4-Ethynylpyridine derivatives as GCN2 inhibitors

Abstract

The present invention provides compounds of formula I, wherein the substituents are as further described in the specification. The compounds are effective inhibitors of GCN2, and they have excellent pharmacokinetic properties. The compounds can be used to treat or prevent a variety of conditions, particularly cancer. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention and uses of the compounds and compositions. #imgabs0#

Description

Technical Field

[0001] The present invention relates to compounds of formula (I) and pharmaceutical compositions thereof, and their use as drugs. The compounds of the present invention are inhibitors of general regulatory repressor protein kinase 2 (GCN2), and thus can be used to treat or prevent a variety of conditions, in particular for treating diseases such as cancer. Background Art

[0002] The general regulatory repressor protein kinase 2 (GCN2) encoded by EIF2AK4 is a key regulator for cell adaptation to amino acid deficiency (Castilho, BA et al., (2014) Biochim Biophys Acta 1843, 1948-1968). When uncharged tRNA accumulates due to low amino acid levels, GCN2 is activated (Romano, PR et al., (1998) Aut Mol Cell Biol 18, 2282-2297; and Wek, SA et al., (1995) Mol Cell Biol 15, 4497-4506). Activated GCN2 phosphorylates its only known target, the translation initiation factor eIF2α, resulting in a decrease in overall protein synthesis. GCN2 also regulates Sestrin2-mediated repression of mTORC1 and induces autophagy (Talloczy, Z. et al., (2002) Proc Natl Acad Sci USA 99, 190-195; Wengrod, J. et al., (2015) Sci Signal 8, ra27; B'Chir, W. et al., (2013) Nucleic Acids Res 41, 7683-7699; Ye, J. et al., (2015) Genes Dev 29, 2331-2336; and Ravindran, R. et al., (2016) Nature 531, 523-527). In summary, these GCN2 effects promote cell recovery from amino acid deficiency.

[0003] In solid tumors, GCN2 signaling is critical for cancer cell survival under nutrient-deficient conditions (Wang, Y. et al., (2013) Neoplasia 15, 989-997; Ye, J. et al., (2010) EMBO J 29, 2082-2096; and Parzych, K. et al., (2019) Oncogene 38, 3216–3231). GCN2 has also been shown to play a key role in MYC-driven tumor progression by adjusting protein synthesis to ensure that the translation rate is compatible with the bioenergetic capacity and survival of cancer cells (Tameire, F. et al., (2019) Nat Cell Biol 21, 889-899; and Schmidt, S. et al., (2019) Nat Cell Biol 21, 1413-1424). In addition, some tumors may rely on myeloid GCN2 signals to protect against anticancer immune attacks (Halaby, MJ et al., (2019). Sci Immunol 4 (42), eaax8189). GCN2 depletion enhances the anti-tumor effect of asparaginase treatment (Ye, J. et al., (2010) EMBO J 29, 2082-2096; and Bunpo, P. et al., (2009) J Biol Chem 284, 32742-32749). Importantly, mice lacking GCN2 do not show gross pathology unless they receive a diet lacking essential amino acids (Anthony, TG et al., (2004) J Biol Chem 279, 36553-36561; and Zhang, P. et al., (2002) Mol Cell Biol 22, 6681-6688). In summary, these data suggest that GCN2 inhibition may be an effective cancer therapy for a variety of cancers.

[0004] It has also been shown that proteasome inhibitors trigger intracellular amino acid deficiency, and this effect may be the main cause of multiple myeloma cell death after proteasome inhibitor treatment (Parzych, K. et al., (2015) Cell death & disease 6, e2031; Suraweera, A. et al., (2012) Mol Cell 48, 242-253; and Vabulas, RM and Hartl, FU, (2005) Science 310, 1960-1963). It is therefore predicted that GCN2 inhibition is particularly effective in combination with proteasome inhibitors for the treatment of multiple myeloma.

[0005] There are very few known GCN2 inhibitors. WO 2018 / 030466 (Takeda Pharmaceutical Company Limited) discloses a series of GCN2 inhibitor compounds with an alkynyl-phenyl core. Other GCN2 inhibitor compounds are disclosed in Fujimoto, J. et al., (2019) ACS Med. Chem. Lett 10 (1), 1498-1503 and US published patent applications US2019 / 0233411 and US 2019 / 0233425.

[0006] There is a need in the art for additional GCN2 inhibitor compounds, particularly GCN2 inhibitor compounds with high potency, and GCN2 inhibitor compounds that have good pharmacokinetic properties (such as good solubility) and are therefore useful as drugs for treating, for example, cancer. Summary of the invention

[0007] The present invention provides a compound of formula (I) or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a pharmaceutically acceptable salt of such ester, amide or carbamate:

[0008]

[0009] in

[0010] Cy is a 5-, 6-, 7-, 8-, 9- or 10-membered monocyclic or bicyclic heteroaryl group containing at least 1 N heteroatom and optionally 1, 2 or 3 further heteroatoms selected from N, S and O;

[0011] m is 0 or 1;

[0012] n is 0, 1 or 2;

[0013] When present, R 1 Selected from: -NH 2 ;-NR A (C 1-6 Alkyl); -NR A (OC substituted by 1, 2 or 3 independently selected from OH, halogen and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 Alkyl); -NR A (optionally substituted with 1, 2 or 3 independently selected from OH, halogen and OC optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted C(O)C 1-6 Alkyl); -NR A (C 0-3 Alkylene-C 3-6wherein the cycloalkyl is optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl group substituted); -NR A (C 0-3 Alkylene-C 3-6 wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl group substituted); -NR A (optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C(O)C 3-6 cycloalkyl); and -NR A (a 5- or 6-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N, S and O, wherein the 5- or 6-membered heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from: OC optionally substituted with 1, 2 or 3 independently selected from halogen, OH and optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-3 alkyl; halogen; optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -OC 1-3 Alkyl; OH; NH 2 NH(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; cyano; optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 3-4 cycloalkyl).

[0014] When present, R Ais selected from: hydrogen; optionally substituted by 1, 2 or 3 independently selected from OH, halogen and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted-C 1-6 Alkyl; -C 0-3 Alkylene-C 3-6 wherein the cycloalkyl is optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl radical substitution; -C 0-3 Alkylene-C 3-6 wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl; optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -C(O)C 3-6 Cycloalkyl; optionally substituted by 1, 2 or 3 halogens independently selected from OH, halogen and OC 1-3 Alkyl-substituted -C(O)C 1-6 alkyl; optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -C(O)C 3-6 Cycloalkyl; and a 5 or 6-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N, S and O, wherein the 5 or 6-membered heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from: OC optionally substituted with 1, 2 or 3 halogens, OH and 1, 2 or 3 halogens. 1-3 Alkyl-substituted C 1-3 alkyl; halogen; optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -OC 1-3 Alkyl; OH; NH2 NH(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; cyano; optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 3-4 Cycloalkyl;

[0015] When present, each R 2 independently selected from oxo, optionally substituted with 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; halogen; optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -OC 1-6 Alkyl; OH; =O; NH 2 NH(C 1-6 Alkyl); N(C 1-6 alkyl) 2 ; cyano; and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 Alkyl-substituted C 3-6 Cycloalkyl;

[0016] R 3 is a halogen;

[0017] R 4 is selected from hydrogen and halogen;

[0018] A is selected from phenyl; naphthyl; and a 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group containing 1 N heteroatom and optionally 1 or 2 further heteroatoms selected from N, S and O;

