4-Ethynylpyridine derivatives useful as GCN2 inhibitors

Abstract

The present invention provides compounds of Formula I, wherein the substituents are as further described herein. The compounds are potent inhibitors of GCN2 and have excellent pharmacokinetic properties. The compounds are useful for treating or preventing various conditions, particularly cancer. The present invention further provides pharmaceutical compositions comprising the compounds of the present invention, and uses of the compounds and compositions. [Formula 1] TIFF2023529926000095.tif41128

Description

[Technical Field]

[0001] This invention relates to compounds of formula (I), pharmaceutical compositions thereof, and their use as pharmaceuticals. The compounds of this invention are inhibitors of general control nonderepressible 2 (GCN2) and are therefore useful for the treatment or prevention of various conditions, particularly in the treatment of diseases such as cancer. [Background technology]

[0002] The kinase Generalized Unrepressive 2 (GCN2), encoded by EIF2AK4, is a crucial regulator of cellular adaptation to amino acid deficiencies (Non-Patent Document 1). GCN2 is activated when uncharged tRNAs accumulate as a result of low amino acid levels (Non-Patent Documents 2 and 3). Activated GCN2 phosphorylates its only known target, the translation initiation factor eIF2α, leading to an overall attenuation of protein synthesis. GCN2 also modulates sestrin 2-mediated repression of mTORC1 and induces autophagy (Non-Patent Documents 4, 5, 6, and 7). In summary, these GCN2 effects promote cellular recovery from amino acid deficiencies.

[0003] In solid tumors, GCN2 signaling is crucial for cancer cell survival under nutrient-deficient conditions (Non-Patent Documents 8, 9, and 10). GCN2 has also been shown to play a vital role in MYC-driven tumor progression by adapting protein synthesis to ensure that translation rates are compatible with the bioenergy capacity and survival of cancer cells (Non-Patent Documents 11 and 12). Furthermore, some tumors may depend on myeloid GCN2 signaling for protection from anti-cancer immune attacks (Non-Patent Document 13). GCN2 depletion enhances the antitumor effect of asparaginase therapy (Non-Patent Documents 14 and 15). Importantly, GCN2-deficient mice do not exhibit macroscopic lesions unless fed a diet lacking essential amino acids (Non-Patent Documents 16 and 17). Taken together, these data suggest that GCN2 inhibition may be an effective cancer therapy in a diverse range of cancers.

[0004] Furthermore, it has been shown that proteasome inhibitors cause intracellular amino acid deficiency, and that this effect may be a major cause of multiple myeloma cell death during proteasome inhibitor treatment (Non-Patent Documents 18, 19, and 20). Therefore, GCN2 inhibition is predicted to be particularly effective in combination with proteasome inhibitors in the treatment of multiple myeloma.

[0005] There are very few known inhibitors of GCN2. Patent document 1 (Takeda Pharmaceutical Company Limited) discloses a series of GCN2 inhibitor compounds having an alkenylphenyl core. Other GCN2 inhibitor compounds are disclosed in non-patent document 21, as well as in patent documents 2 and 3. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2018 / 030466 [Patent Document 2] U.S. Patent and Trademark Office Publication No. 2019 / 0233411 [License 3] U.S. Patent and Trademark Office Publication No. 2019 / 0233425 [Non-licensed literature]

[0007] [Non-licensed Document 1] Castilho,BA,et al(2014)Biochim Biophys Acta 1843,1948-1968 [Non-licensed Document 2] Romano,PR,et al(1998)AutMol Cell Biol 18,2282-2297 [Non-licensed Document 3] Wek,SA,et al(1995)Mol Cell Biol 15,4497-4506 [Non-licensed Document 4] Talloczy,Z.,et al(2002)Proc Natl Acad Sci USA 99,190-195 [Non-licensed Document 5] Wengrod,J.,et al(2015)Sci Signal 8,ra27,B'Chir,W.,et al(2013)Nucleic Acids Res 41,7683-7699 [Non-licensed Document 6] Ye,J.,et al(2015)Genes Dev 29,2331-2336 [Non-licensed Document 7] Ravindran,R.,et al(2016)Nature 531,523-527 [Non-licensed Document 8] Wang,Y.,et al(2013)Neoplasia 15,989-997 [Non-licensed Document 9] Ye,J.,et al(2010)EMBO J 29,2082-2096 [Non-licensed Document 10] Parzych,K.,et al(2019)Oncogene 38,3216-3231

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Non-Patent Document 17

Non-Patent Document 18

Non-Patent Document 19

Non-Patent Document 20

Non-Patent Document 21

Summary of the Invention

Problems to be Solved by the Invention

[0008] There is a need in the art for additional GCN2 inhibitor compounds, particularly GCN2 inhibitor compounds having high potency, and having good pharmacokinetic properties such as good solubility, and thus being useful, for example, as pharmaceuticals for the treatment of cancer.

Means for Solving the Problems

[0009] The present invention provides a compound of formula (I), or a pharmaceutically acceptable ester, amide, carbamate, or salt thereof (including pharmaceutically acceptable salts of such esters, amides, or carbamates),

[0010]

Chemical Formula

[0011] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier or excipient.

[0012] The present invention further provides a pharmaceutical composition comprising a compound of formula (I), wherein the composition further comprises at least one further therapeutic agent.

[0013] The present invention further provides a compound according to formula (I) or a pharmaceutical composition containing a compound according to formula (I) for use as a pharmaceutical.

[0014] The present invention further provides a compound according to formula (I) or a pharmaceutical composition comprising a compound according to formula (I) for use in the treatment or prevention of diseases or disorders in which inhibition of GCN2 provides a therapeutic effect.

[0015] The present invention further provides a compound according to formula (I) or a pharmaceutical composition comprising a compound according to formula (I) for use in the treatment of a disease or disorder selected from the group consisting of cancer (for example, solid tumors and hematological cancers).

[0016] The present invention further provides a method for treating or preventing a disease or disorder in which inhibition of GCN2 in a mammal results in a therapeutic effect (for example, the treatment or prevention of cancer in a mammal), comprising administering a therapeutically effective amount of a compound according to formula (I) or a pharmaceutical composition containing a compound according to formula (I) to a mammal.

[0017] The present invention further provides the use of a compound according to formula (I) for the manufacture of a pharmaceutical product for the treatment or prevention of a disease or disorder in which inhibition of GCN2 results in a therapeutic effect (e.g., for the treatment or prevention of cancer).

[0018] Further advantageous features of various embodiments of the present invention are defined in the dependent claims and the following embodiments for carrying out the invention. [Modes for carrying out the invention]

[0019] The present invention provides a compound of formula (I) as defined above and a pharmaceutical composition comprising the compound of formula (I).

[0020] The compounds of the present invention have been found to be potent inhibitors of GCN2. Therefore, the compounds of the present invention inhibit GCN2 activity and / or translation of the initiation factor eIF2α, resulting in an overall attenuation of protein synthesis in the subject.

[0021] The compounds of the present invention have excellent pharmacokinetic properties. In particular, they have good solubility in aqueous media. The compounds of the present invention also have good bioavailability and very suitable "drug-like" pharmacokinetic properties. Therefore, the present invention also provides therapeutic use of compounds of formula (I) and pharmaceutical compositions comprising compounds of formula (I).

[0022] As stated in the introduction, International Publication No. 2018 / 030466 (Takeda Pharmaceutical Company Limited) discloses a series of GCN2 inhibitor compounds having an alkynylphenyl core. The compounds of the present invention have been found to have remarkably superior properties compared to the compounds disclosed in International Publication No. 2018 / 030466. As demonstrated by the data herein, the compounds of the present invention are remarkably soluble in aqueous media and also exhibit strong efficacy in inhibiting GCN2 activity.

[0023] Furthermore, the inventors have found that the compounds of the present invention exhibit good kinase selectivity for GCN2. The inventors have also found that the kinase selectivity of the compounds of the present invention is superior to that of the compounds described in International Publication No. 2018 / 030466 in the KINOMEscan® assay.

[0024] The implementation of the present invention utilizes conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology, unless otherwise indicated. Such techniques are described in literature such as "Comprehensive Organic Synthesis" (BMTrost & I. Fleming, eds., 1991–1992), "Handbook of Experimental Immunology" (DMWeir & CCBlackwell, eds., 1986), "Current Protocols in Molecular Biology" (FMAusubelet al., eds., 1987, and periodically updated), and "Current Protocols in Immunology" (JEColiganet al., eds., 1991), each of which is incorporated herein by reference in whole.

[0025] Various aspects of the present invention are described in the following sections, however, the aspects of the present invention described in one particular section are not limited to any particular section. Furthermore, if a variable is not defined, the preceding definition of the variable may apply.

[0026] Embodiments of the Invention The present invention provides compounds according to general formula (I) (for example, the compounds are compounds of the following formulas (IA) or (IB)), or pharmaceutically acceptable esters, amides, carbamates, or salts thereof (including pharmaceutically acceptable salts of such esters, amides, or carbamates).

[0027] [ka]

[0028] Depending on the substituents present in the compound of the present invention, the compound may exist as a stereoisomer. In particular, the compound of the present invention may contain a chiral (asymmetric) center, or the compound as a whole may be chiral. All individual stereoisomers, as well as mixtures thereof, are within the scope of the present invention.

[0029] Diastereomer mixtures can be separated into their individual diastereoisomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by chiral HPLC column. Enantiomers can also be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or moscherate), separating the diastereomers, and converting the individual diastereomers back into their corresponding pure enantiomers (e.g., by hydrolysis).

[0030] Isotope forms are also included within the scope of the present invention, for example, when a hydrogen atom is substituted with deuterium or tritium, or when a carbon atom is substituted with a carbon-13 atom. Certain isotope forms may have beneficial biological properties, such as improved metabolic stability or enhanced therapeutic activity compared to other isotope forms, or certain isotope forms may be useful for biological imaging purposes, for example, carbon-11, nitrogen-13, oxygen-15, or fluorine-18 isotope variants can be used in positron emission tomography.

[0031] In one preferred embodiment, R 4 is hydrogen, and therefore, the compound of the present invention is a compound of formula (IA).

[0032] [ka]

[0033] In another particularly preferred embodiment, the compound of the present invention is a compound of formula (IB).

[0034] [ka] During the ceremony, m=0 or 1, n=0 R 1 However, it is an amino acid, Cy is a 5, 6, 7, 8, 9, or 10-membered monocyclic or bicyclic heteroaryl group comprising at least one N heteroatom and optionally one, two, or three further heteroatoms selected from the group consisting of N, such as pyrimidinyl, pyrazolopyridinyl, naphthilidinyl (e.g., 1,7-naphthilidinyl and 1,6-naphthilidinyl), pyridopyradinyl, pyrazolopyridinyl, imidazopyridyl, quinoxalinyl, or imidazopyradinyl. R 3 However, halogens, for example, F, A is a 5-membered, 6-membered, or 7-membered heteroaryl group, such as pyridyl, comprising one N heteroatom and one or two further heteroatoms selected from the group consisting of N. R 5 However, it is a halogen, R 6 However, OC 1~3 It is alkyl, R 7 But it's hydrogen.

[0035] In one embodiment, -A(R 5 , R 6 , R 7 ) is 2-C 1~3 Alkoxy 5-halopyridyls, for example, 2-methoxy-5-chloropyrido-3-yl.

[0036] In the compound of the present invention, R 3 is a halogen, for example, R 3 is F or Cl. In a preferred embodiment, R 3 It is F.

[0037] In the compound of the present invention, R 4R is selected from the group consisting of hydrogen and halogens. In one preferred embodiment, 4 is selected from the group consisting of hydrogen, F, and Cl. In another preferred embodiment, R 4 is selected from the group consisting of hydrogen and F.

[0038] In a very preferred embodiment, R 4 It is hydrogen.

[0039] In another very preferred embodiment, R 3 is F or Cl, and R 4 It is hydrogen.

[0040] In the compounds of the present invention, Cy is a 5, 6, 7, 8, 9, or 10-membered heteroaryl group comprising at least one N heteroatom and optionally one, two, or three further heteroatoms selected from the group consisting of N, S, and O (preferably N and S, more preferably N).

[0041] Preferably, Cy is a 5, 6, 7, 8, 9, or 10-membered heteroaryl group comprising at least one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N, S, and O (preferably N and S, more preferably N).

[0042] In one preferred embodiment, Cy is a 5, 6, 7, 8, 9, or 10-membered heteroaryl group comprising at least one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N and S (preferably N). In another preferred embodiment, Cy is a 5 or 6-membered heteroaryl group comprising at least one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N and S (preferably N), or Cy is a 9 or 10-membered heteroaryl group comprising at least one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N and S (preferably N). In another preferred embodiment, Cy is a five- or six-membered heteroaryl group comprising at least one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N and S (preferably N) (preferably one further heteroatom), or Cy is a nine- or ten-membered heteroaryl group comprising at least two N heteroatoms and optionally one further heteroatom selected from the group consisting of N and S (preferably N).

[0043] In certain embodiments, where Cy is a 5, 6, 7, 8, 9, or 10-membered heteroaryl group comprising at least one N heteroatom and optionally one, two, or three further heteroatoms selected from the group consisting of N, S, and O, the heteroaryl is pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, imidazolyl, thiazolyl, indolyl, pyryl, oxazolyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzimidazolyl (e.g., benzo[a]imidazolyl), benzopi The group can be selected from lazolyl (e.g., benzo[e]pyrazolyl), benzopyridazinyl (e.g., benzo[b]pyridazinyl, indolinyl, pyridoimidazolyl (e.g., pyrido[2,3-a]imidazol, pyrido[3,4-a]imidazole, pyrido[3,4-d]imidazole), pyridothiazolyl (e.g., pyrido[3,4-d]thiazolyl), pyridopyrazolyl (e.g., pyrido[3,4-c]pyrazolyl, pyrido[3,4-d]pyrazolyl, or pyrido[3,4-e]pyrazolyl), pyridopyridyl (e.g., pyrido[2,3-c]pyridyl), and pyrazinopyridyl (e.g., pyrazino[2,3-c]pyridyl). In one particularly preferred embodiment, Cy is a pyrimidinyl group.

[0044] In a particular embodiment, Cy is preferably selected from the group consisting of the following:

[0045] [ka]

[0046] [ka]

[0047] More preferably, Cy is selected from the group consisting of the following:

[0048] [ka]

[0049] In a particular embodiment, Cy is preferably selected from the group consisting of the following:

[0050] [ka]

[0051] [ka]

[0052] More preferably, Cy is selected from the group consisting of the following:

[0053] [ka]

[0054] [ka]

[0055] In a particular embodiment, Cy is selected from the group consisting of the following:

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] [ka]

[0062] [ka]

[0063] More preferably, Cy is selected from the group consisting of the following:

[0064] [ka]

[0065] [ka]

[0066] To avoid misunderstanding, a ring system containing two or more rings that are condensed with each other is drawn, R 1 and / or R 2 R 1 and / or R 2 When the base is drawn, R 1 and / or R 2 The group can be bonded at any chemically feasible point on any ring.

[0067] In the compound of the present invention, m is 0 or 1, and n is 0, 1, or 2. In one embodiment, m is 0 or 1, and n is 0 or 1.

[0068] In a particular preferred embodiment, m is 1 and n is 0, 1, or 2 (more preferably, n is 0 or 1). In one preferred embodiment, m is 1 and n is 1. In another preferred embodiment, m is 1 and n is 0.

[0069] In a particular embodiment, m is 0 and n is 0, 1, or 2 (more preferably, n is 0 or 1). In one embodiment, m is 0 and n is 1. In another embodiment, m is 0 and n is 0. In yet another embodiment, m is 0 and n is 2.

[0070] In embodiments of the present invention, R 1 If present, -NH2;-NR A (C 1~6 Alkyl) (e.g., -NR) A (C 1~3 Alkyl));-NR A (OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 C is substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl) (e.g., -NR) A (OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 C is substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl));-NR A (OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl) (e.g., -NR) A (OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl));-NR A(C 0~3 Alkylene-C 3~6 A cycloalkyl group in which the cycloalkyl group is optionally substituted with an OH group, a halogen, or one, two, or three halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Cycloalkyl;-NR A (C 0~3 Alkylene-C 3~6 A heterocycloalkyl group in which the heterocycloalkyl group is optionally substituted with OH, a halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Heterocycloalkyl;-NR A (C optionally substituted with OH, halogen, or 1, 2, or 3 halogens) 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~6 Cycloalkyl); and -NR A (OC) A 5 or 6-membered heteroaryl group comprising at least one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N, S, and O (preferably N and S, more preferably N), wherein the 5 or 6-membered heteroaryl group is optionally substituted with a halogen, OH, and one, two, or three halogens. 1~3C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; halogen; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 -OC is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl;OH;NH2;NH(C 1~6 Alkyl); N(C 1~6 C optionally substituted with alkyl)2;cyano;OH, halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~4 Selected from the group consisting of 5- or 6-membered heteroaryl groups, which are optionally substituted with one or two substituents independently selected from the group consisting of cycloalkyl groups.

[0071] In one preferred embodiment, R A is hydrogen, and therefore, R 1 If present, -NH2;-NH(C 1~6 Alkyl) (e.g., -NH(C) 1~3 Alkyl));-NH(OH, halogen, and OC optionally substituted with 1, 2, or 3 halogens 1~3 C is substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl) (e.g., NH(OH), halogen, and OC optionally substituted with 1, 2, or 3 halogens) 1~3 C is substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl);-NH(OH, halogen, and OC optionally substituted with 1, 2, or 3 halogens) 1~3 C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups.1~6 Alkyl) (e.g., OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 -NH(C(O)C) is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl));-NH(C 0~3 Alkylene-C 3~6 A cycloalkyl group in which the cycloalkyl group is optionally substituted with an OH group, a halogen, or one, two, or three halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Cycloalkyl;-NH(C 0~3 Alkylene-C 3~6 A heterocycloalkyl group in which the heterocycloalkyl group is optionally substituted with OH, a halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Heterocycloalkyl;-NH(OH, halogen, 1, 2, or 3 halogens optionally substituted with C 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~6Cycloalkyl); and -NH(a 5 or 6-membered heteroaryl group comprising at least one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N, S, and O (preferably N and S, more preferably N), wherein the 5 or 6-membered heteroaryl group is optionally substituted with halogen, OH, and 1, 2, or 3 halogens) OC 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; halogen; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 -OC is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl;OH;NH2;NH(C 1~6 Alkyl); N(C 1~6 C optionally substituted with alkyl)2;cyano;OH, halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~4 Selected from the group consisting of 5- or 6-membered heteroaryl groups, which are optionally substituted with one or two substituents independently selected from the group consisting of cycloalkyl groups.

