄ Or two R's １ｆ are taken together with the atom(s) to which they are attached to form a 3- to 12-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R １ｋ is replaced by R １ｇ , R １ｈ , and R １ｉ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R １ｊ and R １ｋ are each independently hydrogen, halogen, or -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR １ｌ , -SO ２ R １ｌ , -SO ２ N.R. １ｌ R １ｍ , -COR １ｌ , -CO ２ R １ｌ , -CONR １ｌ R １ｍ , -NO ２ , -NR １ｌ R １ｍ , -NR １ｌ C.O.R. １ｍ , -NR １ｌ CO ２ R １ｍ , -NR １ｌ C.O.N.R. １ｍ R １ｎ or -NR １ｌ SO ２ R １ｍ and said -C １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl. R １ｌ , R １ｍ , and R １ｎ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R ２ is hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ２ａ is replaced by R ２ａ are each independently hydrogen, halogen, or -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ２ｂ , -SO ２ R ２ｂ , -SO ２ N.R. ２ｂ R ２ｃ , -COR ２ｂ , -CO ２ R ２ｂ , -CONR ２ｂ R ２ｃ , -NO ２ , -NR ２ｂ R ２ｃ , -NR ２ｂ C.O.R. ２ｃ , -NR ２ｂ CO ２ R ２ｃ , -NR ２ｂ C.O.N.R. ２ｃ R ２ｄ , or -NR ２ｂ SO ２ R ２ｃ and said -C １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ２ｅ is replaced by, or Two R's ２ａ are taken together with the atom(s) to which they are attached to form a 3- to 12-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R ２ｆ is replaced by R ２ｂ , R ２ｃ , and R ２ｄ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R ２ｅ and R ２ｆ are each independently hydrogen, halogen, or -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, -C １－８ alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ alkynyl, the above-C １－８ Each of the alkoxy, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R ３ and R ４ are each independently hydrogen, halogen, or -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ３ａ , -SO ２ R ３ａ , -SO ２ N.R. ３ａ R ３ｂ , -COR ３ａ , -CO ２ R ３ａ , -CONR ３ａ R ３ｂ , -NR ３ａ R ３ｂ , -NR ３ａ C.O.R. ３ｂ , -NR ３ａ CO ２ R ３ｂ , -NR ３ａ C.O.N.R. ３ｂ R ３ｃ or -NR ３ａ SO ２ R ３ｂ and said -C １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ３ｄ is replaced by R ３ａ , R ３ｂ , and R ３ｃ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ３ｆ is replaced by, or (R ３ａ and R ３ｂ ), (R ３ｂ and R ３ｃ ), or (R ３ａ and R ３ｃ ) together with the atom(s) to which they are attached form a 3- to 12-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R ３ｆ is replaced by R ３ｄ and R ３ｆ are each independently hydrogen, halogen, or -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ３ｇ , -SO ２ R ３ｇ , -SO ２ N.R. ３ｇ R ３ｈ , -COR ３ｇ , -CO ２ R ３ｇ , -CONR ３ｇ R ３ｈ , -NO ２ , -NR ３ｇ R ３ｈ , -NR ３ｇ C.O.R. ３ｈ , -NR ３ｇ CO ２ R ３ｈ , -NR ３ｇ C.O.N.R. ３ｈ R ３ｉ or -NR ３ｇ SO ２ R ３ｈ and said -C １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R ３ｇ , R ３ｈ , and R ３ｉ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R ５ is halogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ５ａ , -SR ５ａ , -SO ２ R ５ａ , -P(O)R ５ａ R ５ｂ , -SO ２ N.R. ５ａ R ５ｂ , -COR ５ａ , -CO ２ R ５ａ , -CONR ５ａ R ５ｂ , -NR ５ａ R ５ｂ , -NR ５ａ C.O.R. ５ｂ , -NR ５ａ CO ２ R ５ｂ , -NR ５ａ C.O.N.R. ５ｂ R ５ｃ or -NR ５ａ SO ２ R ５ｂ and said C １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ５ｄ is replaced by R ５ａ , R ５ｂ , and R ５ｃ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ５ｆ is replaced by, or (R ５ａ and R ５ｂ ), (R ５ｂ and R ５ｃ ), or (R ５ａ and R ５ｃ ) together with the atom(s) to which they are attached form a 3- to 12-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R ５ｆ is replaced by R ５ｄ and R ５ｆ are each independently hydrogen, halogen, or -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ５ｇ , -SO ２ R ５ｇ , -SO ２ N.R. ５ｇ R ５ｈ , -COR ５ｇ , -CO ２ R ５ｇ , -CONR ５ｇ R ５ｈ , -NO ２ , -P(O)R ５ｇ R ５ｈ , -NR ５ｇ R ５ｈ , -NR ５ｇ C.O.R. ５ｈ , -NR ５ｇ CO ２ R ５ｈ , -NR ５ｇ C.O.N.R. ５ｈ R ５ｉ , or -NR ５ｇ SO ２ R ５ｈ and said -C １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ５ｊ is replaced by, or Two R's ５ｄ Or two R's ５ｆ are taken together with the atom(s) to which they are attached to form a 3- to 12-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R ５ｋ is replaced by R ５ｇ , R ５ｈ , and R ５ｉ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; (R ５ｇ and R ５ｈ ), (R ５ｈ and R ５ｉ ), or (R ５ｇ and R ５ｉ ) together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R ５ｊ and R ５ｋ are each independently hydrogen, halogen, or -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ５ｌ , -SO ２ R ５ｌ , -SO ２ N.R. ５ｌ R ５ｍ , -COR ５ｌ , -CO ２ R ５ｌ , -CONR ５ｌ R ５ｍ , -NO ２ , -NR ５ｌ R ５ｍ , -NR ５ｌ C.O.R. ５ｍ , -NR ５ｌ CO ２ R ５ｍ , -NR ５ｌ C.O.N.R. ５ｍ R ５ｎ or -NR ５ｌ SO ２ R ５ｍ and said -C １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl. R ５ｌ , R ５ｍ , and R ５ｎ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R ｚ is, at each occurrence, hydrogen, halogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ｚａ , -SO ２ R ｚａ , -SO ２ N.R. ｚａ R ｚｂ , -COR ｚａ , -CO ２ R ｚａ , -CONR ｚａ R ｚｂ , -NR ｚａ R ｚｂ , -NR ｚａ C.O.R. ｚｂ , -NR ｚａ CO ２ R ｚｂ , -NR ｚａ C.O.N.R. ｚｂ R ｚｃ or -NR ｚａ SO ２ R ｚｂ and said -C １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ｚｄ is replaced by R ｚａ , R ｚｂ , and R ｚｃ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ｚｆ is replaced by, or (R ｚａ and R ｚｂ ), (R ｚｂ and R ｚｃ ), or (R ｚａ and R ｚｃ ) together with the atom(s) to which they are attached form a 3- to 12-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R ｚｆ is replaced by R ｚｄ and R ｚｆ are each independently hydrogen, halogen, or -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ｚｇ , -SO ２ R ｚｇ , -SO ２ N.R. ｚｇ R ｚｈ , -COR ｚｇ , -CO ２ R ｚｇ , -CONR ｚｇ R ｚｈ , -NO ２ , -NR ｚｇ R ｚｈ , -NR ｚｇ C.O.R. ｚｈ , -NR ｚｇ CO ２ R ｚｈ , -NR ｚｇ C.O.N.R. ｚｈ R ｚｉ , or -NR ｚｇ SO ２ R ｚｈ and said -C １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ｚｊ is replaced by, or Two R's ｚｄ Or two R's ｚｆ are taken together with the atom(s) to which they are attached to form a 3- to 12-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R ｚｋ is replaced by R ｚｇ , R ｚｈ , and R ｚｉ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R ｚｊ and R ｚｋ are each independently hydrogen, halogen, or -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, -C １－８ alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－８ Alkyl, the above-C ２－８ alkenyl, the above-C ２－８ alkynyl, the above-C １－８ Each of the alkoxy, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, -C １－８ Alkyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; n1 is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