[0019] R 5 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogen 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6alkyl); and N(C 1-6 alkyl) 2 ;and

[0020] R 6 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogen 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; optionally substituted phenyl; optionally substituted naphthyl; an optionally substituted 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group containing 1 N heteroatom and optionally 1 or 2 other heteroatoms independently selected from N, S and O (preferably N and S); an optionally substituted 5-, 6-, 7-, 8-, 9-, 10- or 11-membered non-aromatic heterocyclic group containing 1 N heteroatom and optionally 1 or 2 other heteroatoms independently selected from N, S and O (preferably N and S); and optionally substituted C 3-10 wherein the phenyl, naphthyl, 5, 6, 7, 8, 9, 10 or 11-membered heteroaryl group, 5, 6, 7, 8, 9, 10 or 11-membered non-aromatic heterocyclic group and C 3-11 Cycloalkyl is optionally substituted with 1, 2 or 3 groups independently selected from halogen; OH; OC optionally substituted with 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted with 1, 2 or 3 halogens. 1-3 Alkyl-substituted C 1-3 alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogen 1-3 OC substituted with alkyl groups 1-3 Alkyl; and

[0021] R 7 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6alkyl); and N(C 1-6 alkyl) 2 .

[0022] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier or excipient.

[0023] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), wherein the composition further comprises at least one other therapeutic agent.

[0024] The invention also provides a compound according to formula (I) or a pharmaceutical composition comprising a compound of formula (I) for use as a medicament.

[0025] The present invention also provides a compound according to formula (I) or a pharmaceutical composition comprising a compound of formula (I) for use in the treatment or prevention of a disease or condition in which inhibition of GCN2 provides a therapeutic effect.

[0026] The present invention also provides a compound according to formula (I) or a pharmaceutical composition comprising a compound of formula (I) for use in treating a disease or condition selected from cancer (eg solid cancers and haematological cancers).

[0027] The present invention also provides a method for treating or preventing a disease or condition in which inhibition of GCN2 provides a therapeutic effect in a mammal (e.g., treating or preventing cancer in a mammal), the method comprising administering to the mammal a therapeutically effective amount of a compound according to formula (I) or a pharmaceutical composition comprising a compound of formula (I).

[0028] The invention also provides the use of a compound according to formula (I) in the preparation of a medicament for the treatment or prevention of a disease or condition in which inhibition of GCN2 provides a therapeutic effect, such as the treatment or prevention of cancer.

[0029] Further advantageous features of the various embodiments of the invention are defined in the dependent claims and in the following detailed description. DETAILED DESCRIPTION

[0030] The present invention provides compounds of formula (I) as defined above and pharmaceutical compositions comprising compounds of formula (I).

[0031] It has been found that the compounds of the present invention are potent inhibitors of GCN2. Thus, the compounds of the present invention inhibit GCN2 activity and / or the translation of the initiation factor eIF2α, resulting in a reduction in overall protein synthesis in a subject.

[0032] The compounds of the present invention have excellent pharmacokinetic properties. Specifically, 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 the therapeutic use of the compounds of formula (I) and the pharmaceutical compositions comprising the compounds of formula (I).

[0033] As described in the introduction, WO 2018 / 030466 (Takeda Pharmaceutical Company Limited) discloses a series of GCN2 inhibitor compounds with alkynyl-phenyl cores. It has been found that the compounds of the present invention have surprisingly superior properties compared to the compounds disclosed in WO 2018 / 030466. As demonstrated by the data herein, the compounds of the present invention are significantly more soluble in aqueous media, and they also have strong potency in inhibiting GCN2 activity.

[0034] In addition, the inventors have found that the compounds of the present invention have good kinase selectivity for GCN2. TM The assay found that the kinase selectivity of the compounds of the present invention is superior to that of the compounds of WO 2018 / 030466.

[0035] Unless otherwise indicated, the practice of the present invention adopts the conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant technology), cell biology, biochemistry and immunology. These technologies are explained in the literature, such as in " Comprehensive Organic Synthesis " (BM Trost & I. Fleming compiles, 1991-1992); " Handbook of Experimental Immunology " (DM Weir and CC Blackwell compile, 1986); " Current Protocols in Molecular Biology " (FM Ausubel et al. compile, 1987, and regularly updated); and " Current Protocols in Immunology " (JE Coligan et al. compile, 1991), each of which is incorporated herein by reference in its entirety.

[0036] Various aspects of the present invention are set forth in the following sections; however, aspects of the present invention described in a particular section are not limited to any particular section. In addition, when a variable is not accompanied by a definition, the previous definition of the variable may apply.

[0037] Embodiments of the present invention

[0038] The present invention provides a compound according to the general formula (I) (for example, the compound is a compound of formula (IA) or (IB) as described below), or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a pharmaceutically acceptable salt of such an ester, amide or carbamate:

[0039]

[0040] Depending on the substituents present in the compounds of the present invention, the compounds may exist in the form of stereoisomers. Specifically, the compounds of the present invention may contain chiral (asymmetric) centers, or the compounds may be chiral as a whole. All individual stereoisomers and mixtures thereof are included within the scope of the present invention.

[0041] Diastereomeric mixtures can be separated into their individual diastereomers 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 columns. Enantiomers can also be separated as follows: by reacting an enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acyl chloride), converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers and converting (e.g., hydrolyzing) the various diastereomers into the corresponding pure enantiomers.

[0042] Isotopic forms (e.g., wherein hydrogen atoms are replaced by deuterium or tritium, or carbon atoms are replaced by carbon-13 atoms) are also included in the present invention. Certain isotopic forms may have beneficial biological properties, such as improved metabolic stability or enhanced therapeutic activity compared to other isotopic forms; alternatively, specific isotopic forms may be useful for biological imaging purposes, for example, carbon-11, nitrogen-13, oxygen-15, or fluorine-18 isotopic variants may be useful for positron emission tomography.

[0043] In a preferred embodiment, R 4 is hydrogen, that is, the compound of the present invention is a compound of formula (IA):

[0044]

[0045] In another particularly preferred embodiment, the compound of the invention is a compound of formula (IB):

[0046]

[0047] in:

[0048] m = 0 or 1;

[0049] n=0

[0050] R 1 It is amino group;

[0051] Cy is a 5-, 6-, 7-, 8-, 9- or 10-membered monocyclic or bicyclic heteroaryl group containing at least 1 N heteroatom and optionally 1, 2 or 3 further heteroatoms selected from N, such as pyrimidinyl, pyrazolopyridinyl, naphthyridinyl (e.g., 1,7-naphthyridinyl and 1,6-naphthyridinyl), pyridopyrazinyl, pyrazolopyrimidinyl, imidazopyridinyl, quinoxalinyl or imidazopyrazinyl.

[0052] R 3 is a halogen, such as F;

[0053] A is a 5-, 6- or 7-membered heteroaryl group containing 1 N heteroatom and optionally 1 or 2 further heteroatoms selected from N, for example pyridyl;

[0054] R 5 is a halogen;

[0055] R 6 For OC 1-3 Alkyl; and

[0056] R 7 For hydrogen.

[0057] In one embodiment, -A(R 5 ,R 6 ,R 7 ) is 2-C 1-3 Alkoxy 5-halopyridinyl, for example 2-methoxy-5-chloropyridin-3-yl.

[0058] In the compounds of the present invention, R 3 is a halogen, for example, R 3 In a preferred embodiment, R 3 For F.