[0072] In one embodiment of the present invention, R 1 If present, -NH2;-NR A (C 1~6 Alkyl);-NR A (OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 C is substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl);-NR A (OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl);-NR A (C 0~3 Alkylene-C 3~6 A cycloalkyl group in which the cycloalkyl group is optionally substituted with an OH group, a halogen, or one, two, or three halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Cycloalkyl;-NR A (C 0~3 Alkylene-C 3~6 A heterocycloalkyl group in which the heterocycloalkyl group is optionally substituted with OH, a halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Heterocycloalkyl; and -NR A (C optionally substituted with OH, halogen, or 1, 2, or 3 halogens) 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~6 Selected from the group consisting of cycloalkyls.

[0073] In one embodiment of the present invention, R 1 If present, -NH2;-NR A (C 1~6 Alkyl);-NR A(OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 C is substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl);-NR A (C 0~3 Alkylene-C 3~6 A cycloalkyl group in which the cycloalkyl group is optionally substituted with an OH group, a halogen, or one, two, or three halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Cycloalkyl); and -NR A (C 0~3 Alchien-C 3~6 A heterocycloalkyl group in which the heterocycloalkyl group is optionally substituted with OH, a halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alchien-C 3~6 Selected from the group consisting of heterocycloalkyls.

[0074] In another embodiment of the present invention, R 1 If present, -NH2;-NR A (C 1~6 Alkyl) (e.g., -NR) A (C 1~3 Alkyl)); and -NR A (OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 C is substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6Alkyl) (e.g., -NR) A (OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 C is substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 Selected from the group consisting of alkyl groups.

[0075] In one preferred embodiment of the present invention, R 1 If present, it is -NH2.

[0076] R 1 However, -NR A (C 1~6 Alkyl);-NR A (OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 C is substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl); or -NR A (OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 C(O)C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 In embodiments where C is an alkyl group, 1~6 The alkyl group can preferably be selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.

[0077] R 1 However, -NR A (C 1~6 Alkyl);-NR A (OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 A C molecule substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl); or -NR A(OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens) 1~3 C(O)C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 In certain embodiments, C may be alkyl. 1~6 Alkyl is C 1~4 Alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl groups), or C 1~3 It may also be an alkyl group (for example, methyl, ethyl, n-propyl, or i-propyl group).

[0078] R 1 However, -NR A (C 0~3 Alkylene-C 3~6 A cycloalkyl group in which the cycloalkyl group is optionally substituted with an OH group, a halogen, or one, two, or three halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Cycloalkyl); or -NR A (OH, halogen, C which is optionally substituted with 1, 2, or 3 halogens) 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C(O)C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 3~6 In embodiments where it may be a cycloalkyl, preferably C 3~6 Cycloalkyl groups are monocyclic C 3~6 A cycloalkyl group, for example, C selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 It is a cycloalkyl group.

[0079] R 1 However, -NR A (C 0~3 Alkylene-C 3~6 A heterocycloalkyl group in which the heterocycloalkyl group is optionally substituted with OH, a halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 In embodiments where the heterocycloalkyl group is present, preferably C 3~6 Heterocycloalkyl groups are monocyclic C 3~6 A heterocycloalkyl C selected from the group consisting of, for example, aziridine, oxirane, pyrrolidine, imidazolidine, pyrazolazine, piperidine, dioxane, morpholine, dithiane, oxatiane, and thiomorpholine. 3~6 It is a heterocycloalkyl group.

[0080] R 1 However, NR A (OC) A 5 or 6-membered heteroaryl group comprising at least one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N, S, and O, wherein the 5 or 6-membered heteroaryl group is optionally substituted with a halogen, OH, and one, two, or three halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; halogen; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 -OC is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl;OH;NH2;NH(C 1~6 Alkyl); N(C 1~6C optionally substituted with alkyl)2;cyano;OH, halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~4 In embodiments where the heteroaryl group may be a 5- or 6-membered heteroaryl group optionally substituted with one or two substituents independently selected from the group consisting of cycloalkyls, the 5- or 6-membered heteroaryl group preferably comprises at least one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N and S, more preferably N. In another preferred embodiment, the 5- or 6-membered heteroaryl group is selected from the group consisting of pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, imidazolyl, thiazolyl, indolyl, pyryl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, and isothiazolyl.

[0081] In the compound of the present invention, R A If present, hydrogen;OH, halogen, and OC optionally substituted with 1, 2, or 3 halogens. 1~3 -C is optionally substituted with 1, 2, or 3 elements independently selected from the group consisting of alkyl groups. 1~6 Alkyl (e.g., OH, halogen, and OC optionally substituted with 1, 2, or 3 halogens) 1~3 -C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl);-C 0~3 Alkylene-C 3~6 A cycloalkyl group in which the cycloalkyl group is optionally substituted with an OH group, a halogen, or one, two, or three halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3-C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Cycloalkyl;-C 0~3 Alkylene-C 3~6 A heterocycloalkyl group in which the heterocycloalkyl group is optionally substituted with OH, a halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 -C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Heterocycloalkyl; C optionally substituted with OH, halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 -C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~6 Cycloalkyl; OC optionally substituted with OH, halogen, and 1, 2, or 3 halogens. 1~3 -C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl (e.g., OH, halogen, and OC optionally substituted with 1, 2, or 3 halogens) 1~3 -C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; C optionally substituted with OH, halogen, or 1, 2, or 3 halogens 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 -C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~6Cycloalkyl; and a 5 or 6-membered heteroaryl group comprising at least one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N, S, and O, wherein the 5 or 6-membered heteroaryl group is optionally substituted with a halogen, OH, and one, two, or three halogens (OC) 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; halogen; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 -OC is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl;OH;NH2;NH(C 1~6 Alkyl); N(C 1~6 C optionally substituted with alkyl)2;cyano;OH, halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~4 The group consists of 5- or 6-membered heteroaryl groups, which are optionally substituted with one or two substituents independently selected from the group consisting of cycloalkyl groups.

[0082] In one embodiment, R A If present, OC is optionally substituted with hydrogen-OH, halogen, or 1, 2, or 3 halogens. 1~3 -C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;-C 0~3 Alkylene-C 3~6 A cycloalkyl group in which the cycloalkyl group is optionally substituted with an OH group, a halogen, or one, two, or three halogens. 1~3 Alkyl, C 1~3OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 -C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Cycloalkyl;-C 0~3 Alkylene-C 3~6 A heterocycloalkyl group in which the heterocycloalkyl group is optionally substituted with OH, a halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 -C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Heterocycloalkyl; C optionally substituted with OH, halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 -C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~6 Cycloalkyl; and C optionally substituted with OH, halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 -C(O)C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~6 Selected from the group consisting of cycloalkyl groups.

[0083] In one embodiment, R A If present, OC is optionally substituted with hydrogen-OH, halogen, or 1, 2, or 3 halogens. 1~3 -C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6Alkyl;-C 0~3 Alkylene-C 3~6 A cycloalkyl group in which the cycloalkyl group is optionally substituted with an OH group, a halogen, or one, two, or three halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 -C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Cycloalkyl; and -C 0~3 Alkylene-C 3~6 A heterocycloalkyl group in which the heterocycloalkyl group is optionally substituted with OH, a halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 -C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Selected from the group consisting of heterocycloalkyl groups.

[0084] In one embodiment, R A If present, hydrogen; as well as OH, halogens, and OC optionally substituted with one, two, or three halogens. 1~3 -C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl (e.g., OH, halogen, and OC optionally substituted with 1, 2, or 3 halogens) 1~3 -C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Selected from the group consisting of alkyl groups.

[0085] In one preferred embodiment, R A If present, it is hydrogen.

[0086] R A However, OC is optionally substituted with OH, halogen, and one, two, or three halogens. 1~3 -C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; or OH, halogen, and OC optionally substituted with 1, 2, or 3 halogens 1~3 -C(O)C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 In embodiments where C is an alkyl group, 1~6 The alkyl group can preferably be selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.

[0087] R A However, OC is optionally substituted with OH, halogen, and one, two, or three halogens. 1~3 -C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; or OH, halogen, and OC optionally substituted with 1, 2, or 3 halogens 1~3 -C(O)C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 In certain embodiments, C may be alkyl. 1~6 Alkyl is C 1~4 Alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl groups), or C 1~3 It is an alkyl group (for example, methyl, ethyl, n-propyl, or i-propyl group).

[0088] R A However, -C 0~3 Alkylene-C 3~6A cycloalkyl group in which the cycloalkyl group is optionally substituted with an OH group, a halogen, or one, two, or three halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 -C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 0~3 Alkylene-C 3~6 Cycloalkyl; or C optionally substituted with OH, halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 -C(O)C is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 3~6 In embodiments where cycloalkyl is possible, preferably C 3~6 Cycloalkyl groups are monocyclic C 3~6 A cycloalkyl group, for example, C selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 It is a cycloalkyl group.

[0089] R A However, -C 0~3 Alkylene-C 3~6 A heterocycloalkyl group in which the heterocycloalkyl group is optionally substituted with OH, a halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 In embodiments in which the group is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups, preferably C 3~6 Heterocycloalkyl groups are monocyclic C 3~6A heterocycloalkyl C selected from the group consisting of, for example, aziridine, oxirane, pyrrolidine, imidazolidine, pyrazolazine, piperidine, dioxane, morpholine, dithiane, oxatiane, and thiomorpholine. 3~6 It is a heterocycloalkyl group.

[0090] R A However, the OC is a 5 or 6-membered heteroaryl group comprising at least one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N, S, and O, wherein the 5 or 6-membered heteroaryl group is optionally substituted with a halogen, OH, and one, two, or three halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; halogen; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 -OC is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl;OH;NH2;NH(C 1~6 Alkyl); N(C 1~6 C optionally substituted with alkyl)2;cyano;OH, halogen, or 1, 2, or 3 halogens. 1~3 Alkyl, C 1~3 OCs optionally substituted with alkyl-OH and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~4In embodiments where the 5- or 6-membered heteroaryl group is optionally substituted with one or two substituents independently selected from the group consisting of cycloalkyls, the 5- or 6-membered heteroaryl group preferably comprises at least one N heteroatom and one or two further heteroatoms selected from the group consisting of N and S, more preferably N. In another preferred embodiment, the 5- or 6-membered heteroaryl group is selected from the group consisting of pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, imidazolyl, thiazolyl, indolyl, pyryl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, and isothiazolyl.

[0091] In the compound of the present invention, each R 2 If present, halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl (e.g., halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens) 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; halogen; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens. 1~3 -OC is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl (e.g., halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens) 1~3 -OC is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl);OH;=O;NH2;NH(C 1~6 Alkyl) (e.g., NH C) 1~3 Alkyl); N(C 1-6 Alkyl)2 (for example, NC 1~3Alkyl)2; cyano; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~6 It is independently selected from the group consisting of cycloalkyls.

[0092] One embodiment, each R 2 If present, OC is optionally substituted with oxo, halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; halogen; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 -OC is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;OH; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 3~6 It is independently selected from the group consisting of cycloalkyls.

[0093] One embodiment, each R 2 If present, halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; halogen; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 -OC is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 It is independently selected from the group consisting of alkyl and OH.

[0094] One embodiment, each R 2If present, halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; halogen; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 -OC is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 It is independently selected from the group consisting of alkyl and OH.

[0095] In one embodiment, Cy is an optionally substituted nitrogen-containing 6-membered aromatic ring having the following formula:

[0096] [ka] In the formula, Z 1 However, it is CH or N, Z 2 However, it is CH or N, Z 3 However, hydrogen or optionally substituted amino groups (e.g., hydrogen, NH2, or C) 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 3~10 Cycloalkyl groups, C 3~14 Aryl group, C 7~26 Aralkyl group, C 1~6 Alkyl-carbonyl group, C 6~14 Aryl-carbonyl group, C 1~16 Aralkyl-carbonyl group, 5-14 member aromatic heterocyclic carbonyl group, 3-14 member non-aromatic heterocyclic carbonyl group, C 1~6 Alkoxycarbonyl groups, 5-14 member aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1~6 Alkyl-carbamoyl group, Mono- or di-C 7~16 Aralkyl-carbamoyl group, C 1~6 Alkyl sulfonyl group, and C 6~14An amino group having one or two substituents selected from the group consisting of arylsulfonyl groups, each of which optionally has one to three substituents selected from the following substituent group A, (1) halogen atom, (2) nitro group, (3) cyano group, (4) oxo group, (5) hydroxyl group, (6) optionally halogenated C 1~6 Alkoxy group, (7)C 6~14 Aryloxy group (e.g., phenoxy, naphthoxy), (8)C 7~16 (9) Aralkyloxy group (e.g., benzyloxy), (10) 5-14 member aromatic heterocyclic oxy group (e.g., pyridyloxy), (11) C 1~6 Alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy), (12)C 6~14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13)C 1~6 Alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) mono- or di-C 1~6 Alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15)C 6~14 (16) Aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy), (17) 5-14 member aromatic heterocyclic carbonyloxy groups (e.g., nicotinoyloxy), (17) 3-14 member non-aromatic heterocyclic carbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) C 1~6 Alkyl sulfonyloxy group (e.g., methyl sulfonyloxy, trifluoromethyl sulfonyloxy), (19)C 1~6 C optionally substituted with alkyl groups 6~14Aryl sulfonyloxy group (e.g., phenyl sulfonyloxy, toluene sulfonyloxy), (20) optionally halogenated C 1~6 (21) an alkylthio group, (22) a 5-14 member aromatic heterocyclic group, (23) a 3-14 member non-aromatic heterocyclic group, (24) a formyl group, (25) an optionally halogenated C 1~6 Alkyl-carbonyl group, (26)C 6~14 (27) Aryl carbonyl group, (28) 5-14 member aromatic heterocyclic carbonyl group, (29) C 1~6 Alkoxy-carbonyl group, (30)C 6~14 Aryloxycarbonyl group (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31)C 7~16 (32) Aralkyloxycarbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (33) Carbamoyl group, (34) Thiocarbamoyl group, (34) Mono- or di-C 1~6 Alkyl-carbamoyl group, (35)C 6~14 (36) Aryl carbamoyl (e.g., phenyl carbamoyl), (37) 5-14 member aromatic heterocyclic carbamoyl (e.g., pyridyl carbamoyl, thienyl carbamoyl), (38) Optionally halogenated 01-6 alkylsulfonyl group, (39) C 6~14 (40) Aryl sulfonyl group, (40) 5-14 member aromatic heterocyclic sulfonyl group (e.g., pyridyl sulfonyl, thienyl sulfonyl), (41) optionally halogenated C 1~6 Alkyl sulfinyl group, (42)C 6~14 (43) Aryl sulfinyl groups (e.g., phenyl sulfinyl, 1-naphthyl sulfinyl, 2-naphthyl sulfinyl), (44) 5-14 member aromatic heterocyclic sulfinyl groups (e.g., pyridyl sulfinyl, thienyl sulfinyl), (45) amino groups, (46) mono- or di-C 1~6Alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino), (46) mono- or di-C 6~14 Arylamino group (e.g., phenylamino), (47) 5-14 member aromatic heterocyclic amino group (e.g., pyridylamino), 30(48)C 7~16 (49) Aralkylamino group (e.g., benzylamino), (50) C 1~6 Alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino), (51)(C 1~6 Alkyl)(C 1~6 Alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), (52)C 6~14 Aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino), (53)C 1~6 Alkoxycarbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54)C 7~16 Aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)C 1~6 Alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1~6 C optionally substituted with alkyl groups 6~14 C arylsulfonylamino group (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) optionally halogenated C 1~6 Alkyl group, (58)C 2~6 Alkenyl group, (59)C 2~6 Alkynyl group, (60)C 3~10 Cycloalkyl group, (61)C 3~10 Cycloalkenyl group, and (62)C 6~14 Aryl group; or hydrogen, or the above R 1 basis), Or, Z2 and Z 3 These are bonded to each other and optionally substituted rings (for example, optionally substituted 4, 5, 6, or 7 rings, for example, optionally substituted 4, 5, 6, or 7 aryl, heteroaryl, non-aromatic carbocyclic, or non-aromatic heterocyclic rings, for example, optionally substituted by 1, 2, or 3 groups independently selected from substituent group A, or the above 1 R 1 base and / or one or two R 2 It forms (which are arbitrarily substituted by the base).

[0097] In one embodiment, Cy is as follows:

[0098] [ka] Z 1 and Z 2 combination with (Z 1 , Z 2 ) is (CH, N), (N, CH), or (N, N), and Cy is (1) C 1~6 (2) Optionally further substituted with 1 to 3 substituents selected from alkyl groups and amino groups (-NH2), and Z 3 C is optionally substituted with (1)OH and 1, 2, or 3 substituents selected from 3- to 14-membered non-aromatic heterocyclic groups. 1~6 (2) C which is optionally substituted with an alkyl group, or 1, 2, or 3 OH groups. 3~10 (3) Cycloalkyl groups, (4) 3-14 member non-aromatic heterocyclic groups, and (5) 1-3 C 1~6 An amino group (-NH2 or Z) optionally substituted with one or two substituents selected from a 5-14 member aromatic heterocyclic group optionally substituted with an alkyl group. 2 and Z 3 These atoms bond to each other to form 5-14 member aromatic heterocycles.

[0099] In such an embodiment, Cy is as follows:

[0100] [ka] Z 1 and Z 2 combination with (Z 1 , Z 2 ) is (CH,N), (N,CH), or (N,N), and Cy is 1 to 3 C 1~6 Optionally further substituted with alkyl groups, and Z 3 (1) C is arbitrarily substituted with 1 to 3 OH groups. 1~6 (2) C atoms optionally substituted with alkyl groups, or 1 to 3 OH groups. 3~10 (3) an amino group (-NH2) optionally substituted with one or two substituents selected from a cycloalkyl group and a 3- to 14-membered non-aromatic heterocyclic group, or Z 2 and Z 3 These atoms bond to each other to form 5-14 member aromatic heterocycles.