2. 2. The compound of claim 1, wherein the compound is selected from formula (IIa), (IIb), (IIc), (IId), or (IIe). 【Chemistry 507】 [In the formula, Z １ , Z ２ , Z ３ , and Z ４ are each independently N or CR ｚ And Z ５ is N.R. ｚ , O, or S; R １ , R ２ , R ３ , R ４ , and R ５ are each defined as claim 1.

3. 2. The compound according to any one of the preceding claims, wherein the compound is selected from formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), or (IIIk). 【Chemistry 508】 【Chemistry 509】 [In the formula, n1, R ｚ , R １ , R ２ , R ３ , R ４ , and R ５ are each defined as claim 1.

4. 2. The compound according to any one of the preceding claims, wherein the compound is selected from formula (IVa), (IVb), (IVc), or (IVd). 【Chemistry 510】 [In the formula, CyB and CyC are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl; AlkD and AlkE are each -C １－８ Alkyl, -C ２－８ alkenyl, or -C ２－８ is alkynyl, n2 and n3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; R １ , R ２ , R ３ , R ４ , R ５ｄ , R ５ｆ , R ｚ , n1, and CyA are each defined as in any one of the preceding claims.

5. The compound according to any one of claims 2 to 4, wherein the compound is selected from formula (Va), (Vb), (Vc), (Vd). 【Chemistry 511】 [In the formula, CyB, CyC, AlkD, AlkE, R １ , R ２ , R ３ , R ４ , R ５ｄ , R ５ｆ , Z １ , Z ２ , Z ３ , Z ４ , n2, and n3 are defined as in any one of the preceding claims.

6. 2. A compound according to any one of the preceding claims, wherein ring CyA is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from N, O, or S as ring member(s).

7. 2. A compound according to any one of the preceding claims, wherein the ring CyA is a 5- or 6-membered heteroaromatic ring containing 1-2 heteroatoms selected from N, O or S as ring member(s), preferably pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, isoimidazolyl, oxazolyl, thiazolyl, furanyl or thiophenyl.

8. R １ is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl, oxo, -CN, -OR １ａ , -SO ２ R １ａ , -SO ２ N.R. １ａ R １ｂ , -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -NR １ａ R １ｂ , -NR １ａ C.O.R. １ｂ , -NR １ａ CO ２ R １ｂ , -NR １ａ C.O.N.R. １ｂ R １ｃ or -NR １ａ SO ２ R １ｂ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R １ｄ is replaced by R １ａ , R １ｂ , and R １ｃ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R １ｆ is replaced by, or (R １ａ and R １ｂ ), (R １ｂ and R １ｃ ), or (R １ａ and R １ｃ ), taken together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R １ｆ is replaced by R １ｄ and R １ｆ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the aryl, the heteroaryl, oxo, -CN, -OR １ｇ , -SO ２ R １ｇ , -SO ２ N.R. １ｇ R １ｈ , -COR １ｇ , -CO ２ R １ｇ , -CONR １ｇ R １ｈ , -NO ２ , -NR １ｇ R １ｈ , -NR １ｇ C.O.R. １ｈ , -NR １ｇ CO ２ R １ｈ , -NR １ｇ C.O.N.R. １ｈ R １ｉ , or -NR １ｇ SO ２ R １ｈ , the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R １ｊ is replaced by, or Two R's １ｄ Or two R's １ｆ are taken together with the atom(s) to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R １ｋ is replaced by R １ｇ , R １ｈ , and R １ｉ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; ２－８ alkenyl, the above-C ２－８ The alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R １ｊ and R １ｋ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR １ｌ , -SO ２ R １ｌ , -SO ２ N.R. １ｌ R １ｍ , -COR １ｌ , -CO ２ R １ｌ , -CONR １ｌ R １ｍ , -NO ２ , -NR １ｌ R １ｍ , -NR １ｌ C.O.R. １ｍ , -NR １ｌ CO ２ R １ｍ , -NR １ｌ C.O.N.R. １ｍ R １ｎ or -NR １ｌ SO ２ R １ｍ wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R １ｌ , R １ｍ , and R １ｎ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ 20. A compound according to any one of the preceding claims substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl.