[0059] In the compounds of the present invention, R 4 In a preferred embodiment, R 4 is selected from hydrogen, F and Cl. In another preferred embodiment, R 4 Selected from hydrogen and F.

[0060] In a very preferred embodiment, R 4 For hydrogen.

[0061] In another very preferred embodiment, R 3 is F or Cl; and R 4 For hydrogen.

[0062] In the compounds of the present invention, Cy is a 5-, 6-, 7-, 8-, 9- or 10-membered heteroaryl group containing at least 1 N heteroatom and optionally 1, 2 or 3 further heteroatoms selected from N, S and O (preferably N and S, more preferably N).

[0063] Preferably, Cy is a 5-, 6-, 7-, 8-, 9- or 10-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 further heteroatoms selected from N, S and O (preferably N and S, more preferably N).

[0064] In a preferred embodiment, Cy is a 5-, 6-, 7-, 8-, 9- or 10-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N and S (preferably N). In another preferred embodiment, Cy is a 5- or 6-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N and S (preferably N); or Cy is a 9- or 10-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N and S (preferably N). In another preferred embodiment, Cy is a 5- or 6-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N and S (preferably N) (preferably optionally 1 other heteroatom); or Cy is a 9- or 10-membered heteroaryl group containing at least 2 N heteroatoms and optionally 1 other heteroatom selected from N and S (preferably N).

[0065] In certain embodiments, wherein Cy is a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl group containing at least 1 N heteroatom and optionally 1, 2, or 3 additional heteroatoms selected from N, S, and O, the heteroaryl group may be selected from azophenyl (i.e., pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzimidazolyl (e.g., benzo[a]imidazolyl), benzopyrazolyl (e.g., benzo[e]pyrazolyl), benzo[ Pyridazinyl (e.g., benzo[b]pyridazinyl, indolinyl, pyridoimidazolyl (e.g., pyrido[2,3-a]imidazolyl, 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), pyridopyridinyl (e.g., pyrido[2,3-c]pyridinyl) and pyrazinopyridinyl (e.g., pyrazino[2,3-c]pyridinyl). In a particularly preferred embodiment, Cy is a pyrimidinyl group.

[0066] In certain embodiments, preferably Cy is selected from:

[0067]

[0068]

[0069]

[0070] More preferably, Cy is selected from:

[0071]

[0072]

[0073] In certain embodiments, preferably Cy is selected from:

[0074]

[0075]

[0076]

[0077] More preferably, Cy is selected from:

[0078]

[0079]

[0080]

[0081] In certain embodiments, Cy is selected from:

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090] More preferably, Cy is selected from:

[0091]

[0092]

[0093] For the avoidance of doubt, when drawing a ring system containing two or more rings fused together and when drawing R 1 and / or R 2 The group makes R 1 and / or R 2 When the position of the group is not fixed on the ring, R 1 and / or R 2 The groups may be bonded at any chemically feasible point on any ring.

[0094] In the compounds 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.

[0095] In certain preferred embodiments, 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.

[0096] In certain embodiments, 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 another embodiment, m is 0; and n is 2.

[0097] In an embodiment of the present invention, when present, R 1 Selected from -NH 2 ;-NR A (C 1-6 Alkyl) (e.g. -NR A (C 1-3 Alkyl)); -NR A (OC substituted by 1, 2 or 3 independently selected from OH, halogen and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 Alkyl) (e.g. -NR A (OC substituted by 1, 2 or 3 independently selected from OH, halogen and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-3 Alkyl)); -NR A (optionally substituted with 1, 2 or 3 independently selected from OH, halogen and OC optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted C(O)C 1-6 Alkyl) (e.g., -NR A(optionally substituted with 1, 2 or 3 independently selected from OH, halogen and OC optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted C(O)C 1-3 Alkyl)); -NR A (C 0-3 Alkylene-C 3-6 wherein the cycloalkyl is optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl group substituted); -NR A (C 0-3 Alkylene-C 3-6 wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl group substituted); -NR A (optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C(O)C 3-6 cycloalkyl); and -NR A (a 5- or 6-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N, S and O (preferably N and S, more preferably N), wherein the 5- or 6-membered heteroaryl group is optionally substituted by 1 or 2 substituents independently selected from: OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-3 alkyl; halogen; optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -OC 1-3 Alkyl; OH; NH 2 NH(C 1-6 Alkyl); N(C 1-6 alkyl) 2 ; cyano; optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 3-4 cycloalkyl).

[0098] In a preferred embodiment, R A is hydrogen, therefore, when present, R 1 Selected from -NH 2 ; -NH(C 1-6 Alkyl) (e.g. -NH(C 1-3 -NH(substituted by 1, 2 or 3 groups independently selected from OH, halogen and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl) (e.g. NH (substituted by 1, 2 or 3 independently selected from OH, halogen and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-3 -NH(optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen and OC 1-3 Alkyl-substituted C(O)C 1-6 alkyl) (e.g. -NH (optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen and OC 1-3 Alkyl-substituted C(O)C 1-3 Alkyl)); -NH(C 0-3 Alkylene-C 3-6 wherein the cycloalkyl is optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl group substituted); -NH(C 0-3 Alkylene-C 3-6 wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 -NH (optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C(O)C 3-6-NH (a 5- or 6-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N, S and O (preferably N and S, more preferably N), wherein the 5- or 6-membered heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from: optionally substituted with 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-3 alkyl; halogen; optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -OC 1-3 Alkyl; OH; NH 2 NH(C 1-6 Alkyl); N(C 1-6 alkyl) 2 ; cyano; optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 3-4 cycloalkyl).

[0099] In one embodiment of the invention, when present, R 1 Selected from -NH 2 ;-NR A (C 1-6 Alkyl); -NR A (OC substituted by 1, 2 or 3 independently selected from OH, halogen and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 Alkyl); -NR A (optionally substituted with 1, 2 or 3 independently selected from OH, halogen and OC optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted C(O)C 1-6 Alkyl); -NR A (C 0-3 Alkylene-C 3-6 wherein the cycloalkyl is optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl group substituted); -NR A (C 0-3 Alkylene-C 3-6wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl group); and -NR A (optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C(O)C 3-6 cycloalkyl).

[0100] In one embodiment of the invention, when present, R 1 Selected from -NH 2 ;-NR A (C 1-6 Alkyl); -NR A (OC substituted by 1, 2 or 3 independently selected from OH, halogen and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 Alkyl); -NR A (C 0-3 Alkylene-C 3-6 wherein the cycloalkyl is optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl group); and -NR A (C 0-3 Alkylene-C 3-6 wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl group substitution).

[0101] In another embodiment of the present invention, when present, R 1 Selected from -NH 2 ;-NR A (C 1-6 Alkyl) (e.g. -NR A (C 1-3 -NR A(OC substituted by 1, 2 or 3 independently selected from OH, halogen and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 Alkyl) (e.g. -NR A (OC substituted by 1, 2 or 3 independently selected from OH, halogen and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-3 alkyl)).

[0102] In a preferred embodiment of the present invention, when present, R 1 For -NH 2 .