[0101] In such an embodiment, Cy is as follows:

[0102] [ka] Z 1 and Z 2 combination with (Z 1 ,Z 2 ) is (CH, N), Cy has 1 to 3 C 1-6 Optionally further substituted with alkyl groups, and Z 3 C is arbitrarily substituted with 1 to 3 OH groups. 1~6 (2) C which is optionally substituted with an alkyl group or 1 to 3 hydroxyl groups. 3~10 (3) An amino group (-NH2) optionally substituted with one or two substituents selected from a cycloalkyl group and a 3- to 14-membered non-aromatic heterocyclic group.

[0103] In the compounds of the present invention, A is selected from the group consisting of phenyl; naphthyl; and a 5, 6, 7, 8, 9, 10, or 11-membered heteroaryl group comprising one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N, S, and O (preferably N and S, more preferably N).

[0104] In one embodiment, A is selected from the group consisting of 5, 6, 7, 8, 9, 10, or 11-membered heteroaryl groups comprising one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N, S, and O (preferably N and S, more preferably N). For example, A is selected from the group consisting of pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, imidazolyl, thiazolyl, indolyl, pyryl, oxazolyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzimidazolyl, and indolinyl. In one particularly preferred embodiment, A is pyridyl.

[0105] In one embodiment, A is selected from the group consisting of 6, 7, 8, 9, 10, or 11-membered heteroaryl groups comprising phenyl; naphthyl; and one N heteroatom, and optionally one or two further heteroatoms selected from the group consisting of N, S, and O (preferably N and S, more preferably N).

[0106] In another embodiment, A is selected from the group consisting of 6, 7, 8, 9, 10, or 11-membered heteroaryl groups comprising one N heteroatom and optionally one or two further heteroatoms selected from the group consisting of N, S, and O (preferably N and S, more preferably N).

[0107] In one preferred embodiment, A is selected from the group consisting of pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, indazolyl, benzimidazolyl, and indolinyl.

[0108] In one preferred embodiment, A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyridazinyl, and pyrimidinyl.

[0109] In one particularly preferred embodiment, A is a pyridyl group. In another preferred embodiment, A is a phenyl group or pyridyl.

[0110] In one preferred embodiment, A is selected from the group consisting of the following:

[0111] [ka]

[0112] More preferably, A is selected from the group consisting of the following:

[0113] [ka]

[0114] In one preferred embodiment, R 7 is hydrogen, and A is selected from the following group:

[0115] [ka]

[0116] In another preferred embodiment, R 7 is hydrogen, and A is selected from the following group:

[0117] [ka]

[0118] In the compound of the present invention, R 5 OC is optionally substituted with hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;NH2;NH(C 1~6 Alkyl); and N(C 1~6 Selected from the group consisting of alkyl(2).

[0119] In one preferred embodiment, R 5 OC is optionally substituted with hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Selected from the group consisting of alkyl groups.

[0120] In one preferred embodiment, R 5 OC is optionally substituted with hydrogen; halogen; OH; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups.1~6 Selected from the group consisting of alkyl groups.

[0121] In one preferred embodiment, R 5 OC is optionally substituted with hydrogen; halogen; OH; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 Selected from the group consisting of alkyl groups.

[0122] In one embodiment, R 5 Hydrogen; halogens; OH; halogens and OC 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with 1, 2, or 3 halogen groups 1~6 Selected from the group consisting of alkyl groups.

[0123] In another embodiment, R 5 Hydrogen; halogens; OH; halogens and OC 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with 1, 2, or 3 halogen groups 1~6 Selected from the group consisting of alkyl groups.

[0124] In the compound of the present invention, R 6 OC is optionally substituted with hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6Alkyl; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;NH2;NH(C 1~6 Alkyl); N(C 1~6 Alkyl)2; optionally substituted phenyl; optionally substituted naphthyl; optionally substituted 5, 6, 7, 8, 9, 10, or 11-membered heteroaryl group comprising one N heteroatom and optionally one or two further heteroatoms independently selected from the group consisting of N, S, and O (preferably N and S); optionally substituted 5, 6, 7, 8, 9, 10, or 11-membered non-aromatic heterocyclic group comprising one N heteroatom and optionally one or two further heteroatoms independently selected from the group consisting of N, S, and O (preferably N and S); and optionally substituted C 3~10 Selected from the group consisting of cycloalkyl groups, the group comprises a phenyl, naphthyl, 5, 6, 7, 8, 9, 10, or 11-membered heteroaryl group, a 5, 6, 7, 8, 9, 10, or 11-membered non-aromatic heterocyclic group, and C 3~11 OC is a cycloalkyl group optionally substituted with halogens;OH;halogen,OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; halogen, OH and OC optionally substituted with 1, 2, or 3 halogens 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 It is optionally substituted with one, two, or three groups selected individually from the group consisting of alkyl groups.

[0125] R 6 However, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 5, 6, 7, 8, 9, 10, or 11-membered heteroaryl group, optionally substituted 5, 6, 7, 8, 9, 10, or 11-membered non-aromatic heterocyclic group, or optionally substituted C3~11 In embodiments where the group is cycloalkyl, it is preferably a phenyl, naphthyl, 5, 6, 7, 8, 9, 10, or 11-membered heteroaryl group, a 5, 6, 7, 8, 9, 10, or 11-membered non-aromatic heterocyclic group, or C 3~11 Cycloalkyl groups are optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of halogen;OH;halogen. 1~3 Alkyl; OC optionally substituted with 1, 2, or 3 halogens 1~3 It is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. For example, the phenyl, naphthyl, 5, 6, 7, 8, 9, 10, or 11-membered heteroaryl group, a 5, 6, 7, 8, 9, 10, or 11-membered non-aromatic heterocyclic group, or C 3~11 Cycloalkyl groups are optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of halogen;OH;halogen. 1~3 Alkyl; OC optionally substituted with 1, 2, or 3 halogens 1~3 It is optionally substituted with one or two groups independently selected from the group consisting of alkyl groups. For example, the phenyl, naphthyl, 5, 6, 7, 8, 9, 10, or 11-membered heteroaryl group, a 5, 6, 7, 8, 9, 10, or 11-membered non-aromatic heterocyclic group, or C 3~11 Cycloalkyl groups are optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of halogen;OH;halogen. 1~3 Alkyl; OC optionally substituted with 1, 2, or 3 halogens 1~3 It is optionally substituted with one group selected from the group consisting of alkyl groups.

[0126] In one preferred embodiment, R 6 OC is optionally substituted with hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6Alkyl; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;NH2;NH(C 1~6 Alkyl); and N(C 1~6 Selected from the group consisting of alkyl(2).

[0127] In one preferred embodiment, R 6 OC is optionally substituted with hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Selected from the group consisting of alkyl groups.

[0128] In one preferred embodiment, R 6 OC is optionally substituted with hydrogen; halogen; OH; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Selected from the group consisting of alkyl groups.

[0129] In another preferred embodiment, R 6 OC is optionally substituted with hydrogen; halogen; OH; halogen, OH, and 1, 2, or 3 halogens. 1~3C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Selected from the group consisting of alkyl groups.

[0130] In another preferred embodiment, R 6 OC is optionally substituted with hydrogen; halogen; OH; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 Selected from the group consisting of alkyl groups.

[0131] In one embodiment, R 6 OC is optionally substituted with hydrogen; halogen; OH; halogen and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with 1, 2, or 3 halogen groups 1~6 Selected from the group consisting of alkyl groups.

[0132] In another embodiment, R 6 OC is optionally substituted with hydrogen; halogen; OH; halogen and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with 1, 2, or 3 halogen groups1~6 Selected from the group consisting of alkyl groups.

[0133] In the compound of the present invention, R 7 OC is optionally substituted with hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;NH2;NH(C 1~6 Alkyl); and N(C 1~6 Selected from the group consisting of alkyl(2).

[0134] In one preferred embodiment, R 7 It is hydrogen.

[0135] In one embodiment, R 7 OC is optionally substituted with hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Selected from the group consisting of alkyl groups.

[0136] In another embodiment, R 7 OC is optionally substituted with hydrogen; halogen; OH; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Selected from the group consisting of alkyl groups.

[0137] In another embodiment, R 7 OC is optionally substituted with hydrogen; halogen; OH; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 Selected from the group consisting of alkyl groups.

[0138] In one embodiment, R 7 OC is optionally substituted with hydrogen; halogen; OH; halogen and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with 1, 2, or 3 halogen groups 1~6 Selected from the group consisting of alkyl groups.

[0139] In another embodiment, R 7 OC is optionally substituted with hydrogen;OH;halogen and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with 1, 2, or 3 halogen groups 1~6 Selected from the group consisting of alkyl groups.

[0140] In one particularly preferred embodiment, R 5 OC is optionally substituted with hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;NH2;NH(C 1~6 Alkyl); and N(C 1~6 Selected from the group consisting of alkyl)2, R 6 OC is optionally substituted with hydrogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;NH2;NH(C 1~6 Alkyl); N(C 1~6 Alkyl)2; optionally substituted phenyl; optionally substituted naphthyl; optionally substituted 5, 6, 7, 8, 9, 10, or 11-membered heteroaryl group comprising one N heteroatom and optionally one or two further heteroatoms independently selected from the group consisting of N, S, and O (preferably N and S); optionally substituted 5, 6, 7, 8, 9, 10, or 11-membered non-aromatic heterocyclic group comprising one N heteroatom and optionally one or two further heteroatoms independently selected from the group consisting of N, S, and O (preferably N and S); and optionally substituted C 3~10Selected from the group consisting of cycloalkyl groups, the group comprises a phenyl, naphthyl, 5, 6, 7, 8, 9, 10, or 11-membered heteroaryl group, a 5, 6, 7, 8, 9, 10, or 11-membered non-aromatic heterocyclic group, and C 3~11 OC is a cycloalkyl group optionally substituted with halogens;OH;halogen,OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 Alkyl; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 It is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups, and R 7 OC is optionally substituted with hydrogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;NH2;NH(C 1~6 Alkyl); and N(C 1~6 Selected from the group consisting of alkyl)2. More preferably, R 7 It is hydrogen.

[0141] In another particularly preferred embodiment, R 5 OC is optionally substituted with hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6Alkyl; halogen, OH, and OC optionally substituted with 1, 2, or 3 halogens 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;NH2;NH(C 1~6 Alkyl); and N(C 1~6 Selected from the group consisting of alkyl)2, R 6 OC is optionally substituted with hydrogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;NH2;NH(C 1~6 Alkyl); and N(C 1~6 Selected from the group consisting of alkyl)2, R 7 OC is optionally substituted with hydrogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1-6 Alkyl; and OC optionally substituted with halogens, OH, and 1, 2, or 3 halogens. 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl;NH2;NH(C 1~6 Alkyl); and N(C 1~6 Selected from the group consisting of alkyl)2. More preferably, R 7 It is hydrogen.

[0142] In another particularly preferred embodiment, R 5 Hydrogen; halogens; OH; halogens and OC 1~3C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with 1, 2, or 3 halogen groups 1~6 Selected from the group consisting of alkyl groups, R 6 OC is optionally substituted with hydrogen;OH;halogen and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with 1, 2, or 3 halogen groups 1~6 Selected from the group consisting of alkyl, and R 7 OC is optionally substituted with hydrogen;OH;halogen and 1, 2, or 3 halogens. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~6 Alkyl; and OC optionally substituted with 1, 2, or 3 halogen groups 1~6 Selected from the group consisting of alkyl groups. More preferably, R 7 It is hydrogen.

[0143] In one preferred embodiment, A is selected from the group consisting of the following:

[0144] [ka]

[0145] [ka]

[0146] [ka]

[0147] [ka]

[0148] [ka]

[0149] In a particular embodiment, A is an optionally substituted 6-membered aryl or heteroaryl ring of formula B,

[0150] [ka] In the formula, Y 1 , Y 2 , and Y 3 Two of them are CH, and the remaining one is either CH or N. R 5 However, halogens; OH; halogens, OH, and OC 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 alkyl; as well as halogens, OH, and OC 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 Selected from the group consisting of alkyl groups, R 6 However, halogens; OH; halogens, OH, and OC 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 alkyl; halogens, OH, and OC 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 alkyl; and selected from the group consisting of rings of the following formulas,

[0151] [ka] In the formula, ring C is an optionally substituted 6-membered aromatic ring, and ring D is an optionally further substituted 5, 6, or 7-membered ring. Y 4 and Y 4 One of them is CH, and the other is either CH or N. The C ring is a halogen; OH; halogen, OH, and OC. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 alkyl; halogens, OH, and OC 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 It is optionally substituted with alkyl, and The D ring is a halogen; OH; halogen, OH, and OC. 1~3 C is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl groups. 1~3 alkyl; halogens, OH, and OC 1~3 OCs are optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl groups. 1~3 It is arbitrarily substituted with alkyl.

[0152] In a particular embodiment, A is equation (1),

[0153] [ka] In the formula, Y 1 , Y 2 , and Y 3 combination (Y 1 , Y 2 , Y 3 ) is (CH, CH, CH) or (CH, CH, N), R 5 However, (1) a fluorine atom, a chlorine atom, a bromine atom, (2) methyl, trifluoromethyl, or (3) a hydroxyl group optionally substituted with methyl, difluoromethyl, or trifluoromethyl, R 6However, C is optionally substituted with (1) a halogen atom, (2) a cyano group, or (3) one to three substituents selected from a halogen atom and a hydroxyl group. 1~6 (4) C atoms optionally substituted with alkyl groups or 1 to 3 halogen atoms. 1~6 Alkoxy group, or (5) mono- or di-C 1~6 It is an alkylamino group, Furthermore, ring B is optionally substituted with (1) a halogen atom and (2) 1 to 3 hydroxyl groups. 1~6 Alkyl groups, and (3)C 1~6 Formula (1) or formula (2), which is optionally further substituted with 1 to 3 substituents selected from the alkoxy group,

[0154] [ka] In the formula, Y 4 and Y 5 combination (Y 4 , Y 5 ) is (CH, CH), The carbon ring is further optionally substituted with 1 to 3 halogen atoms. Ring D is a 5-7 member aromatic heterocycle or a 5-7 member non-aromatic heterocycle. Formula (2) is obtained in which ring D is optionally further substituted with 1 to 3 substituents selected from (1) halogen atoms and (2) hydroxyl groups.

[0155] In such embodiments, R 4 This can be a hydrogen atom, a fluorine atom, or a chlorine atom.

[0156] In such embodiments, R 3 This can be a fluorine atom or a chlorine atom.

[0157] In such embodiments, Cy may be:

[0158] [ka] Z 1 and Z 2 combination with (Z 1 , Z 2 ) is (CH, N), (N, CH), or (N, N), Cy is (1)C 1~6 (2) The alkyl group is optionally further substituted with 1 to 3 substituents selected from amino groups, and Z 3 (1) C is optionally substituted with 1 to 3 substituents selected from a hydroxyl group and a 3 to 14-membered non-aromatic heterocyclic group. 1~6 (2) C which is optionally substituted with an alkyl group or 1 to 3 hydroxyl groups. 3~10 (3) Cycloalkyl groups, (4) 3-14 member non-aromatic heterocyclic groups, and (5) 1-3 C 1~6 An amino group optionally substituted with one or two substituents selected from a 5-14 member aromatic heterocyclic group optionally substituted with an alkyl group, or Z 2 and Z 3 These atoms bond to each other to form 5-14 member aromatic heterocycles.

[0159] In a particular embodiment, A is equation (1),

[0160] [ka] In the formula, Y 1 , Y 2 , and Y 3 combination (Y 1 , Y 2 , Y 3 ) is (CH, CH, CH) or (CH, CH, N), R 5 However, (1) a chlorine atom, a bromine atom, (2) methyl, trifluoromethyl, or (3) a hydroxyl group substituted with methyl or trifluoromethyl, R 6 However, C is optionally substituted with (1) a halogen atom, or (2) 1 to 3 substituents selected from a halogen atom and a hydroxyl group. 1~6C is optionally substituted with an alkyl group or (3) 1 to 3 halogen atoms. 1~6 It is an alkoxy group, Ring B is optionally substituted with (1) a halogen atom and (2) 1 to 3 hydroxyl groups. 1~6 Formula (1) or formula (2), which is optionally further substituted with 1 to 3 substituents selected from alkyl groups,

[0161] [ka] In the formula, Y 4 and Y 5 combination (Y 4 , Y 5 ) is (carbon atoms, carbon atoms), The carbon ring is further optionally substituted with 1 to 3 halogen atoms. Equation (2) shows that ring D is a 5- to 7-membered non-aromatic heterocycle.

[0162] In such embodiments, R 4 This can be a hydrogen atom, a fluorine atom, or a chlorine atom.

[0163] In such embodiments, R 3 This can be a fluorine atom or a chlorine atom.

[0164] In such embodiments, Cy may be:

[0165] [ka] Z 1 and Z 2 combination with (Z 1 , Z 2 ) is (carbon atom, nitrogen atom), (nitrogen atom, carbon atom), or (nitrogen atom, nitrogen atom), and Cy is 1 to 3 C 1~6 It is optionally further substituted with an alkyl group, and Z 3(1) C is optionally substituted with 1 to 3 hydroxyl groups. 1~6 (2) C which is optionally substituted with an alkyl group or 1 to 3 hydroxyl groups. 3~10 (3) An amino group optionally substituted with one or two substituents selected from a cycloalkyl group and a 3- to 14-membered non-aromatic heterocyclic group, or Z 2 and Z 3 These atoms bond to each other to form 5-14 member aromatic heterocycles.

[0166] In a particular embodiment, A is equation (1),

[0167] [ka] In the formula, Y 1 , Y 2 , and Y 3 combination (Y 1 , Y 2 , Y 3 ) is (CH, CH, CH) or (CH, CH, N), R 5 However, (1) a chlorine atom, a bromine atom, (2) methyl, trifluoromethyl, or (3) a hydroxyl group substituted with methyl or trifluoromethyl, R 6 However, C is optionally substituted with (1) a halogen atom, or (2) 1 to 3 substituents selected from a halogen atom and a hydroxyl group. 1~6 C is optionally substituted with an alkyl group or (3) 1 to 3 halogen atoms. 1~6 It is an alkoxy group, Ring B is optionally substituted with (1) a halogen atom and (2) 1 to 3 hydroxyl groups. 1~6 It is optionally further substituted with 1 to 3 substituents selected from alkyl groups.