9. R １ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, dihydropiperazinyl, phenyl, indazolyl, benzodioxolyl, benzoxazinyl, dihydrobenzoxazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, quinolinyl, or isoquinolinyl, and Each of the cyclohexyl, the cycloheptyl, the cyclooctyl, the morpholinyl, the piperidinyl, the piperazinyl, the dihydropyridinyl, the dihydropiperazinyl, the phenyl, the indazolyl, the benzodioxolyl, the benzoxazinyl, the dihydrobenzoxazinyl, the indolyl, the benzimidazolyl, the benzoxazolyl, the benzofuranyl, the quinolinyl, or the isoquinolinyl may optionally be selected from the group consisting of at least one substituent R １ｄ is replaced by R １ｄ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 6-membered heterocyclyl, aryl, or heteroaryl; and ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, the heteroaryl, oxo, -CN, -OR １ｇ , -SO ２ R １ｇ , -SO ２ N.R. １ｇ R １ｈ , -COR １ｇ , -CO ２ R １ｇ , -CONR １ｇ R １ｈ , -NO ２ , -NR １ｇ R １ｈ , -NR １ｇ C.O.R. １ｈ , -NR １ｇ CO ２ R １ｈ , -NR １ｇ C.O.N.R. １ｈ R １ｉ , or -NR １ｇ SO ２ R １ｈ , the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R １ｊ is replaced by, or Two R's １ｄ are taken together with the atom(s) to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R １ｋ is replaced by R １ｇ , R １ｈ , and R １ｉ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; ２－８ alkenyl, the above-C ２－８ The alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R １ｊ and R １ｋ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR １ｌ , -SO ２ R １ｌ , -SO ２ N.R. １ｌ R １ｍ , -COR １ｌ , -CO ２ R １ｌ , -CONR １ｌ R １ｍ , -NO ２ , -NR １ｌ R １ｍ , -NR １ｌ C.O.R. １ｍ , -NR １ｌ CO ２ R １ｍ , -NR １ｌ C.O.N.R. １ｍ R １ｎ or -NR １ｌ SO ２ R １ｍ wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R １ｌ , R １ｍ , and R １ｎ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ 20. A compound according to any one of the preceding claims substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl.

10. R １ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, dihydropiperazinyl, phenyl, indazolyl, benzodioxolyl, benzoxazinyl, dihydrobenzoxazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, quinolinyl, or isoquinolinyl, and Each of the cyclohexyl, the cycloheptyl, the cyclooctyl, the morpholinyl, the piperidinyl, the piperazinyl, the dihydropyridinyl, the dihydropiperazinyl, the phenyl, the indazolyl, the benzodioxolyl, the benzoxazinyl, the dihydrobenzoxazinyl, the indolyl, the benzimidazolyl, the benzoxazolyl, the benzofuranyl, the quinolinyl, or the isoquinolinyl may optionally be selected from the group consisting of at least one substituent R １ｄ is replaced by R １ｄ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, oxo, -CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, methoxy, ethoxypropoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, pyranyl, morpholinyl, oxiranyl, azetidinyl, azocanyl, thiiranyl, azetidinyl, -CF ３ , -CONH ２ , -CH ２ OCH ３ , -SO ２ (CH ３ ) ２ , -CH ２ OH, -NO ２ Selected from, or Two R's １ｄ are taken together with the atom(s) to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R １ｋ is replaced by R １ｋ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -CF ３ , -CONH ２ , -CH ２ OCH ３ , -SO ２ (CH ３ ) ２ , -CH ２ OH, -NO ２ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ 20. A compound according to any one of the preceding claims substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl.