[0103] In which R 1 Can be-NR A (C 1-6 Alkyl); -NR A (OC substituted by 1, 2 or 3 independently selected from OH, halogen and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 or -NR A (optionally substituted with 1, 2 or 3 independently selected from OH, halogen and OC optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted C(O)C 1-6 In the embodiment of 1-6 The alkyl group may preferably be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

[0104] In which R 1 Can be-NR A (C 1-6 Alkyl); -NR A (OC substituted by 1, 2 or 3 independently selected from OH, halogen and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 or -NR A (optionally substituted with 1, 2 or 3 independently selected from OH, halogen and OC optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted C(O)C 1-6 In certain embodiments of the invention, C 1-6 The alkyl group can be C 1-4 an alkyl group (e.g. a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl group) or a C 1-3 Alkyl groups (eg methyl, ethyl, n-propyl or isopropyl groups).

[0105] In which R 1 Can be-NR A (C 0-3 Alkylene-C 3-6 wherein the cycloalkyl is optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl group substituted); or -NR A (optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C(O)C 3-6 Cycloalkyl), preferably C 3-6 A cycloalkyl group is a monocyclic C 3-6 Cycloalkyl, for example, C selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl 3-6 Cycloalkyl groups.

[0106] Wherein R1 can be -NR A (C 0-3 Alkylene-C 3-6 Heterocycloalkyl (wherein the heterocycloalkyl is optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 In the embodiment where the alkyl group is substituted)), preferably C 3-6 A heterocycloalkyl group is a monocyclic C 3-6 Heterocycloalkyl, for example, C selected from aziridine, oxirane, pyrrolidine, imidazolidine, pyrazolidine, piperidine, dioxane, morpholine, dithiane, oxathiinane and thiomorpholine. 3-6 Heterocycloalkyl group.

[0107] In which R 1 Can be NR A (a 5- or 6-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N, S and O, wherein the 5- or 6-membered heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from: OC optionally substituted with 1, 2 or 3 independently selected from halogen, OH and optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-3alkyl; halogen; optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -OC 1-3 Alkyl; OH; NH 2 NH(C 1-6 Alkyl); N(C 1-6 alkyl) 2 ; cyano; optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 3-4 In another preferred embodiment, the 5- or 6-membered heteroaryl group is selected from azophenyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl and isothiazolyl.

[0108] In the compounds of the present invention, when present, R A is selected from hydrogen; optionally substituted by 1, 2 or 3 independently selected from OH, halogen and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted-C 1-6 Alkyl (eg, optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen and OC 1-3 Alkyl-substituted-C 1-3 Alkyl); -C 0-3 Alkylene-C 3-6 wherein the cycloalkyl is optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl radical substitution; -C 0-3 Alkylene-C 3-6 wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3alkyl; optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -C(O)C 3-6 Cycloalkyl; optionally substituted by 1, 2 or 3 halogens independently selected from OH, halogen and OC 1-3 Alkyl-substituted -C(O)C 1-6 Alkyl (eg, optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen and OC 1-3 Alkyl-substituted -C(O)C 1-3 alkyl); optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -C(O)C 3-6 Cycloalkyl; and a 5 or 6-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N, S and O, wherein the 5 or 6-membered heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from: OC optionally substituted with 1, 2 or 3 halogens, OH and 1, 2 or 3 halogens. 1-3 Alkyl-substituted C 1-3 alkyl; halogen; optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -OC 1-3 Alkyl; OH; NH 2 NH(C 1-6 Alkyl); N(C 1-6 alkyl) 2 ; cyano; optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 3-4 Cycloalkyl.

[0109] In one embodiment, when present, R A is selected from hydrogen; optionally substituted by 1, 2 or 3 independently selected from OH, halogen and OC optionally substituted by 1, 2 or 3 halogens1-3 Alkyl-substituted-C 1-6 Alkyl; -C 0-3 Alkylene-C 3-6 wherein the cycloalkyl is optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl radical substitution; -C 0-3 Alkylene-C 3-6 wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl; optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -C(O)C 3-6 Cycloalkyl; and optionally substituted by 1, 2 or 3 halogens independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -C(O)C 3-6 Cycloalkyl.

[0110] In one embodiment, when present, R A is selected from hydrogen; optionally substituted by 1, 2 or 3 independently selected from OH, halogen and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted-C 1-6 Alkyl; -C 0-3 Alkylene-C 3-6 wherein the cycloalkyl is optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl radical substitution; and -C 0-3 Alkylene-C 3-6 wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3 independently selected from OH, halogen, C1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl radicals are substituted.

[0111] In one embodiment, when present, R A selected from hydrogen; and optionally substituted by 1, 2 or 3 halogens independently selected from OH, halogen and OC 1-3 Alkyl-substituted-C 1-6 Alkyl (eg, optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen and OC 1-3 Alkyl-substituted-C 1-3 alkyl).

[0112] In a preferred embodiment, when present, R A For hydrogen.

[0113] In which R A may be OC optionally substituted with 1, 2 or 3 independently selected from OH, halogen and optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted-C 1-6 or OC optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen and optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted -C(O)C 1-6 In the alkyl embodiment, C 1-6 The alkyl group may preferably be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

[0114] In which R A may be OC optionally substituted with 1, 2 or 3 independently selected from OH, halogen and optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted-C 1-6 or OC optionally substituted with 1, 2 or 3 halogens independently selected from OH, halogen and optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted -C(O)C 1-6 In certain embodiments of the alkyl group, C 1-6 Alkyl is C 1-4 an alkyl group (e.g. a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl group) or a C 1-3 Alkyl groups (eg methyl, ethyl, n-propyl or isopropyl groups).

[0115] In which R A Can be -C0-3 Alkylene-C 3-6 Cycloalkyl (wherein the cycloalkyl is optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3- or optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -C(O)C 3-6 In the embodiment of cycloalkyl, preferably C 3-6 Cycloalkyl is a monocyclic ring C 3-6 Cycloalkyl, for example, C selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl 3-6 Cycloalkyl groups.

[0116] In which R A Can be -C 0-3 Alkylene-C 3-6 Heterocycloalkyl (wherein the heterocycloalkyl is optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 In the embodiment where the alkyl group is substituted), preferably C 3-6 A heterocycloalkyl group is a monocyclic C 3-6 Heterocycloalkyl, for example, C selected from aziridine, oxirane, pyrrolidine, imidazolidine, pyrazolidine, piperidine, dioxane, morpholine, dithiane, oxathiinane and thiomorpholine. 3-6 Heterocycloalkyl group.

[0117] In which R A It may be a 5- or 6-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N, S and O (wherein the 5- or 6-membered heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from: OC optionally substituted with 1, 2 or 3 halogens, OH and 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-3 alkyl; halogen; optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -OC 1-3 Alkyl; OH; NH2 NH(C 1-6 Alkyl); N(C 1-6 alkyl) 2 ; cyano; optionally substituted by 1, 2 or 3 independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 alkyl-OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 3-4 In another preferred embodiment, the 5- or 6-membered heteroaryl group is selected from azophenyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl and isothiazolyl.

[0118] In the compounds of the present invention, when present, each R 2 independently selected from OC optionally substituted with 1, 2 or 3 independently selected from halogen, OH and optionally substituted with 1, 2 or 3 halogen 1-3 Alkyl-substituted C 1-6 Alkyl (e.g., optionally substituted with 1, 2 or 3 halogens, OH and OC 1-3 Alkyl-substituted C 1-3 alkyl); halogen; OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogen 1-3 Alkyl-substituted -OC 1-6 Alkyl (e.g., optionally substituted with 1, 2 or 3 halogens, OH and OC 1-3 Alkyl-substituted -OC 1-3 alkyl); OH; =O; NH 2 NH(C 1-6 Alkyl) (e.g. NH C 1-3 Alkyl); N(C 1-6 alkyl) 2 (For example, N(C 1-3 alkyl) 2 ); cyano; and optionally 1, 2 or 3 independently selected from halogen, OH and optionally 1, 2 or 3 halogen substituted OC 1-3 Alkyl-substituted C 3-6 Cycloalkyl.