[0168] In such embodiments, R 4 This can be a hydrogen atom, a fluorine atom, or a chlorine atom.

[0169] In such an embodiment, R 3 may be a fluorine atom or a chlorine atom.

[0170] In such an embodiment, Cy may be as follows,

[0171]

Chemical formula

[0172] In a preferred embodiment, the compound of the present invention is a compound of formula (IA),

[0173]

Chemical formula

[0174] In such embodiments, preferably, R 3 is F or Cl. Most preferably R 3 It is F.

[0175] In such embodiments, m is preferably 1 and n is 0, 1, or 2 (more preferably n is 0 or 1).

[0176] In certain preferred embodiments, the compounds of the present invention are the compounds of the present invention described in the following Examples section, or pharmaceutically acceptable esters, amides, carbamates, or salts thereof (including pharmaceutically acceptable salts of such esters, amides, or carbamates). In particular, the compounds of the present invention are N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3-fluoropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 1); N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3-chloropyridine-2-yl}5-chloro-2-methoxypyridine-3-sulfonamide (Example 2); 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridine-5-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 3); N-{4-[2-(8-amino-1,7-naphthyridine-5-yl)ethynyl]-3-fluoropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 4); 5-Chloro-N-{4-[2-(pyrido[3,4-b]pyrazine-8-yl)ethynyl]-3-fluoropyridine-2-yl}-2-methoxypyridine-3-sulfonamide (Example 5); 5-Chloro-N-{4-[2-(1,6-naphthyridine-8-yl)ethynyl]-3-fluoropyridine-2-yl}-2-methoxypyridine-3-sulfonamide (Example 6); N-{4-[2-(7-aminopyrazolo[1,5-a]pyrimidine-3-yl)ethinyl]-3-fluoropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 7); N-{4-[2-(8-aminoimidazo[1,2-a]pyridine-3-yl)ethynyl]-3-fluoropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 8); 5-Chloro-N-{4-[2-(quinoxaline-2-yl)ethynyl]-3-fluoropyridine-2-yl}-2-methoxypyridine-3-sulfonamide (Example 9); N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3,5-difluoropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 10); N-{4-[2-(8-aminoimidazo[1,2-a]pyrazine-3-yl)ethynyl]-3-fluoropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 11); 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridine-5-yl}ethynyl)pyridine-2-yl]-2-methoxybenzene-1-sulfonamide (Example 12); N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3-fluoropyridine-2-yl}-5-chloro-2-methoxybenzene-1-sulfonamide (Example 13); 2,5-Dichloro-N-[3-Fluoro-4-(2-{1H-Pyrazolo[3,4-b]pyridine-5-yl}ethynyl)pyridine-2-yl]benzene-1-sulfonamide (Example 14); N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3-fluoropyridine-2-yl}2,5-dichlorobenzene-1-sulfonamide (Example 15); N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3-fluoropyridine-2-yl}2,5-dichloro-3-(hydroxymethyl)benzene-1-sulfonamide (Example 16); 2,5-Dichloro-N-[3-Fluoro-4-(2-{1H-Pyrazolo[3,4-b]pyridine-5-yl}ethynyl)pyridine-2-yl]-3-(Hydroxymethyl)benzene-1-sulfonamide (Example 17); 5-Chloro-N-[3-fluoro4-(2-{1-methyl1H-imidazo[4,5-c]pyridine-7-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 18); 5-Chloro-N-[3-fluoro-4-(2-{[1,3]thiazolo[4,5-c]pyridine-7-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 19); 5-Chloro-N-[3-fluoro-4-(2-{1-methyl-1H-pyrazolo[3,4-c]pyridine-4-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 20); 5-Chloro-N-[3-fluoro-4-(2-{1Hpyrazolo[3,4-c]pyridine-4-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 21); 5-Chloro-N-[3-fluoro-4-(2-{2-methyl-2H-pyrazolo[3,4-c]pyridine-4-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 22); 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[4,3-c]pyridine-4-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 23); 5-Chloro-N-[3-fluoro-4-(2-{1-methyl-1H-pyrazolo[4,3-c]pyridine-7-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 24); 5-Chloro-N-(3-fluoro-4-{2-[2-(methylamino)pyrimidine-5-yl]ethynyl}pyridine-2-yl)-2-methoxypyridine-3-sulfonamide (Example 25); 5-Chloro-N-[3-fluoro-4-(2-{2-oxo-1H,2H,3H-imidazo[4,5-b]pyridine-6-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 26); 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyrazine-5-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 27); 5-Chloro-N-[3-fluoro-4-(2-{2-oxo-1H,2H,3H-imidazo[4,5-b]pyrazine-5-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 28); 5-Chloro-N-[3-fluoro-4-(2-{3H-imidazo[4,5-b]pyridine-6-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 29); 5-Chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidine-6-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 30); 5-Chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidine-3-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 31); 5-Chloro-N-[3-fluoro-4-(2-{2-oxo-1H,2H,3H-imidazo[4,5-b]pyridine-6-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 32); 5-Chloro-N-[3-fluoro-4-(2-{3-methyl-1H-pyrazolo[3,4-b]pyridine-5-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 33); N-{4-[2-(2-amino-4-methylpyrimidine-5-yl)ethynyl]-3-fluoropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 34); N-{4-[2-(2-amino-4-methoxypyrimidine-5-yl)ethynyl]-3-fluoropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 35); 5-Chloro-N-[3-fluoro-4-(2-{1-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyridine-6-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 36); 5-Chloro-N-[3-fluoro-4-(2-{3-methoxy-1H-pyrazolo[3,4-b]pyridine-5-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 37); and N-[4-(2-{5-aminopyrido[3,4-b]pyrazine-8-yl}ethynyl)-3-fluoropyridine-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide (Example 38) The compound may be selected from the group consisting of the above, or a pharmaceutically acceptable ester, amide, carbamate, or salt thereof (including pharmaceutically acceptable salts of such esters, amides, or carbamates).

[0177] In a more preferred embodiment, the compound of the present invention is 5-Chloro-N-[3-fluoro4-(2-{imidazo[1,2-a]pyrazine-3-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 26); N-[4-(2-{8-aminoimidazo[1,2-b]pyridazine-3-yl}ethynyl)-3-fluoropyridine-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide; N-[4-(2-{5-aminopyrido[3,4-b]pyrazine-8-yl}ethynyl)-3-fluoropyridine-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide (Example 38); 5-Chloro-N-[3-fluoro4-(2-{1H-imidazo[4,5-b]pyrazine-5-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-fluoro-4-{2-[2-(methylamino)pyrimidine-5-yl]ethynyl}pyridine-2-yl)-2-methoxypyridine-3-sulfonamide (Example 25); 5-Chloro-N-[3-fluoro4-(2-{2-oxo-1H,2H,3H-imidazo[4,5-b]pyrazine-5-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 28); 5-Chloro-N-[3-fluoro4-(2-{3-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyrazine-5-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[3-fluoro4-(2-{3H-imidazo[4,5-b]pyridine-6-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 29); 5-Chloro-N-{3-fluoro-4-[2-(2-methylpyrimidine-5-yl)ethynyl]pyridine-2-yl}-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[3-fluoro-4-(2-{2-oxo-1H,2H,3H-imidazo[4,5-b]pyridine-6-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 32); 5-Chloro-N-[3-fluoro-4-(2-{1-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyridine-6-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 36); 5-Chloro-N-[3-fluoro-4-(2-{imidazo[1,2-b]pyridazine-3-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide; N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3-fluoropyridine-2-yl}-5-chloro-2-methoxybenzene-1-sulfonamide (Example 13); 5-Chloro-N-[3-fluoro-4-(2-{imidazo[1,2-b]pyridazine-7-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidine-3-yl}ethynyl)pyridine-2-yl-2-methoxypyridine-3-sulfonamide (Example 31); 5-Chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidine-6-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide (Example 30); N-{4-[2-(5-amino-1,6-naphthyridine-8-yl)ethynyl]-3-fluoropyridine-2-yl}5-chloro-2-methoxypyridine-3-sulfonamide; N-[4-(2-{7-aminopyrazolo[1,5-a]pyridine-3-yl}ethynyl)-3-fluoropyridine-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[3-fluoro-4-(2-{5H-pyrrolo[2,3-b]pyrazine-2-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridine-5-yl}ethynyl)pyridine-2-yl]-2-methoxybenzene-1-sulfonamide (Example 12); N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3-fluoropyridine-2-yl}-2,5-dichlorobenzene-1-sulfonamide (Example 15); and The compound is selected from 2,5-dichloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridine-5-yl}ethynyl)pyridine-2-yl]benzene-1-sulfonamide (Example 14).

[0178] Depending on the substituents present in the compounds of the present invention, the compounds may form esters, amides, carbamates, and / or salts. Salts of the compounds of the present invention suitable for pharmaceutical use are those with pharmaceutically acceptable counterions. Such pharmaceutically acceptable salts are described in standard texts on salt formation; see, for example, P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA / Wiley-VCH, 2002), or SMBerge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. However, salts with pharmaceutically unacceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of the compounds of the present invention, their pharmaceutically acceptable salts, and their physiologically functional derivatives. The term "physiologically functional derivative" means, for example, a chemical derivative of a compound of the present invention that has the same physiological function as the free compound of the present invention by being convertible in the body. Esters, amides, and carbamates are examples of physiologically functional derivatives.

[0179] Suitable salts according to the present invention include those formed using organic or inorganic acids. In particular, suitable salts formed using acids according to the present invention include mineral acids, strong organic carboxylic acids, such as alkane carboxylic acids of 1 to 4 carbon atoms that are unsubstituted or, for example, substituted with halogens, saturated or unsaturated dicarboxylic acids, hydroxycarboxylic acids, amino acids, etc., or organic sulfonic acids, such as unsubstituted or, for example, substituted with halogens (C 1~4 ) Includes those formed using alkyl or aryl sulfonic acids, etc. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, isethionic acid, ascorbic acid, malic acid, phthalic acid, aspartic acid, and those formed from glutamic acid, lysine, and arginine. Other acids such as oxalic acid are not pharmaceutically acceptable in themselves, but may be useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0180] Suitable salts according to the present invention include those formed using organic or inorganic bases. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, such as potassium and sodium salts, alkaline earth metal salts, such as calcium and magnesium salts, and salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di- or tri-lower alkylamines, such as ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or mono-, di- or trihydroxy lower alkylamines, such as mono-, di- or triethanolamine.

[0181] The compounds of the present invention may have suitable groups that can be converted to esters, amides, or carbamates. -OH or -NHR in the compounds of the present invention G Typical ester, amide, and carbamate groups formed from this group include OC(O)R G , NR G C(O)R G , NR G CO2R G OSO2R G , and NR G SO2R G R G C 1~8 Alkyl, C 2~8 Alkenil, C 2~8 Alkinyl, C 3~8 Cycloalkyl and C 3~8 Cycloalkyl C 1~8 Alkyl, Halo C 1~8 Alkyl, Dihalo C 1~8 Alkyl, Trihalo C 1~8 Alkyl, phenyl, and phenyl C 1~4 Selected from the group consisting of alkyl, more preferably R G C 1~8 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, and C 3~8 Cycloalkyl C 1~8 Selected from the group consisting of alkyl groups.

[0182] Those skilled in organic chemistry will understand that many organic compounds can form complexes with solvents from which they react or from which they precipitate or crystallize. These complexes are known as “solvates.” “Pharmacologically acceptable solvates” means molecular complexes comprising the compound of the present invention and one or more pharmaceutically acceptable solvent molecules, such as water or ethanol. For example, a complex with water is known as a “hydrate.” When an active pharmaceutical ingredient (API) incorporates a solvent such as water into its crystal lattice in either stoichiometric or non-stoichiometric amounts, solvates such as hydrates exist. Since solvent incorporation may be encountered at any stage of the drug manufacturing process or during storage of the API or dosage form, APIs are routinely screened for the presence of hydrates. For more information on solvates, see S. Byrn et al., Pharmaceutical Research, 12(7), 1995, 954-954, and Water-Insoluble Drug Formulation, 2 nd These are described in edn, R. Liu, CRC Press, page 553, and are incorporated herein by reference. Those skilled in the art will therefore understand that the compounds of the present invention, as well as their esters, amides, carbamates, and / or salts, may exist in the form of solvates, which are also within the scope of the present invention. Solvates of the compounds of the present invention that are suitable for pharmaceutical use are those in which the associated solvent is pharmaceutically acceptable. For example, as described above, hydrates are an example of a pharmaceutically acceptable solvate. However, solvates with associated solvents that are pharmaceutically unacceptable may find use as intermediates in the preparation of the compounds of the present invention, as well as their pharmaceutically acceptable esters, amides, carbamates, and / or salts.

[0183] A compound that can be converted to the compound of the present invention, or its active metabolite or residue, upon administration to a recipient, as described above, is known as a "prodrug." For example, a prodrug can be converted in the body to its active form having a medical effect, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series (1976), "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.

[0184] Definition: In the context of this application and the present invention, the following definitions apply. As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine. Fluorine, chlorine, or bromine are preferred. Fluorine and chlorine are particularly preferred.

[0185] As used herein, “alkyl” used alone or as a suffix or prefix is ​​intended to include both branched and linear saturated aliphatic hydrocarbon groups of a certain number of carbon atoms. For example, “C 1~6 "Alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.

[0186] As used herein, "alkylenyl" or "alkylene," used alone or as a suffix or prefix, is intended to contain a linear saturated aliphatic hydrocarbon group of a certain number of carbon atoms. For example, "C 1~6 "Alkyrenyl" or "C 1~6 "Alkylene" refers to an alkylenyl or alkylene having 1, 2, 3, 4, 5, or 6 carbon atoms. When the specific number indicating an alkylenyl or alkylene group is an integer 0 (zero), the bond is intended to link the group to which the alkylenyl or alkylene group is substituted. For example, "-C0 alkylene OH" is equivalent to "-OH" (hydroxyl). As used herein, the group linked by an alkylene or alkylenyl group is intended to be bonded to the first and last carbons of the alkylene or alkylenyl group. In the case of methylene, the first and last carbons are the same. Examples of alkylenes or alkylenyls include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene.

[0187] As used herein, the term "aryl" means phenyl or naphthyl.

[0188] As used herein, the term "cycloalkyl" refers to a saturated group in a ring system of a specific number of carbon atoms. For example, "C 3~6"Cycloalkyl" means a cycloalkyl group having 3, 4, 5, or 6 carbon atoms. Cycloalkyl groups can be monocyclic, spirocyclic, or bicyclic. Cycloalkyl groups may have crosslinks in their cyclic structure. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl. Other examples of monocyclic cycloalkyl groups include cyclohexyl, cycloheptyl, and cyclooctyl. Examples of crosslinked cycloalkyl groups include bicyclo[2.2.1]hepta-2-yl and adamantanil. Examples of spirocyclic cycloalkyl groups include spiro[5.5]undecanyl and spiro[5.4]decanyl. Preferably, cycloalkyl groups are monocyclic or spirocyclic, and monocyclic or spirocyclic cycloalkyl groups may optionally be crosslinked.

[0189] As used herein, the terms “non-aromatic heterocyclyl” or “non-aromatic heterocyclic” mean a non-aromatic cyclic group of carbon atoms in which 1 to 3 of the carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. Non-aromatic heterocyclic groups may be monocyclic, spirocyclic, or bicyclic, for example. Non-aromatic heterocyclic groups may have bridges in the cyclic structure, for example. In a bicyclic heterocyclyl group, there may be one or more heteroatoms in each ring, or only one of the rings. As described above, the heteroatoms in the non-aromatic heterocyclic may be selected from the group consisting of S, O, and N, preferably from the group consisting of O and N. A suitable nitrogen atom-containing heterocyclyl group contains the corresponding N-oxide. Non-aromatic heterocyclyl groups may be partially saturated, i.e., they may contain one of more double bonds but not enough bonds to form a completely delocalized ring of electrons.

[0190] Examples of monocyclic non-aromatic heterocyclic groups (also called monocyclic heterocycloalkyl rings) include azilidinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranil, tetrahydropyranil, morpholinyl, thiomorpholinyl, and azepanil.

[0191] Examples of crosslinked non-aromatic heterocyclyl groups include morphanyl and 1,4-diazabicyclo[2.2.2]octanyl.

[0192] Examples of spirocyclic non-aromatic heterocyclic groups include 1,4-dioxaspiro[4.5]decanyl, 6-azaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, 2-azaspiro[3.4]octanyl, 1,1-dimethylethyl ester, and 1,4,6-triazaspiro[4.4]nonane.

[0193] As used herein, the term “heteroaryl” means an aromatic cyclic group of carbon atoms in which one to three carbon atoms are replaced by one or more heteroatoms (e.g., one, two, three, or four, preferably one, two, or three) independently selected from nitrogen, oxygen, or sulfur. Heteroaryl groups may be monocyclic or bicyclic, for example. In a bicyclic heteroaryl group, one or more heteroatoms may be present in each ring, or only one of the rings. In a bicyclic heteroaryl group, both rings may be aromatic, or only one of the rings may be aromatic. As described above, the heteroatoms in a heteroaryl group may be selected from the group consisting of S, O, and N, preferably from the group consisting of N and S.

[0194] Examples of monocyclic aromatic heterocyclyl groups (also called monocyclic heteroaryl groups) include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl groups.

[0195] Examples of bicyclic heterocyclyl groups in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, and benzoazepanyl groups.

[0196] Examples of bicyclic aromatic heterocyclyl groups (also called bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyradinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthilidinyl, quinolinyl, benzofuranil, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl, isoquinolinyl, and the benzodroxazolyl group.

[0197] Preferred examples of heteroaryl groups of the present invention include pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, imidazolyl, thiazolyl, indolyl, pyril, oxazolyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzimidazolyl, and indolinyl.

[0198] As described above, the compounds of the present invention have activity as inhibitors of GCN2 and are GCN2 inhibitors. Therefore, the present invention also provides the compounds of the present invention or compositions containing the compounds of the present invention for use as pharmaceuticals or for use in therapy. For example, the present invention provides the compounds of the present invention or compositions containing the compounds of the present invention together with a pharmaceutically acceptable carrier for use as pharmaceuticals or for use in therapy.