11. R １ but, 【Chemistry 512】 2. A compound according to any one of the preceding claims,

12. R ｚ is, at each occurrence, independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR ｚａ , -SO ２ R ｚａ , -SO ２ N.R. ｚａ R ｚｂ , -COR ｚａ , -CO ２ R ｚａ , -CONR ｚａ R ｚｂ , -NR ｚａ R ｚｂ , -NR ｚａ C.O.R. ｚｂ , -NR ｚａ CO ２ R ｚｂ , -NR ｚａ C.O.N.R. ｚｂ R ｚｃ or -NR ｚａ SO ２ R ｚｂ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ｚｄ is replaced by R ｚａ , R ｚｂ , and R ｚｃ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ｚｆ is replaced by, or (R ｚａ and R ｚｂ ), (R ｚｂ and R ｚｃ ), or (R ｚａ and R ｚｃ ) taken together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R ｚｆ is replaced by R ｚｄ and R ｚｆ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR ｚｇ , -SO ２ R ｚｇ , -SO ２ N.R. ｚｇ R ｚｈ , -COR ｚｇ , -CO ２ R ｚｇ , -CONR ｚｇ R ｚｈ , -NO ２ , -NR ｚｇ R ｚｈ , -NR ｚｇ C.O.R. ｚｈ , -NR ｚｇ CO ２ R ｚｈ , -NR ｚｇ C.O.N.R. ｚｈ R ｚｉ , or -NR ｚｇ SO ２ R ｚｈ wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ｚｊ is replaced by, or Two R's ｚｄ Or two R's ｚｆ are taken together with the atom(s) to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R ｚｋ is replaced by R ｚｇ , R ｚｈ , and R ｚｉ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R ｚｊ and R ｚｋ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN; wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of alkynyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptoxy, the octoxy, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent. -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ 20. A compound according to any one of the preceding claims substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

13. R ｚ is, at each occurrence, independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR ｚａ , -COR ｚａ , -CO ２ R ｚａ , -CONR ｚａ R ｚｂ or -NR ｚａ R ｚｂ wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl optionally comprises at least one substituent R ｚｄ is replaced by R ｚａ and R ｚｂ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl; or R ｚｄ are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ 2. A compound according to any one of the preceding claims, selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, or -OH.

14. R ｚ is, at each occurrence, independently H, —CN, —CH ３ , -Cl, -CH ２ CN, -CF ３ , —F, —COOH, or —CH ２ 2. A compound according to any one of the preceding claims, wherein said compound is OH.

15. The above 【Chemistry 513】 The part is, 【Chemistry 514】 2. A compound according to any one of the preceding claims,

16. The above 【Chemistry 515】 The part is, 【Chemistry 516】 【Chemistry 517】 2. A compound according to any one of the preceding claims,

17. R ２ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R ２ａ is replaced by R ２ａ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, -OR ２ｂ , -SO ２ R ２ｂ , -SO ２ N.R. ２ｂ R ２ｃ , -COR ２ｂ , -CO ２ R ２ｂ , -CONR ２ｂ R ２ｃ , -NO ２ , -NR ２ｂ R ２ｃ , -NR ２ｂ C.O.R. ２ｃ , -NR ２ｂ CO ２ R ２ｃ , -NR ２ｂ C.O.N.R. ２ｃ R ２ｄ , or -NR ２ｂ SO ２ R ２ｃ wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R ２ｅ is replaced by, or Two R's ２ａ are taken together with the atom(s) to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R ２ｆ is replaced by R ２ｂ , R ２ｃ , and R ２ｄ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally contains at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, 5-10 membered heteroaryl, or haloheteroaryl; R ２ｅ and R ２ｆ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; ２－８ alkenyl, the above-C ２－８ Each of alkynyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptoxy, the octoxy, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally contains at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ 20. A compound according to any one of the preceding claims substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

18. R ２ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally contains at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; Preferably, R ２ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; More preferably, R ２ 2. A compound according to any one of the preceding claims, wherein is hydrogen.