[0119] In one embodiment, when present, each R2 independently selected from oxo, optionally substituted with 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted with 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; halogen; optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -OC 1-6 alkyl; OH; and OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 3-6 Cycloalkyl.

[0120] In one embodiment, when present, each R 2 independently selected from OC optionally substituted with 1, 2 or 3 independently selected from halogen, OH and optionally substituted with 1, 2 or 3 halogen 1-3 Alkyl-substituted C 1-6 alkyl; halogen; optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -OC 1-6 an alkyl group; and an OH group.

[0121] In one embodiment, when present, each R 2 independently selected from OC optionally substituted with 1, 2 or 3 independently selected from halogen, OH and optionally substituted with 1, 2 or 3 halogen 1-3 Alkyl-substituted C 1-3 alkyl; halogen; optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted -OC 1-3 an alkyl group; and an OH group.

[0122] In one embodiment, Cy is an optionally substituted nitrogen-containing 6-membered aromatic ring having the formula:

[0123]

[0124] Where Z 1 is CH or N;

[0125] Z 2 is CH or N;

[0126] Z 3 is hydrogen or an optionally substituted amino group (e.g., hydrogen, NH 2 or an amino group having 1 or 2 substituents selected from C1-6 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- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl groups, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl groups and C 6-14 Arylsulfonyl groups, each of which optionally has 1 to 3 substituents selected from the substituent group A:

[0127] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxyl group, (6) an optionally halogenated C 1-6 Alkoxy group, (7)C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8) C 7-16 arylalkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy groups (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., morpholinyloxy, piperidyloxy), (11) C 1-6 Alkyl-carbonyloxy group (e.g., acetoxy, propionyloxy), (12) C 6-14 Aryl-carbonyloxy group (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 group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15) C 6-14 aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy), (16) 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),

[0128] (18) optionally halogenated C 1-6Alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19) are optionally substituted by C 1-6 Alkyl substituted C 6-14 Arylsulfonyloxy group (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) optionally halogenated C 1-6 alkylthio group, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxyl group, (25) an optionally halogenated C 1-6 Alkyl-carbonyl group, (26)C 6-14 aryl-carbonyl group, (27) 5- to 14-membered aromatic heterocyclylcarbonyl group, (28) 3- to 14-membered non-aromatic heterocyclylcarbonyl group, (29) C 1-6 Alkoxy-carbonyl group, (30)C 6-14 Aryloxy-carbonyl group (e.g., phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl), (31) C 7-16 Aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) carbamoyl groups, (33) thiocarbamoyl groups, (34) mono- or di-C 1-6 Alkyl-carbamoyl group, (35)C 6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl), (36) 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) optionally halogenated 0.1-6 alkylsulfonyl group, (39) C 6-14 arylsulfonyl group, (40) a 5- to 14-membered aromatic heterocyclic sulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl), (41) an optionally halogenated C 1-6 Alkylsulfinyl group, (42)C 6-14 arylsulfinyl group (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) a 5- to 14-membered aromatic heterocyclic sulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl), (44) an amino group, (45) a mono- or di-C 1-6 Alkylamino 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- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), 30 (48) C 7-16Aralkylamino group (e.g., benzylamino), (49) formylamino group, (50) C 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propionylamino, butyrylamino), (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 Alkoxy-carbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54) C 7-16 Aralkyloxy-carbonylamino group (eg, benzyloxycarbonylamino), (55) C 1-6 Alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino), (56) optionally substituted by C 1-6 Alkyl substituted C 6-14 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 groups and (62)C 6-14 Aryl groups;

[0129] or hydrogen or R as above 1 Group),

[0130] or Z 2 and Z 3 are bonded to each other to form an optionally substituted ring (e.g., an optionally substituted 4, 5, 6 or 7 membered ring, such as an optionally substituted 4, 5, 6 or 7 membered aryl, heteroaryl, non-aromatic carbocyclic ring or non-aromatic heterocyclic ring; for example, optionally substituted with 1, 2 or 3 groups independently selected from the substituent group A; or optionally substituted with 1 R 1 Group and / or 1 or 2 R 2 Group substitution, as described above).

[0131] In one embodiment, Cy is

[0132]

[0133] Z 1 and Z 2 The combination of 1 , Z 2) is (CH,N), (N,CH) or (N,N); and

[0134] Cy is optionally further substituted by 1 to 3 selected from (1) C 1-6 Alkyl groups and (2) amino groups (-NH 2 ) is substituted with a substituent; and Z 3 is an amino group (—NH 2 ): (1) C optionally substituted by 1, 2 or 3 substituents selected from OH and 3 to 14-membered non-aromatic heterocyclic groups 1-6 Alkyl group, (2) C optionally substituted by 1, 2 or 3 OH groups 3-10 a cycloalkyl group, (3) a 3- to 14-membered non-aromatic heterocyclic group and (4) optionally substituted by 1 to 3 C 1-6 an alkyl-substituted 5- to 14-membered aromatic heterocyclic group; or 2 and Z 3 Bonded to each other to form a 5- to 14-membered aromatic heterocyclic ring.

[0135] In such embodiments, Cy is

[0136]

[0137] Z 1 and Z 2 The combination of 1 , Z 2 ) is (CH, N), (N, CH) or (N, N); and Cy is optionally further replaced by 1 to 3 C 1-6 substituted with an alkyl group; and Z 3 is an amino group (—NH 2 ): (1) C optionally substituted with 1 to 3 OH groups 1-6 Alkyl group, (2) C optionally substituted by 1 to 3 OH groups 3-10 a cycloalkyl group and (3) a 3- to 14-membered non-aromatic heterocyclic group; or Z 2 and Z 3 Bonded to each other to form a 5- to 14-membered aromatic heterocyclic ring.

[0138] In such embodiments, Cy is

[0139]

[0140] Z 1 and Z 2 The combination of (Z 1 , Z 2 ) is (CH, N);

[0141] and Cy is optionally further replaced by 1 to 3 C 1-6 substituted with an alkyl group; and Z 3 is an amino group (—NH 2 ): (1) C optionally substituted with 1 to 3 OH groups 1-6 Alkyl group, (2) C optionally substituted by 1 to 3 hydroxyl groups 3-10 a cycloalkyl group and (3) a 3- to 14-membered non-aromatic heterocyclic group.

[0142] In the compounds of the present invention, A is selected from phenyl; naphthyl; and a 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group containing 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N, S and O (preferably N and S, more preferably N).

[0143] In one embodiment, A is selected from a 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group containing 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N, S and O (preferably N and S, more preferably N). For example, A is selected from azophenyl (i.e., pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzimidazolyl and dihydroindole. In a particularly preferred embodiment, A is pyridyl.

[0144] In one embodiment, A is selected from phenyl; naphthyl; and 6, 7, 8, 9, 10 or 11 membered heteroaryl groups containing 1 N heteroatom and optionally 1 or 2 further heteroatoms selected from N, S and O (preferably N and S, more preferably N).

[0145] In another embodiment, A is selected from a 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group containing 1 N heteroatom and optionally 1 or 2 further heteroatoms selected from N, S and O (preferably N and S, more preferably N).