[0199] To avoid misunderstanding, as used herein, the terms “therapy,” “treatment,” and “to treat” include both preventive and curative measures for a condition, disease, or disorder. They also include slowing, interrupting, controlling, or stopping the progression of a condition, disease, or disorder. They also include preventing, curing, slowing, interrupting, controlling, or stopping the symptoms of a condition, disease, or disorder. For example, if the disease or disorder is cancer, this includes preventing the metastasis of cancer.

[0200] The compounds of the present invention, or compositions containing the compounds of the present invention, can be used to treat diseases or disorders in which inhibition of GCN2 provides a therapeutic effect. Therefore, the compounds of the present invention can be used to treat or prevent diseases or disorders in which inhibition of GCN2 is observed.

[0201] The compounds of the present invention find specific applications in the treatment or prevention of diseases or disorders selected from the group consisting of diseases or disorders in which inhibition of GCN2 results in a therapeutic effect, such as cancer (e.g., solid tumors and hematological cancers).

[0202] The present invention also provides a method for treating a subject suffering from a medical disorder or disease. This method involves administering a therapeutically effective amount of the compound of the present invention, or a composition described herein, to a subject in order to treat the disorder or disease. As described above, several diseases or disorders in which inhibition of GCN2 results in a therapeutic effect can be treated with the compounds of the present invention. For example, the compounds described herein can be used to treat cancer (e.g., solid tumors and hematological cancers).

[0203] When a compound of the present invention, or a composition containing a compound of the present invention, is used therapeutically as a pharmacopoeia for the treatment or prevention of a disease or disorder, for example, in the therapeutic uses and methods described herein, such use or method may include the step of administering a therapeutically effective amount of the compound of the present invention to a mammal, including a human, that is in need of such treatment or prevention.

[0204] The compounds of the present invention find specific applications in the treatment or prevention of cancer. In certain embodiments, the cancer is a solid tumor or a hematological cancer (e.g., leukemia or multiple myeloma). In certain embodiments, the cancer is a cancer having a MYC mutation.

[0205] Cancers for which the compounds of the present invention find specific applications in treatment or prevention include: colorectal cancer (e.g., colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma, pancreatic endocrine tumors), pharyngeal cancer, laryngeal cancer, esophageal cancer, and gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous cell carcinoma). ), duodenal cancer, small intestine cancer, breast cancer (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, low-grade ovarian tumor), testicular cancer, prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer, castration-resistant prostate cancer), liver cancer (e.g., liver cancer, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma) , kidney cancer (e.g., renal cell carcinoma (e.g., clear cell renal cell carcinoma), transitional cell carcinoma of the renal pelvis and ureter), uterine cancer (e.g., cervical cancer, endometrial cancer, uterine sarcoma), choriocarcinoma of pregnancy, brain tumors (e.g., medulloblastoma, glioma, glioblastoma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, undifferentiated astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (e.g., basal cell carcinoma, malignant melanoma (melanoma)) Examples of cancers that fall under this category include, but are not limited to, sarcomas (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma, osteosarcoma), malignant bone tumors, bladder cancer, and hematological cancers (e.g., multiple myeloma, smoldering myeloma, plasmacytoma, leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia (including acute transformation of chronic leukemia)), non-Hodgkin lymphoma, malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disorders), and cancers of unknown primary origin.

[0206] The compounds of the present invention also find applications as cancer growth inhibitors, cancer metastasis inhibitors, and apoptosis promoters, as well as for the prevention or treatment of precancerous lesions (e.g., myelospinal dysplasia syndrome, monoclonal immunoglobulinemia of unknown significance).

[0207] In one embodiment, the compounds of the present invention find specific applications in the treatment or prevention of osteosarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, pancreatic cancer, colorectal cancer, melanoma, and malignant lymphoma.

[0208] Examples of solid cancers for which the compounds of the present invention find specific applications in treatment or prevention include: colorectal cancer (e.g., colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma, pancreatic endocrine tumors), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous cell carcinoma), duodenal cancer, small intestine cancer, breast cancer (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, low-grade ovarian tumor), testicular tumors, and prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer). This includes, but is not limited to, cancers (castration-resistant prostate cancer), liver cancers (e.g., hepatic cancer, primary liver cancer, extrahepatic cholangiocarcinoma), thyroid cancers (e.g., medullary thyroid carcinoma), kidney cancers (e.g., renal cell carcinoma (e.g., clear cell renal cell carcinoma), transitional cell carcinoma of the renal pelvis and ureter), uterine cancers (e.g., cervical cancer, endometrial cancer, uterine sarcoma), gestational choriocarcinoma, brain tumors (e.g., medulloblastoma, glioma, glioblastoma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, undifferentiated astrocytoma, pituitary adenoma), retinoblastoma, skin cancers (e.g., basal cell tumor, malignant melanoma), sarcomas (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma, osteosarcoma), malignant bone tumors, and bladder cancer.

[0209] Examples of hematological cancers in which the compounds of the present invention find particular applications in treatment or prevention include, but are not limited to, multiple myeloma, smoldering myeloma, plasmacytoma, leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia (including acute transformation of chronic leukemia)), non-Hodgkin lymphoma, malignant lymphoma, Hodgkin's disease, and chronic myeloproliferative disorders.

[0210] In one embodiment, the compounds of the present invention find specific applications in the treatment or prevention of cancers with high levels of MYC (i.e., cancers in which the MYC gene or protein is expressed at high levels). Examples of cancers with MYC mutations for which the compounds of the present invention find specific applications in the treatment or prevention include, but are not limited to, prostate cancer, breast cancer (e.g., triple-negative breast cancer), lung cancer (e.g., small cell lung cancer), ovarian cancer, neuroblastoma, and leukemia (e.g., acute lymphoblastic leukemia and mixed lineage leukemia).

[0211] The compounds of the present invention also find applications in conditions selected from diabetic retinopathy, myocardial ischemia, diabetic cardiomyopathy, allergic airway inflammation, doxorubicin-induced cardiotoxicity, and nonalcoholic fatty liver disease (NAFLD).

[0212] The present invention also provides a method for treating or preventing a disease or disorder in a mammal in which inhibition of GCN2 has a therapeutic effect, the method comprising administering a therapeutically effective amount of a compound according to the present invention, or a composition containing a compound according to the present invention, to a mammal. The diseases and disorders that can be treated by this method of the present invention are preferably those described above.

[0213] The present invention also provides the use of compounds according to the present invention for the manufacture of pharmaceuticals for the treatment or prevention of diseases or disorders in which inhibition of GCN2 results in a therapeutic effect. Diseases and disorders that can be treated by this use of the present invention are preferably those described above.

[0214] Of course, the amount of active ingredient required to achieve a therapeutic effect varies depending on the specific compound, route of administration, the subject being treated (including the type, species, age, weight, sex, and condition of the subject), the subject's renal and hepatic function, and the specific disorder or disease being treated, as well as its severity. A typical, experienced physician, veterinarian, or clinician can easily determine and prescribe the effective dose of medication needed to prevent, counteract, or halt the progression of a condition.

[0215] The oral dosage of the present invention, when used for the indicated effects, for adults, will be in the range of about 0.01 mg (mg / kg / day) to about 100 mg / kg / day per kg of body weight per day, preferably 0.01 mg (mg / kg / day) to 10 mg / kg / day per kg of body weight per day, most preferably in the range of 0.1 to 5.0 mg / kg / day. For oral administration, the composition is preferably provided in the form of tablets or other presenting forms, provided in separate units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of the active ingredient for symptomatic dosage adjustment for the patient being treated. The pharmacopoeia typically contains about 0.01 mg to about 500 mg of the active ingredient, preferably about 1 mg to about 100 mg of the active ingredient. Intravenously, the most preferred dose is in the range of about 0.1 to about 10 mg / kg / min during a constant rate infusion. Advantageously, the compound of the present invention may be administered in a once-daily dose, or the total daily dose may be administered in two, three, or four divided doses per day. Furthermore, the compound of the present invention can be administered in an intranasal form via topical use of a suitable intranasal vehicle, or via a transdermal route using a transdermal skin patch, as is well known to those skilled in the art. Because it is administered in the form of a transdermal delivery system, the dose will, of course, be continuous rather than intermittent throughout the entire administration plan.

[0216] While it is possible to administer the active ingredient alone, it is preferable that the active ingredient be present in a pharmaceutical preparation or composition. Therefore, the present invention provides a pharmaceutical preparation or composition comprising the compound of the present invention and a pharmaceutically acceptable diluent, excipient, or carrier (collectively referred to herein as "carrier" material). The pharmaceutical compositions and preparations of the present invention may take the forms of pharmaceutical compositions or preparations as described below.

[0217] The pharmaceutical compositions according to the present invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or injection], and intra-articular), inhalation (including particulate dust or mist which can be produced by various types of quantitatively pressurized aerosols), nebulizer or inhaler, rectal, intraperitoneal, and topical (including transdermal, oral, sublingual, and intraocular) administration, but the most preferred route may depend, for example, on the recipient's condition and impairment.

[0218] The compositions may be conveniently presented in unit dosage forms and may be prepared by any method well known in the field of pharmacy. All methods involve associating the active ingredient with a carrier constituting one or more auxiliary components. Generally, compositions are prepared by homogeneously and closely associating the active ingredient with a liquid carrier or a fine solid carrier, or both, and then, if necessary, shaping the product into the desired composition.

[0219] The compositions of the present invention, suitable for oral administration, can be presented as individual units such as capsules, cachets, pills, or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids, for example, as elixirs, tinctures, suspensions, or syrups; or as oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be presented as a bolus, lick, or paste.

[0220] Tablets may be prepared by compression or molding, using optionally one or more auxiliary components. Compressed tablets may optionally be prepared by compressing a fluid form of the active ingredient, such as a powder or granules, mixed with a binder, lubricant, inert diluent, lubricant, surfactant, or dispersant, in a suitable machine. Molded tablets may be produced by molding a mixture of powder compounds moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or have a split line, and may be formulated to provide a slow or controlled release of the active ingredient therein. The compounds of the present invention can be administered, for example, in a form suitable for immediate release or sustained release. Immediate release or sustained release can be achieved by using a suitable pharmaceutical composition containing the compounds of the present invention, or, in the case of sustained release, by using a device such as a subcutaneous implant or osmotic pump.

[0221] Exemplary compositions for oral administration include, for example, suspensions that may contain microcrystalline cellulose for bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents (e.g., those known in the art), and immediate-release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and / or lactose and / or other excipients, binders, fillers, disintegrants, diluents, and lubricants (e.g., those known in the art). Suitable binders include natural sugars such as starch, gelatin, glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, and wax. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum. The compounds of the present invention may also be delivered orally by sublingual and / or buccal administration. Molded tablets, compressed tablets, or lyophilized tablets are exemplary forms that may be used. Exemplary compositions include those in which the compounds of the present invention are combined with fast-dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrin. Such compositions may also contain high molecular weight excipients such as cellulose (avicel) or polyethylene glycols (PEG). Such compositions may also contain excipients to aid adhesion to mucous membranes, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and maleic anhydride copolymers (e.g., Gantrez), and agents to control release, such as polyacrylic copolymers (e.g., Carbopol 934). Lubricants, flow enhancers, flavorings, colorants, and stabilizers may also be added to facilitate manufacture and use.Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. For oral administration in liquid form, the oral drug component can be combined with any oral, non-toxic, pharmaceutically acceptable, inert carrier such as ethanol, glycerol, or water.

[0222] The compounds of the present invention can also be administered in the form of liposome delivery systems such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. The liposomes can be formed from various phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (cephalin), or phosphatidylcholine (lecithin).

[0223] Compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic agents, and solutes that are isotonic with the blood of the recipient to which the composition is intended; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners. Compositions may be supplied in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried state which requires only the addition of a sterile liquid carrier, such as physiological saline or distilled water for injection, immediately before use. Immediate injection solutions and suspensions may be prepared from the sterile powders, granules, and tablets of the types described above. Exemplary compositions for parenteral administration include, for example, other suitable dispersions, wetting agents, and suspensions, which may contain a suitable non-toxic, parenterally acceptable diluent or solvent, such as 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or synthetic monoglycerides or diglycerides, as well as an injectable solution or suspension, which may contain a fatty acid containing oleic acid, or Cremaphor®.

[0224] Exemplary compositions for intranasal aerosol or inhalation administration include, for example, a solution in physiological saline that may contain benzyl alcohol or other suitable preservatives, absorption enhancers for improving bioavailability, and / or other solubilizers or dispersants (such as those known in the art).

[0225] Compositions for rectal administration may be presented as suppositories with a common carrier such as cocoa butter, synthetic glyceride esters, or polyethylene glycol. Such carriers are typically solid at room temperature but liquefy and / or dissolve in the rectal lumen to release the drug.

[0226] Compositions for topical administration in the oral cavity, such as buccal or sublingual administration, include lozenges containing the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and lozenges containing the active ingredient in a base such as gelatin and glycerin or sucrose and acacia. Exemplary compositions for topical administration include topical carriers such as Plastibase® (mineral oil gelled with polyethylene).

[0227] A preferred unit dose composition contains the above-mentioned effective amount of the active ingredient or a suitable portion thereof.

[0228] In addition to the components specifically mentioned above, the compositions of the present invention may also contain other agents commonly used in the art, depending on the type of composition, and it should be understood that, for example, those suitable for oral administration may contain flavoring agents.

[0229] The compounds of the present invention may be used in pharmaceuticals as the sole active ingredient, but they can also be used in combination with one or more further therapeutic agents. Accordingly, the present invention also provides the compounds of the present invention together with further therapeutic agents for simultaneous, sequential, or separate administration. Such further therapeutic agents may be further compounds according to the present invention, or they may be different therapeutic agents, for example, another GCN2 inhibitor. Further therapeutic agents may also be therapeutic agents for use in the treatment or prevention of diseases or disorders selected from the group consisting of cancer (e.g., solid tumors and hematological cancers) and autoimmune diseases, particularly cancer, in which inhibition of GCN2 results in a therapeutic effect.

[0230] Therefore, in one embodiment, further therapeutic agents may be different therapeutic agents for use in the treatment or prevention of cancer, for example, L-asparaginase (ASNase), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), immunomodulators (e.g., thalidomide, lenalidomide, and pomalidomide), SINE compounds (e.g., selinexol), monoclonal antibodies (e.g., rituximab, daratumumab, isatuximab, herceptin, and avastin, etc.), alkylating agents, etc. Alkyl phosphate, aziridine, ethyleneimine, and methylamelamines, acetogenin, camptothecin, bryostatin, calistatin, CC-1065, cryptophycin, dorastatin, duocalmycin, eruterobin, pancrustacean, sarcodicuciin, spongistatin, nitrogen mustard, antibiotics, enemycin antibiotics, dynemycin, bisphosphonates, esperamicin, pigment proteins, enemycin antibiotics, chromophores, acrasinomycin, actinomycin, autoramycin, azaceri Bleomycin, kactinomycin, carabicin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potophyllomycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, sol Bicin, antimetabolites, erlotinib, vemurafenib, crizotinib, sorafenib, ibrutinib, enzalutamide, folate analogs, purine analogs, androgens, anti-adrenergic drugs, folate supplements, e.g., folinic acid, acegraton, aldofsphamide glycoside, aminolevulinic acid, enyluracil, amsacrine, bestrabusil, bisanthren, editraxate, defofamine, demecorcin, diazicon, eflornithine, eriptinium acetate, epotilon, etogluside, gallium nitrate, hydroxyurea,Lentinan, lonidainine, meitansinoid, mitogwazone, mitoxantrone, mopidammole, nitraerine, pentostatin, fenamet, pirarubicin, losoxantrone, 2-ethylhydrazide podophyllate, procarbazine, PSK® polysaccharide complex (JHS Natural Products, Eugene, OR), razoxane, rhizoxin, schizophyllan, spirogermanium, tenuazonic acid, triadicone; 2,2',2''-trichlorotriethylamine, trichothecenes (especially T-2 toxin, vercaculin A, loridine A, and anguanidine), urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitractol, pipobromane, gasitosine, arabinoside ("Ara-C"), cyclophosphamide Thiotepa, taxoid, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum analog, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminobutyline, xeloda, ibandronate, irinotecan (Camptosar, CPT-11), topoisomerase inhibitor RFS 2000, chemotherapeutic agents selected from the group consisting of difluorometlhylornithine, asparaginase, retinoids, capecitabine, combretastatin, leucovorin, oxaliplatin, inhibitors of PKC-alpha, Raf, H-Ras, EGFR, and VEGF-A that reduce cell proliferation, and pharmaceutically acceptable salts, acids, or derivatives thereof, and combinations thereof.

[0231] In another embodiment, further therapeutic agents may be checkpoint inhibitors, such as drugs or antibodies that inhibit one or more of CTLA4, PD-1, PD-L1, LAG-3, B7-H3, B7-H4, TIM3, VISTA, and KIR.

[0232] In certain embodiments, the compounds of the present invention are administered in combination with L-asparaginase (ASNase). Such combination therapy can be used to treat cancer, particularly acute lymphoblastic leukemia (including acute transformation of chronic leukemia) and non-Hodgkin lymphoma. Such combination therapy can also be used to treat cancerous tumors that are resistant or to asparaginase, for example, cancers selected from the group consisting of acute lymphoblastic leukemia (including acute transformation of chronic leukemia) and non-Hodgkin lymphoma.

[0233] In certain embodiments, the compounds of the present invention are administered in combination with proteasome inhibitors, such as bortezomib, carfilzomib, ixazomib, marozomib, or oprozomib. Such combination therapies can be used to treat cancer, particularly hematological malignancies, such as Hodgkin lymphoma, multiple myeloma, smoldering myeloma, and precancerous conditions, monoclonal immunoglobulinemia of unknown significance.