19. R ３ and R ４ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl, oxo, -CN, -OR ３ａ , -SO ２ R ３ａ , -SO ２ N.R. ３ａ R ３ｂ , -COR ３ａ , -CO ２ R ３ａ , -CONR ３ａ R ３ｂ , -NR ３ａ R ３ｂ , -NR ３ａ C.O.R. ３ｂ , -NR ３ａ CO ２ R ３ｂ , -NR ３ａ C.O.N.R. ３ｂ R ３ｃ or -NR ３ａ SO ２ R ３ｂ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R ３ｄ is replaced by R ３ａ , R ３ｂ , and R ３ｃ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may optionally be selected from the group consisting of at least one substituent R ３ｆ is replaced by, or (R ３ａ and R ３ｂ ), (R ３ｂ and R ３ｃ ), or (R ３ａ and R ３ｃ ), taken together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R ３ｆ is replaced by R ３ｄ and R ３ｆ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl, oxo, -CN, -OR ３ｇ , -SO ２ R ３ｇ , -SO ２ N.R. ３ｇ R ３ｈ , -COR ３ｇ , -CO ２ R ３ｇ , -CONR ３ｇ R ３ｈ , -NO ２ , -NR ３ｇ R ３ｈ , -NR ３ｇ C.O.R. ３ｈ , -NR ３ｇ CO ２ R ３ｈ , -NR ３ｇ C.O.N.R. ３ｈ R ３ｉ or -NR ３ｇ SO ２ R ３ｈ wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally contains at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R ３ｇ , R ３ｈ , and R ３ｉ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally contains at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ 20. A compound according to any one of the preceding claims substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

20. R ３ and R ４ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl, oxo, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy; and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally contains at least one substituent -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl, oxo, -CN, -NO ２ , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy.

21. R ３ and R ４ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl, oxo, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy; Preferably, R ３ and R ４ 4. A compound according to any one of the preceding claims, wherein each is independently hydrogen.

22. R ５ is -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl, oxo, -CN, -OR ５ａ , -SO ２ R ５ａ , -SO ２ N.R. ５ａ R ５ｂ , -COR ５ａ , -CO ２ R ５ａ , -CONR ５ａ R ５ｂ , -NR ５ａ R ５ｂ , -NR ５ａ C.O.R. ５ｂ , -NR ５ａ CO ２ R ５ｂ , -NR ５ａ C.O.N.R. ５ｂ R ５ｃ or -NR ５ａ SO ２ R ５ｂ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R ５ｄ is replaced by R ５ａ , R ５ｂ , and R ５ｃ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, and the 5- to 10-membered heteroaryl may optionally be selected from the group consisting of at least one substituent R ５ｆ is replaced by, or (R ５ａ and R ５ｂ ), (R ５ｂ and R ５ｃ ), or (R ５ａ and R ５ｃ ), taken together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R ５ｆ is replaced by R ５ｄ and R ５ｆ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, -OR ５ｇ , -SO ２ R ５ｇ , -SO ２ N.R. ５ｇ R ５ｈ , -COR ５ｇ , -CO ２ R ５ｇ , -CONR ５ｇ R ５ｈ , -NO ２ , -NR ５ｇ R ５ｈ , -NR ５ｇ C.O.R. ５ｈ , -NR ５ｇ CO ２ R ５ｈ , -NR ５ｇ C.O.N.R. ５ｈ R ５ｉ , or -NR ５ｇ SO ２ R ５ｈ wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R ５ｊ is replaced by, or Two R's ５ｄ Or two R's ５ｆ are taken together with the atom(s) to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R ５ｋ is replaced by R ５ｇ , R ５ｈ , and R ５ｉ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally contains at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, or 5-10 membered heteroaryl; (R ５ｇ and R ５ｈ ), (R ５ｈ and R ５ｉ ), or (R ５ｇ and R ５ｉ ), taken together with the atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5- to 8-membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R ５ｊ and R ５ｋ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, heteroaryl, oxo, -CN, -SO ２ R ５ｌ , -SO ２ N.R. ５ｌ R ５ｍ , -COR ５ｌ , -CO ２ R ５ｌ , -CONR ５ｌ R ５ｍ , -NO ２ , -NR ５ｌ R ５ｍ , -NR ５ｌ C.O.R. ５ｍ , -NR ５ｌ CO ２ R ５ｍ , -NR ５ｌ C.O.N.R. ５ｍ R ５ｎ or -NR ５ｌ SO ２ R ５ｍ wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R ５ｌ , R ５ｍ , and R ５ｎ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, or heteroaryl, and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ 2. A compound according to any one of the preceding claims substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