[0146] In a preferred embodiment, A is selected from the group consisting of azophenyl (ie, pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, benzimidazolyl, and indolinyl.

[0147] In a preferred embodiment, A is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl.

[0148] In a particularly preferred embodiment, A is a pyridyl group. In another preferred embodiment, A is a phenyl group or a pyridyl group.

[0149] In a preferred embodiment, A is selected from:

[0150]

[0151] More preferably, A is selected from:

[0152]

[0153]

[0154] In a preferred embodiment, R 7 is hydrogen, and A is selected from:

[0155]

[0156] In another preferred embodiment, R 7 is hydrogen, and A is selected from:

[0157]

[0158]

[0159] In the compounds of the present invention, R 5 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogen 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 .

[0160] In a preferred embodiment, R 5 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 alkyl.

[0161] In a preferred embodiment, R 5is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 alkyl.

[0162] In a preferred embodiment, R 5 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-3 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-3 alkyl.

[0163] In one embodiment, R 5 selected from hydrogen; halogen; OH; optionally 1, 2 or 3 independently selected from halogen and OC 1-3 Alkyl-substituted C 1-6 alkyl; and OC optionally substituted by 1, 2 or 3 halogen groups 1-6 alkyl.

[0164] In another embodiment, R 5 selected from hydrogen; halogen; OH; optionally 1, 2 or 3 independently selected from halogen and OC 1-3 Alkyl-substituted C 1-6 alkyl; and OC optionally substituted by 1, 2 or 3 halogen groups 1-6 alkyl.

[0165] In the compounds of the present invention, R 6 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogen 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6 Alkyl); N(C 1-6 alkyl) 2; optionally substituted phenyl; optionally substituted naphthyl; an optionally substituted 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group containing 1 N heteroatom and optionally 1 or 2 other heteroatoms independently selected from N, S and O (preferably N and S); an optionally substituted 5-, 6-, 7-, 8-, 9-, 10- or 11-membered non-aromatic heterocyclic group containing 1 N heteroatom and optionally 1 or 2 other heteroatoms independently selected from N, S and O (preferably N and S); and optionally substituted C 3-10 wherein the phenyl, naphthyl, 5, 6, 7, 8, 9, 10 or 11-membered heteroaryl group, 5, 6, 7, 8, 9, 10 or 11-membered non-aromatic heterocyclic group and C 3-11 Cycloalkyl is optionally substituted with 1, 2 or 3 groups independently selected from halogen; OH; OC optionally substituted with 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted with 1, 2 or 3 halogens. 1-3 Alkyl-substituted C 1-3 alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogen 1-3 Alkyl-substituted -OC 1-3 alkyl.

[0166] In which R 6 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted 5, 6, 7, 8, 9, 10 or 11-membered heteroaryl group, an optionally substituted 5, 6, 7, 8, 9, 10 or 11-membered non-aromatic heterocyclic group or an optionally substituted C 3-11 In the cycloalkyl embodiment, preferably the phenyl, naphthyl, 5, 6, 7, 8, 9, 10 or 11-membered heteroaryl group, 5, 6, 7, 8, 9, 10 or 11-membered non-aromatic heterocyclic group or C 3-11 Cycloalkyl is optionally substituted with 1, 2 or 3 groups independently selected from halogen; OH; C optionally substituted with 1, 2 or 3 groups independently selected from halogen; 1-3 OC optionally substituted by 1, 2 or 3 halogens 1-3 For example, the phenyl, naphthyl, 5, 6, 7, 8, 9, 10 or 11-membered heteroaryl group, 5, 6, 7, 8, 9, 10 or 11-membered non-aromatic heterocyclic group or C 3-11 Cycloalkyl is optionally substituted with 1 or 2 groups independently selected from halogen; OH; C optionally substituted with 1, 2 or 3 groups independently selected from halogen. 1-3 OC optionally substituted by 1, 2 or 3 halogens 1-3 For example, the phenyl, naphthyl, 5, 6, 7, 8, 9, 10 or 11-membered heteroaryl group, 5, 6, 7, 8, 9, 10 or 11-membered non-aromatic heterocyclic group or C3-11 Cycloalkyl is optionally substituted with 1 group selected from halogen; OH; C optionally substituted with 1, 2 or 3 groups independently selected from halogen. 1-3 OC optionally substituted by 1, 2 or 3 halogens 1-3 alkyl.

[0167] In a preferred embodiment, R 6 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogen 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 .

[0168] In a preferred embodiment, R 6 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 alkyl.

[0169] In a preferred embodiment, R 6 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 alkyl.

[0170] In another preferred embodiment, R 6 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 alkyl.

[0171] In another preferred embodiment, R 6 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-3 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-3 alkyl.

[0172] In one embodiment, R 6 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected halogens and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; and OC optionally substituted by 1, 2 or 3 halogen groups 1-6 alkyl.

[0173] In another embodiment, R 6 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected halogens and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; and OC optionally substituted by 1, 2 or 3 halogen groups 1-6 alkyl.

[0174] In the compounds of the present invention, R 7 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 .

[0175] In a preferred embodiment, R 7 For hydrogen.

[0176] In one embodiment, R 7 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 alkyl.

[0177] In another embodiment, R 7 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 alkyl.

[0178] In another embodiment, R 7 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-3 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-3 alkyl.

[0179] In one embodiment, R 7 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected halogens and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; and OC optionally substituted by 1, 2 or 3 halogen groups 1-6 alkyl.

[0180] In another embodiment, R 7 OH; OC optionally substituted by 1, 2 or 3 independently selected halogens and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; and OC optionally substituted by 1, 2 or 3 halogen groups 1-6 alkyl.

[0181] In a particularly preferred embodiment, R 5 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogen 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 ;

[0182] R 6 is selected from hydrogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogen 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6 Alkyl); N(C 1-6 alkyl) 2 ; optionally substituted phenyl; optionally substituted naphthyl; an optionally substituted 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group containing 1 N heteroatom and optionally 1 or 2 other heteroatoms independently selected from N, S and O (preferably N and S); an optionally substituted 5-, 6-, 7-, 8-, 9-, 10- or 11-membered non-aromatic heterocyclic group containing 1 N heteroatom and optionally 1 or 2 other heteroatoms independently selected from N, S and O (preferably N and S); and optionally substituted C 3-10 wherein the phenyl, naphthyl, 5, 6, 7, 8, 9, 10 or 11-membered heteroaryl group, 5, 6, 7, 8, 9, 10 or 11-membered non-aromatic heterocyclic group and C 3-11 Cycloalkyl is optionally substituted with 1, 2 or 3 groups independently selected from halogen; OH; OC optionally substituted with 1, 2 or 3 groups independently selected from halogen, OH and OC optionally substituted with 1, 2 or 3 halogens. 1-3 Alkyl-substituted C 1-3 alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogen 1-3 OC substituted with alkyl groups 1-3Alkyl; and

[0183] R 7 is selected from hydrogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 More preferably, R 7 For hydrogen.

[0184] In another particularly preferred embodiment, R 5 is selected from hydrogen; halogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC optionally substituted by 1, 2 or 3 halogen 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 ;

[0185] R 6 is selected from hydrogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 ;and

[0186] R 7 is selected from hydrogen; OH; cyano; OC optionally substituted by 1, 2 or 3 groups independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 Alkyl; NH 2 NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 More preferably, R 7 For hydrogen.