[0234] In embodiments in which the compounds of the present invention are used in combination with other agents for the treatment or prevention of diseases or disorders in which inhibition of GCN2 provides a therapeutic effect, the individual components of such combinations may be administered separately or simultaneously in divided or single combined forms at different points in time during the course of treatment. Accordingly, the present invention should be understood to encompass all such treatment plans of concurrent or alternating treatment, and the term “administer” shall be interpreted accordingly. The scope of combinations of the compounds of the present invention with other agents for the treatment or prevention of diseases or disorders in which inhibition of GCN2 provides a therapeutic effect will be understood, in principle, to include any combination with any pharmaceutical composition useful for treating diseases or disorders in which inhibition of GCN2 provides a therapeutic effect.

[0235] When used in combination with the compounds of the present invention, the other therapeutic agents described above may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR), or otherwise in amounts determined by those skilled in the art.

[0236] The compounds of the present invention described above also find use in combination with radiotherapy for the treatment of cancer.

[0237] Furthermore, the compounds of the present invention may be used in combination with non-pharmacological therapies. Specifically, the compounds of the present invention or the combination agents of the present invention can be used in combination with non-pharmacological therapies such as (1) surgery, (2) hypertension chemotherapy using angiotensin II, etc., (3) gene therapy, (4) hyperthermia, (5) cryotherapy, (6) laser ablation, (7) radiotherapy, and (8) dietary therapy (e.g., amino acid-restricted diet).

[0238] For example, by using the compounds of the present invention or the combination agents of the present invention before or after the above-mentioned surgery, or before or after treatment using two or three of them in combination, effects such as inhibition of resistance development, extension of disease-free survival, suppression of cancer metastasis or recurrence, and life extension can be obtained.

[0239] In addition, treatment with the compounds of the present invention or the combination agents of the present invention can be combined with supportive therapies, such as (i) administration of antibiotics for complications of various infections (e.g., P-lactam antibiotics such as Pansporin, macrolide antibiotics such as Clarithromycin), (ii) administration of intravenous hypernutrition, amino acid preparations, and complex vitamin preparations to improve malnutrition, (iii) administration of morphine for pain relief, (iv) administration of pharmaceuticals to improve side effects such as nausea, vomiting, anorexia nervosa, diarrhea, leukopenia, thrombocytopenia, decreased hemoglobin concentration, alopecia, liver damage, kidney damage, DIC, and fever, and (v) administration of pharmaceuticals to suppress multidrug resistance in cancer.

[0240] The compounds of the present invention described above also find use in optionally labeled forms as diagnostic agents for diagnosing conditions associated with diseases or disorders in which inhibition of GCN2 provides a therapeutic effect. For example, such compounds may be radiolabeled.

[0241] In addition to their use in therapeutics, the compounds according to the present invention may also be useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for evaluating other compounds having similar activity. Furthermore, the compounds of the present invention can be used as molecular probes to identify and / or locate targets of their action, such as targets in the airways, and can also be used as diagnostic tools for diagnosing diseases or conditions in vivo, ex vivo, or in vitro, or as precursors for the synthesis of such probes. The molecular probes of the present invention may include reactive, labeled (i.e., compounds of the present invention enriched with radioactive or otherwise detectable isotopes) and fluorescent compounds, which are well known to those skilled in the art.

[0242] The following embodiments illustrate the present invention.

[0243] List of abbreviations: anh.-anhydrous ACN-acetonitrile Boc-tert-butoxycarbonyl CDCl 3- - Deuterated chloroform CD3OD - Deuterated methanol DCM-Dichloromethane DIPEA-N,N-diisopropylethylamine DMAP-4-dimethylaminopyridine DMSO-dimethyl sulfoxide DMSO-d6-Deuterated Dimethyl Sulfoxide EA-ethyl acetate eq. or Equiv-equivalent FC-Flash Chromatography 11H NMR - Proton Nuclear Magnetic Resonance HPLC - High-Performance Liquid Chromatography MeOH-methanol MS-Mass spectrometry NCS-N-chlorosuccinimide rt - room temperature RT-retention time sat.- saturation TEA-triethylamine THF-tetrahydrofuran TMS-trimethylsilyl Y-Yield

[0244] Explanation of analysis method: all 1 The 1H NMR spectrum was measured using a Bruker Avance III HD 400 MHz or Bruker Fourier 300 MHz NMR spectrometer, and interchangeable protons may or may not be observed.

[0245] LCMS (Method A) Instrument: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus Column: Kinetex® 2.6μm XB-C18 (4.6×50mm), 110A, column number 00B-4496-E0. Reagents: Formic acid ≥ 98%, Sigma-Aldrich -Acetonitrile for HPLC UV / Gradient Grade, Baker -μQ-water for LCMS HPLC conditions: - Wavelength range: (190~340) nm ± 4 nm -Flow rate: 1.0ml / min - Column temperature: 25℃ - Autosampler temperature: 20℃ -Analysis time: 6 minutes - Elution: Gradient

[0246] [Table 1]

[0247] LCMS (Method B): Instrument: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus Column: Kinetex® 2.6μm XB-C18 (4.6×50mm), 110A, column number 00B-4496-E0. Reagents: Formic acid ≥ 98%, Sigma-Aldrich -Acetonitrile for HPLC UV / Gradient Grade, Baker -μQ-water for LCMS HPLC conditions: - Wavelength range: (190~340) nm ± 4 nm -Flow rate: 1.0ml / min - Column temperature: 25℃ - Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 6 minutes - Elution: Gradient

[0248] [Table 2]

[0249] LCMS (Method C): Instrument: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus Column: Kinetex® 2.6μm XB-C18 (4.6×50mm), 110A, column number 00B-4496-E0. Reagents: Formic acid ≥ 98%, Sigma-Aldrich -Acetonitrile for HPLC UV / Gradient Grade, Baker -μQ-water for LCMS HPLC conditions: - Wavelength range: (190~340) nm ± 4 nm -Flow rate: 1.0ml / min - Column temperature: 25℃ - Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 6 minutes - Elution: Gradient

[0250] [Table 3]

[0251] LCMS (Method D): Instrument: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus Column: Kinetex® 2.6μm XB-C18 (4.6×50mm), 110A, column number 00B-4496-E0. Reagents: Formic acid ≥ 98%, Sigma-Aldrich -Acetonitrile for HPLC UV / Gradient Grade, Baker -μQ-water for LCMS HPLC conditions: - Wavelength range: (190~340) nm ± 4 nm -Flow rate: 1.0ml / min - Column temperature: 25℃ - Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 6 minutes - Elution: Gradient

[0252] [Table 4]

[0253] LCMS (Method E) Instrument: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus Column: Kinetex® 2.6μm XB-C18 (4.6×50mm), 110A, Column number 00B-4496-E0, Internal column number 019 Reagents: Formic acid ≥ 98%, Sigma-Aldrich -Acetonitrile for HPLC UV / Gradient Grade, Baker -μQ-water for LCMS HPLC conditions: - Wavelength range: (190~340) nm ± 4 nm -Flow rate: 1.0ml / min - Column temperature: 25℃ - Autosampler temperature: 20℃ -Analysis time: 6 minutes - Elution: Gradient

[0254] [Table 5]

[0255] LCMS (Method F) Instrument: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC-mass spectrometer Column: Kinetex® 2.6μm XB-C18 (4.6×50mm), 110A, Column number 00B-4496-E0, Internal column number 036 Reagents: - 28-30% ammonium hydroxide solution, Sigma-Aldrich -Acetonitrile for HPLC UV / Gradient Grade, Baker -μQ-water for LCMS HPLC conditions: - Wavelength range: (190~350) nm ± 4 nm -Flow rate: 1.0ml / min - Column temperature: 25℃ - Autosampler temperature: 20℃ -Analysis time: 6 minutes - Elution: Gradient

[0256] [Table 6]

[0257] LCMS (Method G) Instrument: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC-mass spectrometer Column: Kinetex® 2.6μm XB-C18 (4.6×50mm), 110A, Column number 00B-4496-E0, Internal column number 036 Reagents: - 28-30% ammonium hydroxide solution, Sigma-Aldrich -Acetonitrile for HPLC UV / Gradient Grade, Baker -μQ-water for LCMS HPLC conditions: - Wavelength range: (190~350) nm ± 4 nm -Flow rate: 1.0ml / min - Column temperature: 25℃ - Autosampler temperature: 20℃ -Analysis time: 6 minutes - Elution: Gradient

[0258] [Table 7]

[0259] LCMS (Method H) Instrument: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus Column: Kinetex® 2.6μm XB-C18 (4.6×50mm), 110A, Column number 00B-4496-E0, Internal column number 019 Reagents: Formic acid ≥ 98%, Sigma-Aldrich -Acetonitrile for HPLC UV / Gradient Grade, Baker -μQ-water for LCMS HPLC conditions: - Wavelength range: (190~340) nm ± 4 nm -Flow rate: 1.0ml / min - Column temperature: 25℃ - Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 6 minutes - Elution: Gradient

[0260] [Table 8]

[0261] Example 1: N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3-fluoropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide

[0262] [ka] Step 1: tert-butyl N-(5-bromopyrimidine-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0263] [ka] Di-tert-butyl dicarbonate (15.99 g, 0.073 mol, 2.5 equivalents) was added to a stirred solution of 2-amino-5-bromopyrimidine (5.1 g, 0.029 mol, 1 equivalent) and DMAP (0.72 g, 0.006 mol, 0.2 equivalents) in anhydrous THF (204 ml). The mixture was stirred overnight at room temperature and quenched with water (150 ml). The resulting mixture was extracted with EA (3 × 100 ml). The combined organic layer was washed with water (100 ml) and brine (100 ml), dried over Na₂SO₄, filtered, and evaporated to obtain the crude product (11.62 g) as a brown solid, which was used in the next step without purification.

[0264] 1 H NMR(300MHz,CDCl3)δ:8.80(s,2H),1.49(s,18H) MSm / z:[M+H] + 373.85

[0265] Step 2: tert-butyl N-[(tert-butoxy)carbonyl]-N-{5-[2-(trimethylsilyl)ethynyl]pyrimidine-2-yl}carbamate

[0266] [ka] To a stirred solution of crude tert-butyl N-(5-bromopyrimidine-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (Step 1, 11.62 g, 0.031 mol, 1 equivalent) in ACN (140 ml) in a glass pressure reactor, TMS acetylene (13.26 ml, 9.15 g, 0.093 mol, 3 equivalents), copper(I) iodide (1.18 g, 0.006 mol, 0.2 equivalents), and TEA (13 ml, 9.43 g, 0.093 mol, 3 equivalents) were added. Argon was blown into the mixture for 15 minutes, and PdCl2(PPh3)2 (2.18 g, 0.003 mol, 0.1 equivalent) was added. The reactor was sealed, and the mixture was stirred overnight at 80°C. The mixture was filtered through a Celite pad, and volatile substances were evaporated under reduced pressure. The residue was dissolved in EA (200 ml) and washed with water (100 ml). The phases were separated, and the aqueous phase was extracted with EA (100 ml). The Celite pad was further washed with EA (4 × 100 ml). The combined organic phase was dried over Na2SO4, filtered, and evaporated to obtain the crude product (16.7 g) as a brown solid, which was used without further purification.

[0267] 1 H NMR(300MHz,CDCl3)δ:8.78(s,2H),1.47(s,18H),0.30(s,9H) MSm / z:[M+H] + 392.10

[0268] Step 3: tert-butyl N-(5-ethynylpyrimidine-2-yl)carbamate

[0269] [ka] A solution of crude tert-butyl N-[(tert-butoxy)carbonyl]-N-{5-[2-(trimethylsilyl)ethynyl]pyrimidin-2-yl}carbamate (step 2, 14.0 g, 0.036 mol, 1 eq) in anhydrous MeOH (210 ml) was added with K2CO3 (14.82 g, 0.107 mol, 3 eq). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EA (300 ml) and concentrated under reduced pressure. Purification of the residue by FC (SiO2, hexane / EA 100:0→0:100) gave the product (1.48 g, Y: 23%, over three steps) as a yellowish-brown solid.

[0270] 1 H NMR (300 MHz, CDCl3) δ: 8.71 (s, 2H), 8.20 (s, 1H), 3.31 (s, 1H), 1.58 (s, 9H) MS m / z: [M+H] + 219.95

[0271] Step 4: 3-(Benzylsulfanyl)-5-chloro-2-methoxypyridine

[0272]

Chemical formula

[0273] 1H NMR(300MHz,CDCl3)δ:7.91(d,J=2.4Hz,1H),7.40(d,J=2.4Hz,1H),7.36-7.27(m,5H),4.13(s,2H),4.02(s,3H) MSm / z:[M+H] + 265.90

[0274] Step 5: 5-Chloro-2-methoxypyridine-3-sulfonyl chloride

[0275] [ka] NCS (15 g, 112 mmol, 6 equivalents) was slowly added over 30 minutes to a pre-cooled (5°C) solution of 3-(benzylsulfanyl)-5-chloro-2-methoxypyridine (step 4, 5 g, 18.8 mmol, 1 equivalent) in water (20 ml) and acetic acid (40 ml). The mixture was stirred at 5-10°C for 2 hours and at room temperature for 1 hour. The mixture was then diluted with water, ethyl acetate was added, and the pH was basicized to 7 with sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to obtain the crude residue. The product was extracted with warm hexane and filtered from the cooled solution to obtain the title product (3.64 g, Y: 73.1%).

[0276] 1 H NMR(300MHz,CDCl3)δ:8.45(d,J=2.5Hz,1H),8.24(d,J=2.5Hz,1H),4.21(s,3H)

[0277] Step 6: 3-Fluoro-4-iodopyridine-2-amine

[0278] [ka] 2,3-difluoro-4-iodopyridine (1.14 g, 4.74 mmol, 1 equivalent) and acetamidine hydrochloride (0.538 g, 5.69 mmol, 1.2 equivalents) were combined, and 0.474 g, 11.9 mmol, 2.5 equivalents in 2 mL of NaOH aqueous solution and DMSO (11.5 mL) were added. The reaction mixture was stirred overnight at 130°C. After 22 hours, the reaction mixture was filtered through a silica gel pad, the filtrate was concentrated under vacuum, and purified by FC (SiO2, hexane / EA 100:0 → 50:50) to obtain the desired product (0.307 g, Y: 27.2%) as a solid.

[0279] 1 H NMR(300MHz,CDCl3)δ:7.52(d,J=5.4Hz,1H),7.03(dd,J=5.4,3.9Hz,1H),4.83(s,2H) MSm / z:[M+H] + 238.65.

[0280] Step 7: 5-Chloro-N-(3-fluoro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide

[0281] [ka] To a suspension of NaH (60% of oil, 1.02 g, 2.52 mmol, 4 equivalents) in anhydrous THF (4.5 ml), 3-fluoro-4-iodopyridine-2-amine (step 6, 150 mg, 0.63 mmol, 1 equivalent) was added at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. It was then cooled to 0°C, and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (step 5, 168 mg, 0.69 mmol, 1.1 equivalents) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with methanol and concentrated. The residue was dissolved in EA (15 ml) and washed with saturated NaHCO3 solution (10 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to obtain the desired product as a brown solid (234 mg, Y: 84.0%).

[0282] 1 H NMR(300MHz,DMSO-d6)δ:12.03(br,s,1H),8.43(s,1H),8.20(d,J=2.6Hz,1H),7.53(s,1H),7.37(s,1H),3.86(s,3H) MSm / z:[M+H] + 443.70

[0283] Step 8: N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3-fluoropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide

[0284] [ka] To a stirred solution of 5-chloro-N-(3-fluoro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide (Step 7, 100 mg, 0.230 mmol, 1 equivalent), t-butyl N-(5-ethynylpyrimidine-2-yl)carbamate (Step 3, 59 mg, 0.27 mmol, 1.2 equivalents), and Cs2CO3 (294 mg, 0.900 mmol, 4 equivalents) in anhydrous DMSO (3 mL), PdCl2[P(Cy)3]2 (12 mg, 0.020 mmol, 0.07 equivalents) was added under an argon atmosphere. The reaction mixture was stirred in a microwave at 120°C for 1 hour, then at 150°C for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under vacuum. Purification by preparative HPLC yielded 20.5 mg of a beige solid. The solid product was treated with a saturated solution of NaHCO3 (4 mL), washed with H2O (4 mL), and dried under vacuum to obtain a beige solid product as free base (15.8 mg, Y: 16.1%).

[0285] 1 H NMR(400MHz,DMSO-d6)δ:8.44(s,2H),8.19(s,1H),8.07(d,J=2.6Hz,1H),7.52(d,J=5.0Hz,1H),7.23(s,2H),6.47(s,1H),3.83(s,3H) LCMS (Method A) Retention time: 2.653 minutes MSm / z:[MH] - 432.77

[0286] Example 2: N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3-chloropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide

[0287] [ka] Step 1: 5-Chloro-N-(3-chloro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide

[0288] [ka] To a suspension of NaH (60% of mineral oil, 44 mg, 1.1 mmol, 4 equivalents) in anhydrous THF (4.2 ml) cooled to 0°C, 3-chloro-4-iodopyridine-2-amine (70 mg, 0.28 mmol, 1 equivalent) was added. The mixture was stirred at room temperature for 1 hour, and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (Example 1, Step 5; 70 mg, 0.29 mmol, 1.05 equivalents) was added. The reaction was continued overnight at room temperature. MeOH (4 ml) was added, and the mixture was evaporated to obtain the crude product, which was purified by FC (SiO2, DCM / MeOH 100:0 → 90:10) to obtain the desired product (59 mg, Y: 47%) as a pale yellow solid.

[0289] 1 H NMR(300MHz,CD3OD)δ:8.34(d,J=2.6Hz,1H),8.29(d,J=2.6Hz,1H),7.61(d,J=5.7Hz,1H),7.52(d,J=5.6Hz,1H),3.94(s,3H) MSm / z:[M+H] + 459.70

[0290] Step 2: N-{4-[2-(2-aminopyrimidine-5-yl)ethinyl]-3-chloropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide

[0291] [ka] To a stirred solution of 5-chloro-N-(3-chloro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide (Step 1, 59 mg, 0.13 mmol, 1 equivalent), t-butyl N-(5-ethynylpyrimidine-2-yl)carbamate (Example 1, Step 3; 34 mg, 0.15 mmol, 1.2 equivalents), and Cs2CO3 (167 mg, 0.510 mmol, 4 equivalents) in anhydrous DMSO (2 mL), PdCl2[P(Cy)3]2 (7 mg, 0.01 mmol, 0.07 equivalents) was added under an argon atmosphere. The reaction mixture was stirred in a microwave at 120°C for 1 hour, then at 150°C for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under vacuum and purified by preparative HPLC to obtain 13 mg of a brown solid. The solid product was treated with a saturated solution of NaHCO3 (2 mL), washed with H2O (2 mL), and dried under vacuum to obtain a brown solid product as free base (5.2 mg, Y: 9.0%).