23. R ５ is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl, -OR ５ａ , -CONR ５ａ R ５ｂ , -COR ５ａ , -CO ２ R ５ａ , -NR ５ａ R ５ｂ or -NR ５ａ C.O.R. ５ｂ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R ５ｄ is replaced by R ５ａ , R ５ｂ , and R ５ｃ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, and the 5- to 10-membered heteroaryl may optionally be selected from the group consisting of at least one substituent R ５ｆ is replaced by, or (R ５ａ and R ５ｂ ), (R ５ｂ and R ５ｃ ), or (R ５ａ and R ５ｃ ), taken together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent R ５ｆ is replaced by R ５ｄ and R ５ｆ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, 5-10 membered heteroaryl, oxo, -CN, -OR ５ｇ , -SO ２ R ５ｇ , -SO ２ N.R. ５ｇ R ５ｈ , -COR ５ｇ , -CO ２ R ５ｇ , -CONR ５ｇ R ５ｈ , -NO ２ , -NR ５ｇ R ５ｈ , -NR ５ｇ C.O.R. ５ｈ , -NR ５ｇ CO ２ R ５ｈ , -NR ５ｇ C.O.N.R. ５ｈ R ５ｉ , or -NR ５ｇ SO ２ R ５ｈ wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally has at least one substituent R ５ｊ is replaced by, or Two R's ５ｄ Or two R's ５ｆ are taken together with the atom(s) to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing as ring member(s) 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R ５ｋ is replaced by R ５ｇ , R ５ｈ , and R ５ｉ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the 5- to 10-membered heteroaryl optionally contains at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, or 5-10 membered heteroaryl; (R ５ｇ and R ５ｈ ), (R ５ｈ and R ５ｉ ), or (R ５ｇ and R ５ｉ ), taken together with the atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring optionally containing at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5- to 8-membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R ５ｊ and R ５ｋ each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR ５ｌ , -SO ２ R ５ｌ , -SO ２ N.R. ５ｌ R ５ｍ , -COR ５ｌ , -CO ２ R ５ｌ , -CONR ５ｌ R ５ｍ , -NO ２ , -NR ５ｌ R ５ｍ , -NR ５ｌ C.O.R. ５ｍ , -NR ５ｌ CO ２ R ５ｍ , -NR ５ｌ C.O.N.R. ５ｍ R ５ｎ or -NR ５ｌ SO ２ R ５ｍ wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the heteroaryl may optionally contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R ５ｌ , R ５ｍ , and R ５ｎ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 5-8 membered heterocyclyl, phenyl, or heteroaryl, and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, the above-C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 5- to 8-membered heterocyclyl, the phenyl, or the heteroaryl may optionally contain at least one substituent halogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ 2. A compound according to any one of the preceding claims substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, 5-8 membered heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

24. R ５ but, 【Chemistry 518】 2. A compound according to any one of the preceding claims, [In the formula, CyB, AlkD, CyC, AlkE, R ５ｄ , R ５ｆ , n2, and n3 are each defined as in any one of the preceding claims.

25. R ５ but, 【Chemistry 519】 【Chemistry 520】 2. A compound according to any one of the preceding claims,

26. A compound according to any one of the preceding claims, wherein the compound is selected from: 【Chemistry 521】 【Chemistry 522】 【Chemistry 523】 【Chemistry 524】 【Chemistry 525】 【Chemistry 526】 【Chemistry 527】 【Chemistry 528】 【Chemical 529】 【Chemistry 530】

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, and at least one pharma- ceutically acceptable carrier or excipient.

28. 27. A method of inhibiting Pol theta ATPase activity, comprising administering to an individual a compound according to any one of claims 1 to 26, or a pharma- ceutically acceptable salt or stereoisomer thereof.

29. 27. A method for treating a disease or disorder in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 26, or a pharma- ceutically acceptable salt or stereoisomer thereof, as a Pol theta inhibitor.

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