[0187] In another particularly preferred embodiment, R 5 selected from hydrogen; halogen; OH; optionally 1, 2 or 3 independently selected from halogen and OC 1-3 Alkyl-substituted C 1-6 alkyl; and OC optionally substituted by 1, 2 or 3 halogen groups 1-6 alkyl;

[0188] R 6 is selected from hydrogen; OH; OC optionally substituted by 1, 2 or 3 independently selected halogens and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; and OC optionally substituted by 1, 2 or 3 halogen groups 1-6 Alkyl; and

[0189] R 7 is selected from hydrogen; OH; OC optionally substituted by 1, 2 or 3 independently selected halogens and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl; and OC optionally substituted by 1, 2 or 3 halogen groups 1-6 More preferably, R 7 For hydrogen.

[0190] In a preferred embodiment, A is selected from:

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197] In certain embodiments, A is an optionally substituted 6-membered aryl or heteroaryl ring of formula B:

[0198]

[0199] where Y 1 , Y 2 and Y 3 Two of them are CH, and the remaining one is CH or N;

[0200] R 5 1, 2 or 3 independently selected from halogen, OH and OC 1-3 Alkyl-substituted C 1-3 Alkyl; and optionally 1, 2 or 3 independently selected from halogen, OH and OC 1-3 OC substituted with alkyl groups 1-3 alkyl;

[0201] R 6 OH; optionally 1, 2 or 3 independently selected from halogen, OH and OC 1-3 Alkyl-substituted C 1-3 Alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC 1-3 OC substituted with alkyl groups 1-3 Alkyl; and a ring of the formula:

[0202]

[0203] 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;

[0204] Y 4 and Y 4 One of them is CH, and the other is CH or N;

[0205] wherein the C ring is optionally substituted by: halogen; OH; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC 1-3 Alkyl-substituted C 1-3 Alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC 1-3 OC substituted with alkyl groups 1-3 Alkyl; and

[0206] wherein the D ring is optionally substituted with: halogen; OH; optionally substituted with 1, 2 or 3 independently selected from halogen, OH and OC 1-3 Alkyl-substituted C 1-3Alkyl; optionally substituted by 1, 2 or 3 independently selected from halogen, OH and OC 1-3 OC substituted with alkyl groups 1-3 alkyl.

[0207] In certain embodiments, A is (1) the following formula:

[0208]

[0209] where Y 1 , Y 2 and Y 3 Combination of (Y 1 , Y 2 , Y 3 ) is (CH, CH, CH) or (CH, CH, N);

[0210] R 5 is (1) a fluorine atom, a chlorine atom, a bromine atom, (2) a methyl group, a trifluoromethyl group, or (3) a hydroxy group optionally substituted with a methyl group, a difluoromethyl group or a trifluoromethyl group;

[0211] R 6 is (1) a halogen atom, (2) a cyano group, (3) a C optionally substituted with 1 to 3 substituents selected from a halogen atom and a hydroxyl group 1-6 Alkyl group, (4) C optionally substituted by 1 to 3 halogen atoms 1-6 Alkoxy groups or (5) mono- or di-C 1-6 Alkylamino groups;

[0212] and Ring B is optionally further substituted by 1 to 3 substituents selected from the group consisting of: (1) a halogen atom, (2) C optionally substituted by 1 to 3 hydroxyl groups 1-6 Alkyl groups and (3)C 1-6 An alkoxy group, or (2) the following formula:

[0213]

[0214] where Y 4 and Y 5 Combination of (Y 4 , Y 5 ) is (CH, CH);

[0215] Ring C is optionally further substituted by 1 to 3 halogen atoms;

[0216] Ring D is a 5- to 7-membered aromatic heterocyclic ring or a 5- to 7-membered non-aromatic heterocyclic ring;

[0217] Ring D is optionally further substituted with 1 to 3 substituents selected from (1) a halogen atom and (2) a hydroxyl group.

[0218] In such embodiments, R 4 It may be a hydrogen atom, a fluorine atom or a chlorine atom.

[0219] In such embodiments, R 3 It may be a fluorine atom or a chlorine atom.

[0220] In such embodiments, Cy may be

[0221]

[0222] Z 1 and Z 2 The combination of 1 , Z 2 ) is (CH, N), (N, CH) or (N, N);

[0223] Cy is optionally further substituted by 1 to 3 selected from (1) C 1-6 alkyl group and (2) an amino group; and Z 3 is an amino group optionally substituted by 1 to 2 substituents selected from the following: (1) a C optionally substituted by 1 to 3 substituents selected from a hydroxyl group and a 3 to 14-membered non-aromatic heterocyclic group; 1-6 Alkyl group, (2) C optionally substituted by 1 to 3 hydroxyl groups 3-10 a cycloalkyl group, (3) a 3- to 14-membered non-aromatic heterocyclic group and (4) optionally substituted by 1 to 3 C 1-6 an alkyl-substituted 5- to 14-membered aromatic heterocyclic group; or 2 and Z 3 Bonded to each other to form a 5- to 14-membered aromatic heterocyclic ring.

[0224] In certain embodiments, A is (1) the following formula:

[0225]

[0226] where Y 1 , Y 2 and Y 3 Combination of (Y 1 , Y 2 , Y 3 ) is (CH, CH, CH) or (CH, CH, N);

[0227] R 5 is (1) a chlorine atom, a bromine atom, (2) a methyl group, a trifluoromethyl group, or (3) a hydroxyl group substituted by a methyl group or a trifluoromethyl group;

[0228] R 6is (1) a halogen atom, (2) a C optionally substituted by 1 to 3 substituents selected from halogen atoms and hydroxyl groups 1-6 or (3) a C 1-6 Alkoxy groups;

[0229] Ring B is optionally further substituted with 1 to 3 substituents selected from the group consisting of: (1) a halogen atom and (2) C optionally substituted with 1 to 3 hydroxyl groups. 1-6 An alkyl group, or (2) the following formula:

[0230]

[0231] where Y 4 and Y 5 Combination of (Y 4 , Y 5 ) is (carbon atom, carbon atom);

[0232] Ring C is optionally further substituted by 1 to 3 halogen atoms;

[0233] Ring D is a 5- to 7-membered non-aromatic heterocyclic ring;

[0234] In such embodiments, R 4 It may be a hydrogen atom, a fluorine atom or a chlorine atom.

[0235] In such embodiments, R 3 It may be a fluorine atom or a chlorine atom.

[0236] In such embodiments, Cy may be

[0237]

[0238] Z 1 and Z 2 The combination of (Z 1 , Z 2 ) is (carbon atom, nitrogen atom), (nitrogen atom, carbon atom) or (nitrogen atom, nitrogen atom); and Cy is optionally further replaced by 1 to 3 C 1-6 substituted with an alkyl group; and Z 3 is an amino group optionally substituted by 1 to 2 substituents selected from the following: (1) a C optionally substituted by 1 to 3 hydroxyl groups 1-6 Alkyl group, (2) C optionally substituted by 1 to 3 hydroxyl groups 3-10 a cycloalkyl group and (3) a 3- to 14-membered non-aromatic heterocyclic group; or Z 2 and Z 3 Bonded to each other to form a 5- to 14-membered aromatic heterocyclic ring.