[0292] 1 H NMR(300MHz,DMSO-d6)δ:8.47(s,2H),8.31(s,1H),8.12(s,1H),7.79(s,1H),7.36(s,2H),3.82(s,3H) LCMS (Method A) Retention time: 2.793 minutes MSm / z:[MH] - 448.66

[0293] Example 3: 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridine-5-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide

[0294] [ka] Step 1: 5-[2-(trimethylsilyl)ethynyl]-1H-pyrazolo[3,4-b]pyridine

[0295] [ka] To a stirred solution of 3-bromo-1H-pyrazolo[3,4-b]pyridine (0.5 g, 2.32 mmol, 1 equivalent) in ACN (25 ml) in a glass pressure reactor, TMS acetylene (0.72 ml, 5.1 mmol, 2.2 equivalents), copper(I) iodide (0.09 g, 0.46 mmol, 0.2 equivalents), and TEA (1.31 ml, 13.9 mmol, 6 equivalents) were added. Argon was passed through the mixture for 15 minutes, and PdCl2(PPh3)2 (0.16 g, 0.23 mmol, 0.1 equivalent) was added. The reactor was sealed, and the mixture was stirred overnight at 80°C. The mixture was then filtered through Celite, the ACN was evaporated to obtain the crude residue, which was dissolved in EA (25 ml) and washed with water (30 ml). The aqueous phase was further back-extracted with EA (15 ml). The combined organic layers were dried over Na2SO4, filtered, and evaporated. The resulting residue was purified by column chromatography (SiO2, EA / hexane 2:8) to obtain the title product as a yellow solid (0.29 g, 59%).

[0296] 1 H NMR(300MHz,CDCl3)δ:8.79(s,1H),8.28(s,1H),7.28(s,1H),0.31(s,9H) MSm / z:[M+H] + 215.95

[0297] Step 2: 5-Ethinyl-1H-pyrazolo[3,4-b]pyridine

[0298] [ka] To a solution of 5-[2-(trimethylsilyl)ethynyl]-1H-pyrazolo[3,4-b]pyridine (Step 1, 0.29 g, 1.3 mmol, 1 equivalent) in methanol (6 ml), K2CO3 (0.55 g, 4 mmol, 3 equivalents) was added, and the resulting mixture was stirred at room temperature under an argon atmosphere for 1.5 hours. The methanol was evaporated under vacuum, and the residue was ground with water. The formed crystalline product was filtered and washed with water to obtain the desired product (0.126 g, Y: 68%).

[0299] 1 H NMR(300MHz,DMSO-d6)δ:13.76(br.s,1H),8.59(d,J=2.0Hz,1H),8.42(d,J=2.0Hz,1H),8.18(s,1H),4.29(s,1H) MSm / z:[M+H] + 144.00

[0300] Step 3: 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridine-5-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide

[0301] [ka] To a stirred solution of 5-chloro-N-(3-fluoro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide (Example 1, Step 7, 50 mg, 0.11 mmol, 1 equivalent), 5-ethynyl-1H-pyrzolo[3,4-b]pyridine (Step 2, 19 mg, 0.14 mmol, 1.2 equivalents), and Cs2CO3 (147 mg, 0.450 mmol, 4 equivalents) in anhydrous DMSO (2 mL), PdCl2[P(Cy)3]2 (6 mg, 0.01 mmol, 0.07 equivalents) was added under an argon atmosphere, and the reaction mixture was heated in a microwave at 120°C for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under vacuum and purified by preparative HPLC to obtain 15.8 mg of a beige solid. The solid product was treated with a saturated NaHCO3 solution (3 mL), washed with H2O (3 mL), and dried under vacuum to obtain the product as a beige solid (14.1 mg, Y: 27.3%).

[0302] 1 H NMR(300MHz,CD3OD)δ:14.02(s,1H),8.74(m,1H),8.60(d,J=1.9Hz,1H),8.45(d,J=1.9Hz,1H),8.2 2(d,J=2.6Hz,1H),8.17(d,J=2.5Hz,2H),7.68(d,J=5.3Hz,1H),6.77(t,J=4.9Hz,1H),3.95(s,3H) LCMS (Method B) Retention time: 2.443 minutes MSm / z:[MH] - 456.74

[0303] Intermediate synthesis for Example 10: N-{4-[2-(2-aminopyrimidine-5-yl)ethynyl]-3,5-difluoropyridine-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide

[0304] [ka] Step 1: 3,5-difluoro-4-iodopyridine-2-amine n-butyllithium (36 ml, 1.6 M solution in hexane, 57 mmol, 2.5 equivalents) was added dropwise to a solution of 2-amino-3,5-difluoropyridine (3.8 g, 23 mmol, 1 equivalent) in THF (87 ml) at -78°C. The mixture was stirred at that temperature for 1.5 hours, and then a solution of iodine (17.4 g, 69 mmol, 3 equivalents) in THF (27 ml) was added. The mixture was stirred at -78°C for 15 minutes, and then warmed to room temperature. A saturated sodium thiosulfate aqueous solution was added, and the mixture was extracted with ethyl acetate. The mixed organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0% to 15% ethyl acetate in hexane) to obtain the title compound (3.4 g, 62% yield).

[0305] 1 H NMR(300MHz,CDCl3)δ:7.71(s,1H),4.56(s,2H) MSm / z:[M+H] + 256.90

[0306] Step 2: 5-Chloro-N-(3,5-difluoro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide To a solution of 2-amino-3,5-difluoro-4-iodopyridine (1 g, 4.0 mmol, 1 equivalent) in anhydrous pyridine (15 ml), 2-methoxy-3-sulfonylchloro-5-chloropyridine (1.2 g, 4.6 mmol, 1.2 equivalents) was gradually added at 0-5°C, and the resulting mixture was stirred overnight at ambient temperature. The progress of the reaction was monitored by UPLC. Then, MeOH and all volatile substances were evaporated under vacuum. The crude residue was purified by FC using 5 or 10% MeOH in DCM as the eluent to obtain the desired compound (0.11 g, yield 24%).

[0307] 1 H NMR(300MHz,DMSO-d6)δ:11.49(s,1H),8.52(d,J=2.6Hz,1H),8.21(d,J=2.6Hz,1H),8.03(s,1H),3.93(s,3H) MSm / z:[M+H] + 461.70

[0308] Examples 4-11 Examples 4-11 were synthesized using a method similar to that described above for Examples 1-3.

[0309] [Table 9]

[0310] Examples 12-17 were synthesized using methods similar to those described above for Examples 1-3.

[0311] [Table 10]

[0312] Example 18: 5-Chloro-N-[3-fluoro-4-(2-{1-methyl-1H-imidazo[4,5-c]pyridine-7-yl}ethynyl)pyridine-2-yl]-2-methoxypyridine-3-sulfonamide

[0313] [ka] Step 1: 5-Chloro-N-{2-fluoro-3-[2-(trimethylsilyl)ethynyl]phenyl}-2-methoxypyridine-3-sulfonamide

[0314] [ka] 5-Chloro-N-(3-fluoro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide (Example 1, Step 7, 4.103 g, 8.971 mmol, 1.0 equivalent), ethinyl(trimethyl)silane (2.481 ml, 17.946 mmol, 2.0 equivalent), CuI (0.342 g, 1.796 mmol, 0.2 equivalent), and triethylamine (6.878 ml, 49.347 mmol, 5.5 equivalent) were mixed with anhydrous dimethylformamide (39.8 ml, 10.0 vol) in a 200 ml glass pressure reactor. Argon was blown into the mixture for 15 minutes, and bis(triphenylphosphine)palladium(II) dichloride (0.316 g, 0.449 mmol, 0.05 equivalent) was added. The mixture was stirred overnight at 80°C. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with MeOH. The filtrate was concentrated, and the residue was purified by FC (silica, hexane / ethyl acetate, 100:0~80:20) to obtain 5-chloro-N-{3-fluoro-4-[2-(trimethylsilyl)ethynyl]pyridine-2-yl}-2-methoxypyridine-3-sulfonamide (2.79 g, 6.74 mmol, 71%) as a yellow solid.

[0315] 1 H NMR(300MHz,DMSO-d6)δ:11.65(s,1H),8.49(s,1H),8.31-8.13(m,1H),7.90(s,1H),7.15(s,1H),3.88(s,3H),0.26(s,9H) MSm / z:[M+H] + 413.85

[0316] Step 2: 5-Chloro-N-(3-ethynyl-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide

[0317] [ka] Potassium fluoride (0.43 g, 7.402 mmol, 1.098 equivalents) was added to a solution of 5-chloro-N-{3-fluoro-4-[2-(trimethylsilyl)ethynyl]pyridine-2-yl}-2-methoxypyridine-3-sulfonamide (2.79 g, 6.403 mmol, 0.95 equivalents) in anhydrous methanol (22.32 ml, 8.0 vol) and anhydrous tetrahydrofuran (11.16 ml, 4.0 vol) at room temperature. The mixture was stirred at room temperature for 1 hour to evaporate the volatile substances. The residue was powdered with diethyl ether and dried to obtain 5-chloro-N-(4-ethynyl-3-fluoropyridine-2-yl)-2-methoxypyridine-3-sulfonamide (2.34 g, 6.847 mmol, 97%) as a light brown solid.

[0318] 1 H NMR(300MHz,DMSO-d6)δ:8.19(d,J=2.7Hz,1H),8.06(d,J=2.7Hz,1H),7.49(d ,J=5.1Hz,1H),6.43(dd,J=5.0,4.2Hz,1H),4.54(d,J=0.8Hz,1H),3.83(s,3H) MSm / z:[M+H] + 341.85

[0319] Step 3: 5-Chloro-N-[3-fluoro4-(2-{1-methyl1H-imidazo[4,5-c]pyridine-7yl}ethynyl)pyridine-2yl]-2-methoxypyridine-3 sulfonamide

[0320] [ka] 5-Chloro-N-(4-ethynyl-3-fluoropyridine-2-yl)-2-methoxypyridine-3-sulfonamide (84 mg, 0.25 mmol, 1 equivalent) was dissolved in DMF (4 ml), and then 7-bromo-1-methyl-1H-imidazo[4,5-c]pyridine (55 mg, 0.26 mmol, 1.05 equivalents), CuI (9 mg, 0.05 mmol, 0.2 equivalents), and triethylamine (0.19 ml, 1.35 mmol, 5.5 equivalents) were added. The solution was degassed with argon for 15 minutes, and Pd(P(Cy)3)2Cl2 (18 mg, 0.025 mmol, 0.1 equivalent) was added. The vial was sealed and heated at 80°C overnight. The reaction mixture was filtered through Celite, the filtrate was concentrated under vacuum, and the title compound was purified by preparative HPLC to obtain a white solid (33 mg, 27%).

[0321] 1 H NMR(400MHz,DMSO-d6)δ:11.99(s,1H),9.06(s,1H),8.61(s,1H),8.52-8.41(m ,2H),8.25(d,J=2.5Hz,1H),7.98(s,1H),7.28(s,1H),4.16(s,3H),3.90(s,3H) LCMS (Method C) Retention time: 2.097 min, MSm / z: [M+H] + 472.97

[0322] Examples 19 to 38 were synthesized using a method similar to that described above for Example 18.

[0323] [Table 11-1]

[0324] [Table 11-2]

[0325] [Table 11-3]

[0326] Biological and pharmacokinetic studies (a) GCN2 enzyme inhibition (10 μM and 300 μM assays) Assay protocol overview: The inhibitory activity of the example compounds against the GCN2 enzyme was measured using the LanthaScreen TR-FRET (time-resolved fluorescence resonance energy transfer) kinase activity assay supplied by ThermoFisher Scientific, as described below.

[0327] Full-length human GCN2 enzyme (UniProt accession number Q9P2K8) was used in all experiments (Carna Bioscience). TR-FRET pairs consisted of GFP-eIF2α and LanthaScreen terbium-labeled anti-peIF2α (pSer52) antibody.

[0328] Each example compound was dissolved in DMSO (0.15 mM) and dispensed into a 384-well plate using a D300 dispenser (Tecan). A final concentration range of 3000–0.13 nM was achieved using a double-row logarithmic dilution mode. Complete inhibition (3000 nM commercially available reference inhibitor) and DMSO vehicle control wells were also included in the same plate. All volumes were normalized to a final DMSO concentration of 2% of the reaction volume. Next, 5 μL of H2O was added to each well of the plate.

[0329] The enzyme mixture was prepared to obtain the following concentrations. · GCN2-30nM ·Unloaded tRNA-0.3nM HEPES (pH=7.0) -100mM MgCl2-20mM; MnCl2-10mM

[0330] The mixture was applied by adding 5 μL to each well of the plate. The enzyme and test compound were then incubated at room temperature for 20 minutes with shaking at 450 rpm.

[0331] The substrate mixture was prepared to obtain the following concentrations. ·GFP-eIF2α-240nM • ATP - 900 μM or 30 μM HEPES (pH=7.0) - 50mM MgCl2-10mM MnCl2-5mM.

[0332] The mixture was applied by adding 5 μL to each well of the plate. Therefore, the final concentrations of the 15 μL reaction mixture were as follows: · GCN2-10nM ·Unloaded tRNA-0.1nM ·GFP-eIF2α-80nM • ATP - 300 μM or 10 μM HEPES (1M, pH=7.0) - 50mM MgCl2-10mM MnCl2-5mM.

[0333] The reaction was allowed to proceed at room temperature for 30 minutes while shaking at 450 rpm.

[0334] The antibody mixture was prepared to obtain the following concentrations. ·Na2EDTA·2H2O-40mM in TR-FRET dilution buffer (Life technologies). ·Tb-anti-peIF2a antibody-4nM.

[0335] The mixture was applied by adding 15 μL to each well. The plate was then incubated at room temperature for 60 minutes with shaking at 450 rpm, and then read using a Tecan Spark reader with a specific TR-FRET filter.

[0336] GFP / Tb fluorescence results were analyzed using GraphPad Prism, and ICs were calculated for each of the example compounds using a 4-parameter model: log(inhibitor) vs. response variable gradient. 50 The decision was made. IC 50 and K iValues ​​were calculated using standard methods. The assay was performed 1 to 15 times. The results in the table below are, where applicable, the average results from repeated assays for the compound in question.

[0337] result:

[0338] [Table 12]

[0339] The results in Table 1 demonstrate that the compounds of the present invention are potent inhibitors of GCN2.

[0340] (b) Kinetic solubility Assay protocol overview: Kinetic solubility assays investigate solubility based on the amount of substance remaining in the solution after a precipitation process. Compounds for kinetic solubility testing are prepared as 10 mM stock solutions in DMSO. The assay is performed using a Multiscreen Vacuum Manifold. The target buffer (the standard protocol uses PBS buffer at pH=7.4) is spiked with the stock solution and incubated at room temperature for 90 minutes. The solution / suspension is then filtered. The concentration of each compound is determined based on a prepared calibration curve using UV-VIS spectrophotometry. The assay is performed in triplicate.

[0341] The target buffer solution consists of 0.24 g of KH2PO4, 1.44 g of Na2HPO4, 0.2 g of KCl, and 8 g of NaCl. Dissolve in 1 liter of distilled H2O and adjust the pH to an appropriate value (pH 7.4).

[0342] 190 μl of the target buffer was dispensed into the wells of a 96-well filter plate, followed by 10 μl of the compound (10 mM stock solution in DMSO). The plate was gently shaken at 500 rpm for 90 minutes at room temperature using a BioSan Plate Shaker-Thermostat, PST-60HL-4. After 90 minutes, the plate was filtered using a vacuum manifold and vacuum pump. 100 μl of each filtrate and 100 μl of acetonitrile were transferred to a 96-well UV-Visible transparent plate, and UV-Visible absorption spectra were measured at 250–500 nm with a 10 nm interval using a Biotek Synergy 2 multiplate reader. The amount of the test compound was calculated using calibration curves prepared by serially diluting the compound in equal volumes of DMSO and acetonitrile.

[0343] result:

[0344] [Table 13]

[0345] Comparison Data 1 The inhibitory activity and kinetic solubility of certain comparative compounds against the GCN2 enzyme were measured using the assay described above, and these were compared with the compounds of the present invention. The results are shown below.

[0346] [Table 14]

[0347] Comparative Example 1 is disclosed in Fujimoto, J. et al (2019) ACS Med. Chem. Lett 10(1), 1498-1503, where it is named Compound 6e. In Nakamura et al (2018) PNAS, 115(33), 7776-7785, Comparative Example 1 is named GCN2iB. Comparative Example 2 is disclosed in International Publication No. 2018 / 030466, where it is named Example Compound 123. Comparative Example 3 is disclosed in International Publication No. 2018 / 030466, where it is named Reference Compound 120.

[0348] The compound of Example 1 is superior to the comparative compound in that it possesses both strong GCN2 inhibitory activity and good kinetic solubility, as measured in the assay. It is particularly noteworthy that Comparative Example 3, which has a pyridine ring at its center but in a different orientation than the compound of the present invention (e.g., Example 1), exhibits very low activity in GCN2.

[0349] Comparative Data 2 The inhibitory activity and kinetic solubility of further comparative compounds against the GCN2 enzyme were measured using the assay described above, and these were compared with the compound of the present invention. The results are shown below.

[0350] [Table 15]

[0351] Comparative Example 4 is disclosed in International Publication No. 2018 / 030466, where it is named Example Compound 5. The compound of Example 3 is found to be superior to the comparative compound in that it has both strong GCN2 inhibitory activity and good kinetic solubility, as measured in the assay.

[0352] Kinase selectivity assay: The KINOMEscan® screening platform is used to test compounds for off-target kinase activity. This platform quantitatively measures the interaction between test compounds and hundreds of human kinases and disease-associated mutant variants using a novel and unique active-site-directed competitive binding assay. The KINOMEscan® assay is ATP-free and thereby reports true thermodynamic interaction affinity.

[0353] For most assays, kinase-tagged T7 phage strains were grown in parallel in 24-well blocks in E. coli hosts derived from strain BL21. E. coli was grown to the logarithmic phase, infected with T7 phages from frozen stocks (infection multiplicity = 0.4), and incubated with shaking at 32°C until lysed (90–150 minutes). The lysates were centrifuged (6,000 × g), filtered (0.2 μm), and cell debris removed. The remaining kinase was produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Magnetic beads coated with streptavidin were treated with biotinylated small molecule ligands at room temperature for 30 minutes to produce affinity resins for kinase assays. Ligand-binding beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligands and reduce nonspecific phage binding. The binding reaction was constructed by combining the kinase, ligand-binding affinity beads, and test compound in 1× binding buffer (20% SeaBlock, 0.17× PBS, 0.05% Tween 20, 6 mM DTT). The test compound was prepared as a 40× stock in 100% DMSO and diluted directly during the assay. All reactions were carried out in a 384-well polypropylene plate with a final volume of 0.02 ml. The assay plate was incubated at room temperature for 1 hour with shaking, and the affinity beads were washed with washing buffer (1× PBS, 0.05% Tween 20). Next, the beads were resuspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature for 30 minutes with shaking. The kinase concentration in the eluate was measured by qPCR.

[0354] result:

[0355] [Table 16]

[0356] For comparison, the equivalent findings from Comparative Example 1 (which is named GCN2iB therein), reported in Nakamura et al (2018), PNAS, 115(33), 7776-7785, are as follows:

[0357] [Table 17]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, Cy is a 5-, 6-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl group containing at least one N heteroatom and optionally 1, 2, or 3 additional heteroatoms selected from the group consisting of N, S, and O; m is 0 or 1; n is 0, 1, or 2; R １ When present, -NH ２ ;-NR Ａ (C １～６ alkyl); -NR Ａ (OH, halogen, and O—C optionally substituted with 1, 2, or 3 halogens) １～３ C substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl); -NR Ａ (OH, halogen, and O—C optionally substituted with 1, 2, or 3 halogens) １～３ C(O)C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl); -NR Ａ (C ０～３ Alkylene-C ３～６ Cycloalkyl, wherein the cycloalkyl is optionally substituted with OH, halogen, 1, 2, or 3 halogens. １～３ Alkyl, C １～３ alkyl-OH and O—C optionally substituted with 1, 2, or 3 halogens １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl ０～３ Alkylene-C ３～６ cycloalkyl); -NR Ａ (C ０～３ Alkylene-C ３～６ Heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with OH, halogen, 1, 2, or 3 halogens. １～３ Alkyl, C １～３ alkyl-OH and O—C optionally substituted with 1, 2, or 3 halogens １－３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl ０～３ Alkylene-C ３～６ Heterocycloalkyl; —NR Ａ (OH, halogen, C optionally substituted by 1, 2, or 3 halogens) １～３ Alkyl, C １～３ alkyl-OH and O—C optionally substituted with 1, 2, or 3 halogens １～３ C(O)C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl ３～６ cycloalkyl); and -NR Ａ (5- or 6-membered heteroaryl groups containing at least one N heteroatom and optionally one or two additional heteroatoms selected from the group consisting of N, S, and O, wherein said 5- or 6-membered heteroaryl group is optionally substituted by halogen, OH, and 1, 2, or 3 halogens, O—C １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ alkyl; halogen; halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ -O-C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ Alkyl; OH; NH ２ ; NH(C １～６ alkyl); N(C １～６ alkyl) ２ ; cyano; OH, halogen, C optionally substituted by 1, 2 or 3 halogens １～３ Alkyl, C １～３ alkyl-OH and O—C optionally substituted with 1, 2, or 3 halogens １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl ３～４ a 5- or 6-membered heteroaryl group optionally substituted with 1 or 2 substituents independently selected from the group consisting of cycloalkyl; R Ａ is, if present, hydrogen; —OH, halogen, O—C optionally substituted by 1, 2, or 3 halogens; １～３ -C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ Alkyl; -C ０～３ Alkylene-C ３～６ Cycloalkyl, wherein the cycloalkyl is optionally substituted with OH, halogen, 1, 2, or 3 halogens. １～３ Alkyl, C １～３ alkyl-OH and O—C optionally substituted with 1, 2, or 3 halogens １～３ -C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl; ０～３ Alkylene-C ３～６ cycloalkyl; -C ０～３ Alkylene-C ３～６ Heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with OH, halogen, 1, 2, or 3 halogens. １～３ Alkyl, C １～３ alkyl-OH and O—C optionally substituted with 1, 2, or 3 halogens １～３ -C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl; ０～３ Alkylene-C ３～６ Heterocycloalkyl; C optionally substituted by OH, halogen, 1, 2 or 3 halogens １～３ Alkyl, C １～３ alkyl-OH and O—C optionally substituted with 1, 2, or 3 halogens １～３ -C(O)C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl ３～６ Cycloalkyl; OH, halogen, and O—C optionally substituted with 1, 2, or 3 halogens １～３ -C(O)C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl; C optionally substituted by OH, halogen, 1, 2 or 3 halogens １～３ Alkyl, C １～３ alkyl-OH and O—C optionally substituted with 1, 2, or 3 halogens １～３ -C(O)C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl ３～６ cycloalkyl; and 5- or 6-membered heteroaryl groups containing at least one N heteroatom and optionally one or two additional heteroatoms selected from the group consisting of N, S, and O, wherein said 5- or 6-membered heteroaryl group is optionally substituted with halogen, OH, and 1, 2, or 3 halogens. １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ alkyl; halogen; halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ -O-C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ Alkyl; OH; NH ２ ; NH(C １～６ alkyl); N(C １～６ alkyl) ２ ; cyano; OH, halogen, C optionally substituted by 1, 2 or 3 halogens １～３ Alkyl, C １～３ alkyl-OH and O—C optionally substituted with 1, 2, or 3 halogens １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl ３～４ cycloalkyl; Each R ２ is, when present, oxo, halogen, OH, and O—C optionally substituted by 1, 2, or 3 halogens; １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl; halogen; halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ -O-C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ Alkyl; OH; =O; NH ２ ; NH(C １～６ alkyl); N(C １～６ alkyl) ２ cyano and halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens; １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl ３～６ cycloalkyl; R ３ is a halogen, R ４ is selected from the group consisting of hydrogen and halogen; A is selected from the group consisting of phenyl; naphthyl; and 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heteroaryl groups containing one N heteroatom and optionally one or two additional heteroatoms selected from the group consisting of N, S, and O; R ５ is optionally substituted by hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens; １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl; halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ Alkyl; NH ２ ; NH(C １～６ alkyl); and N(C １～６ alkyl) ２ and R ６ is optionally substituted by hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens; １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl; halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ Alkyl; NH ２ ; NH(C １～６ alkyl); N(C １～６ alkyl) ２ optionally substituted phenyl; optionally substituted naphthyl; optionally substituted 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heteroaryl groups containing one N heteroatom and optionally one or two additional heteroatoms independently selected from the group consisting of N, S, and O; optionally substituted 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered non-aromatic heterocyclic groups containing one N heteroatom and optionally one or two additional heteroatoms independently selected from the group consisting of N, S, and O; and optionally substituted C ３～１０ cycloalkyl, phenyl, naphthyl, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heteroaryl groups, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered non-aromatic heterocyclic groups, and C ３～１１ Cycloalkyl is O—C optionally substituted by halogen; OH; halogen, OH, and 1, 2, or 3 halogens. １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ alkyl; halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl, and R ７ is optionally substituted by hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens; １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl; and halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ Alkyl; NH ２ ; NH(C １～６ alkyl); and N(C １～６ alkyl) ２ 1. A compound of formula (I) selected from the group consisting of:

2. 2. The compound of claim 1, wherein A is selected from the group consisting of phenyl; and 6- or 7-membered heteroaryl groups containing one N heteroatom and optionally one or two additional heteroatoms selected from the group consisting of N, S, and O.

3. A is an optionally substituted 6-membered aryl or heteroaryl ring of the formula: 【Chemistry 2】 wherein, Y １ , Y ２ , and Y ３ two of them are CH, and the remaining one is CH or N, R ５ is halogen; OH; halogen, OH, and O—C １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ Alkyl; and halogen, OH, and O—C １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ is selected from the group consisting of alkyl, R ６ is halogen; OH; halogen, OH, and O—C １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ Alkyl; halogen, OH, and O—C １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ alkyl; and rings of the formula: 【Transformation 3】 wherein ring C is an optionally substituted 6-membered aromatic ring and ring D is an optionally further substituted 5-, 6-, or 7-membered ring; Y ４ and Y5 is a carbon atom, and the other is a carbon atom or a nitrogen atom; The ring C is selected from the group consisting of halogen, OH, halogen, OH, and O—C １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ Alkyl; halogen, OH, and O—C １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ optionally substituted with alkyl; The ring D is selected from the group consisting of halogen, OH, halogen, OH, and O—C １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ Alkyl; halogen, OH, and O—C １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ 3. The compound of claim 1 or 2, optionally substituted with alkyl.

4. A is, 【Chemistry 4】 2. The compound of claim 1 selected from the group consisting of:

5. A is, 【Transformation 5】 5. The compound of claim 4 selected from the group consisting of:

6. R ５ is optionally substituted by hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens; １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl; and halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ alkyl, and R ６ is optionally substituted by hydrogen, halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens; １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl; halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ 6. The compound of any one of claims 1, 2, 4 or 5, wherein the compound is selected from the group consisting of alkyl.

7. R ７ 7. The compound of claim 1, 2, 4, 5 or 6, wherein is hydrogen.

8. R ４ The compound of any one of claims 1 to 7, wherein is H.

9. 9. The compound of any one of claims 1 to 8, wherein Cy is a 5-, 6-, 9-, or 10-membered heteroaryl group containing at least one N heteroatom and optionally 1, 2, or 3 additional heteroatoms selected from the group consisting of N and S.

10. Cy is, 【Transformation 6】 【Transformation 7】 The compound according to any one of claims 1 to 8, selected from the group consisting of:

11. Cy is, 【Transformation 8】 11. The compound of claim 10 selected from the group consisting of:

12. 2. The compound of claim 1, wherein Cy is a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl group containing 1, 2, or 3 N heteroatoms.

13. The compound according to any one of claims 1 to 12, wherein m is 0 or 1 and n is 0 or 1.

14. R １ When present, -NH ２ ;-NR Ａ (C １～６ alkyl); -NR Ａ (OH, halogen, and O—C optionally substituted with 1, 2, or 3 halogens) １～３ C substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl); -NR Ａ (OH, halogen, and O—C optionally substituted with 1, 2, or 3 halogens) １～３ C(O)C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl); -NR Ａ (C ０～３ Alkylene-C ３～６ Cycloalkyl, wherein the cycloalkyl is selected from the group consisting of OH, halogen, C １～３ Alkyl, C １～３ Alkyl-OH and O—C １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl ０～３ Alkylene-C ３～６ cycloalkyl); -NR Ａ (C ０～３ Alkylene-C ３～６ Heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with OH, halogen, 1, 2, or 3 halogens. １～３ Alkyl, C １～３ alkyl-OH and O—C optionally substituted with 1, 2, or 3 halogens １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl ０～３ Alkylene-C ３～６ heterocycloalkyl); and —NR Ａ (OH, halogen, C optionally substituted by 1, 2, or 3 halogens) １－３ Alkyl, C １～３ alkyl-OH and O—C optionally substituted with 1, 2, or 3 halogens １～３ C(O)C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl ３～６ 14. The compound of any one of claims 1 to 13, wherein the compound is selected from the group consisting of: cycloalkyl.

15. R Ａ The compound of any one of claims 1 to 14, wherein, if present, is hydrogen.

16. R １ When present, -NH ２ The compound according to any one of claims 1 to 15,

17. Each R ２ is, when present, halogen, OH, and O—C optionally substituted by 1, 2, or 3 halogens; １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl; halogen; halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ -O-C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ 17. The compound of any one of claims 1 to 16, wherein the aryl group is independently selected from the group consisting of alkyl; and OH.

18. R ５ is optionally substituted by hydrogen; halogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens; １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl; halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ Alkyl; NH ２ ; NH(C １～６ alkyl); and N(C １～６ alkyl) ２ is selected from the group consisting of R ６ is optionally substituted by hydrogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens; １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl; halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ Alkyl; NH ２ ; NH(C １～６ alkyl); N(C １～６ alkyl) ２ optionally substituted phenyl; optionally substituted naphthyl; optionally substituted 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heteroaryl groups containing one N heteroatom and optionally one or two additional heteroatoms independently selected from the group consisting of N, S, and O; optionally substituted 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered non-aromatic heterocyclic groups containing one N heteroatom and optionally one or two additional heteroatoms independently selected from the group consisting of N, S, and O; and optionally substituted C ３～１０ cycloalkyl, phenyl, naphthyl, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heteroaryl groups, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered non-aromatic heterocyclic groups, and C ３～１１ Cycloalkyl is O—C optionally substituted by halogen; OH; halogen, OH, and 1, 2, or 3 halogens. １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ alkyl; halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～３ optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl, and R ７ is optionally substituted by hydrogen; OH; cyano; halogen, OH, and 1, 2, or 3 halogens; １～３ C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ alkyl; and halogen, OH, and O—C optionally substituted with 1, 2, or 3 halogens １～３ O—C optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl １～６ Alkyl; NH ２ ; NH(C １～６ alkyl); and N(C １～６ alkyl) ２ The compound of any one of claims 1 to 4 or 8 to 17, selected from the group consisting of:

19. The compound is N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide, N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-chloropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide, N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide, N-{4-[2-(8-amino-1,7-naphthyridin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide, 5-chloro-N-{4-[2-(pyrido[3,4-b]pyrazin-8-yl)ethynyl]-3-fluoropyridin-2-yl}-2-methoxypyridine-3-sulfonamide, 5-chloro-N-{4-[2-(1,6-naphthyridin-8-yl)ethynyl]-3-fluoropyridin-2-yl}-2-methoxypyridine-3-sulfonamide, N-{4-[2-(7-aminopyrazolo[1,5-a]pyrimidin-3-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide, N-{4-[2-(8-aminoimidazo[1,2-a]pyridin-3-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide, 5-chloro-N-{4-[2-(quinoxalin-2-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide, N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3,5-difluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide, N-{4-[2-(8-aminoimidazo[1,2-a]pyrazin-3-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-2-methoxybenzene-1-sulfonamide, N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxybenzene-1-sulfonamide, 2,5-dichloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]benzene-1-sulfonamide, N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-2,5-dichlorobenzene-1-sulfonamide, N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-2,5-dichloro-3-(hydroxymethyl)benzene-1-sulfonamide, 2,5-dichloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-3-(hydroxymethyl)benzene-1-sulfonamide, 5-chloro-N-[3-fluoro 4-(2-{1-methyl-1H-imidazo[4,5-c]pyridin-7-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3fluoro-4-(2-{[1,3]thiazolo[4,5-c]pyridin-7-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3fluoro-4-(2-{1H-pyrazolo[3,4-c]pyridin-4-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{2-methyl-2H-pyrazolo[3,4-c]pyridin-4-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[4,3-c]pyridin-4-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-(3-fluoro-4-{2-[2-(methylamino)pyrimidin-5-yl]ethynyl}pyridin-2-yl)-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyrazin-5-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{2-oxo-1H,2H,3H-imidazo[4,5-b]pyrazin-5-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{3H-imidazo[4,5-b]pyridin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidin-3-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, N-{4-[2-(2-amino-4-methylpyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide, N-{4-[2-(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{1-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, 5-chloro-N-[3-fluoro-4-(2-{3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide, and N-[4-(2-{5-aminopyrido[3,4-b]pyrazin-8-yl}ethynyl)-3-fluoropyridin-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide 10. The compound of claim 1, selected from the group consisting of:

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and at least one pharmaceutically acceptable carrier or excipient.

21. 21. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

22. 22. The pharmaceutical composition of claim 21, wherein the additional therapeutic agent is an l-asparaginase or proteasome inhibitor.

23. 20. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of GCN2 provides a therapeutic effect, including cancer (including solid cancers and hematological cancers), diabetic retinopathy, myocardial ischemia, diabetic cardiomyopathy, allergic airway inflammation, doxorubicin-induced cardiotoxicity, and non-alcoholic fatty liver disease (NAFLD).

24. The disease or disorder is cancer, and the cancer is selected from the group consisting of colorectal cancer (including rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, and gastrointestinal stromal tumor), lung cancer (including non-small cell lung cancer, small cell lung cancer, and malignant mesothelioma), mesothelioma, pancreatic cancer (including pancreatic ductal carcinoma and pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (including papillary adenocarcinoma, mucinous adenocarcinoma, and adenosquamous carcinoma), duodenal cancer, small intestine cancer, breast cancer (including invasive ductal carcinoma, ductal carcinoma in situ, and inflammatory breast cancer), ovarian cancer (including ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, and ovarian low malignant potential tumor), testicular tumor, prostate cancer (including hormone-dependent prostate cancer, non-hormone-dependent prostate cancer, and castration-resistant prostate cancer), liver cancer (including liver cancer, primary liver cancer, and extrahepatic bile duct cancer), thyroid cancer (including medullary thyroid cancer), kidney cancer (renal cell Cancer (including clear cell renal cell carcinoma), transitional cell carcinoma of the renal pelvis and ureter), uterine cancer (including cervical cancer, endometrial cancer, and uterine sarcoma), gestational choriocarcinoma, brain tumors (including medulloblastoma, glioma, glioblastoma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, and pituitary adenoma), retinoblastoma, skin cancer (including basal cell carcinoma and malignant melanoma), sarcoma ( and / or is selected from the group consisting of: malignant bone tumors, bladder cancer, and hematological cancers (including multiple myeloma, smoldering myeloma, plasmacytoma, leukemia (including acute myeloid leukemia, acute lymphocytic leukemia (including blast crisis of chronic leukemia)), non-Hodgkin's lymphoma, malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disorder), and cancer of unknown primary origin; and / or The disease or disorder is a cancer with a MYC mutation (i.e., a cancer in which a mutation is present in the MYC gene).

24. Use of a compound according to claim 23 for the manufacture of a medicament for the treatment or prevention of said disease or disorder.

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