[0239] In certain embodiments, A is (1) the following formula:

[0240]

[0241] where Y 1 , Y 2 and Y 3 Combination of (Y 1 , Y 2 , Y 3 ) is (CH, CH, CH) or (CH, CH, N);

[0242] R 5 is (1) a chlorine atom, a bromine atom, (2) a methyl group, a trifluoromethyl group, or (3) a hydroxyl group substituted by a methyl group or a trifluoromethyl group;

[0243] R 6 is (1) a halogen atom, (2) a C optionally substituted by 1 to 3 substituents selected from halogen atoms and hydroxyl groups 1-6 or (3) a C 1-6 Alkoxy groups;

[0244] Ring B is optionally further substituted with 1 to 3 substituents selected from the group consisting of: (1) a halogen atom and (2) C optionally substituted with 1 to 3 hydroxyl groups. 1-6 Alkyl group.

[0245] In such embodiments, R 4 It may be a hydrogen atom, a fluorine atom or a chlorine atom.

[0246] In such embodiments, R 3 It may be a fluorine atom or a chlorine atom.

[0247] In such embodiments, Cy may be

[0248]

[0249] Z 1 and Z 2 The combination of (Z 1 , Z 2 ) is (carbon atom, nitrogen atom);

[0250] and Cy is optionally further replaced by 1 to 3 C 1-6 substituted with an alkyl group; and Z 3 is an amino group optionally substituted by 1 to 2 substituents selected from the following: (1) a C optionally substituted by 1 to 3 hydroxyl groups 1-6 Alkyl group, (2) C optionally substituted by 1 to 3 hydroxyl groups 3-10a cycloalkyl group and (3) a 3- to 14-membered non-aromatic heterocyclic group, or a salt thereof.

[0251] In a preferred embodiment, the compound of the present invention is a compound of formula (IA):

[0252]

[0253] Cy is a 5- or 6-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N and S (preferably N); or Cy is a 9- or 10-membered heteroaryl group containing at least 1 N heteroatom and optionally 1 or 2 other heteroatoms selected from N and S (preferably N);

[0254] R 1 Selected from -NH 2 ;-NR A (C 1-6 alkyl); and -NR A (OC substituted by 1, 2 or 3 independently selected from OH, halogen and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 alkyl);

[0255] R A is hydrogen;

[0256] A is selected from a 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group containing 1 N heteroatom and optionally 1 or 2 further heteroatoms selected from N, S and O (preferably N and S, more preferably N);

[0257] R 5 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 alkyl;

[0258] R 6 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 Alkyl; and

[0259] R 7 is selected from hydrogen; halogen; OH; OC optionally substituted by 1, 2 or 3 independently selected from halogen, OH and optionally substituted by 1, 2 or 3 halogens 1-3 Alkyl-substituted C 1-6 and optionally substituted by 1, 2 or 3 halogens, OH and OC 1-3 OC substituted with alkyl groups 1-6 alkyl.

[0260] In such embodiments, preferably R 3 is F or Cl. Most preferably, R 3 For F.

[0261] In such embodiments, preferably m is 1; and n is 0, 1 or 2 (more preferably n is 0 or 1).

[0262] In certain preferred embodiments, the compound of the present invention is a compound of the present invention described in the following Examples section, or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a pharmaceutically acceptable salt of such ester, amide or carbamate. Specifically, the compound of the present invention may be a compound selected from the following:

[0263] N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 1);

[0264] N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-chloropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 2);

[0265] 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 3);

[0266] N-{4-[2-(8-amino-1,7-naphthyridin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 4);

[0267] 5-Chloro-N-{4-[2-(pyrido[3,4-b]pyrazin-8-yl)ethynyl]-3-fluoropyridin-2-yl}-2-methoxypyridine-3-sulfonamide (Example 5);

[0268] 5-Chloro-N-{4-[2-(1,6-naphthyridin-8-yl)ethynyl]-3-fluoropyridin-2-yl}-2-methoxypyridine-3-sulfonamide (Example 6);

[0269] N-{4-[2-(7-aminopyrazolo[1,5-a]pyrimidin-3-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 7);

[0270] N-{4-[2-(8-aminoimidazo[1,2-a]pyridin-3-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 8);

[0271] 5-Chloro-N-{4-[2-(quinoxalin-2-yl)ethynyl]-3-fluoropyridin-2-yl}-2-methoxypyridine-3-sulfonamide (Example 9);

[0272] N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3,5-difluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 10);

[0273] N-{4-[2-(8-aminoimidazo[1,2-a]pyrazin-3-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 11);

[0274] 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-2-methoxybenzene-1-sulfonamide (Example 12);

[0275] N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxybenzene-1-sulfonamide (Example 13);

[0276] 2,5-Dichloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]benzene-1-sulfonamide (Example 14);

[0277] N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-2,5-dichlorobenzene-1-sulfonamide (Example 15);

[0278] N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-2,5-dichloro-3-(hydroxymethyl)benzene-1-sulfonamide (Example 16);

[0279] 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 (Example 17);

[0280] 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 (Example 18);

[0281] 5-Chloro-N-[3-fluoro-4-(2-{[1,3]thiazolo[4,5-c]pyridin-7-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 19);

[0282] 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 (Example 20);

[0283] 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-c]pyridin-4-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 21);

[0284] 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 (Example 22);

[0285] 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[4,3-c]pyridin-4-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 23);

[0286] 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 (Example 24);

[0287] 5-Chloro-N-(3-fluoro-4-{2-[2-(methylamino)pyrimidin-5-yl]ethynyl}pyridin-2-yl)-2-methoxypyridine-3-sulfonamide (Example 25);

[0288] 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 (Example 26);

[0289] 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyrazin-5-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 27);

[0290] 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 (Example 28);

[0291] 5-Chloro-N-[3-fluoro-4-(2-{3H-imidazo[4,5-b]pyridin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 29);

[0292] 5-Chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 30);

[0293] 5-Chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidin-3-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 31);

[0294] 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 (Example 32);

[0295] 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 (Example 33);

[0296] N-{4-[2-(2-amino-4-methylpyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 34);

[0297] N-{4-[2-(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (Example 35);

[0298] 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 (Example 36);

[0299] 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 (Example 37); and

[0300] N-[4-(2-{5-aminopyrido[3,4-b]pyrazin-8-yl}ethynyl)-3-fluoropyridin-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide (Example 38),

[0301] or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a pharmaceutically acceptable salt of such an ester, amide or carbamate.

[0302] In a further preferred embodiment, the compound of the present invention is a compound selected from the group consisting of:

[0303] 5-Chloro-N-[3-fluoro-4-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 26);

[0304] N-[4-(2-{8-aminoimidazo[1,2-b]pyridazin-3-yl}ethynyl)-3-fluoropyridin-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide;

[0305] N-[4-(2-{5-aminopyrido[3,4-b]pyrazin-8-yl}ethynyl)-3-fluoropyridin-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide (Example 38);

[0306] 5-Chloro-N-[3-fluoro-4-(2-{1H-imidazo[4,5-b]pyrazin-5-yl}ethynyl)pyridin-2-yl]-2-

[0307] Methoxypyridine-3-sulfonamide;

[0308] 5-Chloro-N-(3-fluoro-4-{2-[2-(methylamino)pyrimidin-5-yl]ethynyl}pyridin-2-yl)-2-methoxypyridine-3-sulfonamide (Example 25);

[0309] 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 (Example 28);

[0310] 5-Chloro-N-[3-fluoro-4-(2-{3-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyrazin-5-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide;

[0311] 5-Chloro-N-[3-fluoro-4-(2-{3H-imidazo[4,5-b]pyridin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 29);

[0312] 5-Chloro-N-{3-fluoro-4-[2-(2-methylpyrimidin-5-yl)ethynyl]pyridin-2-yl}-2-methoxypyridine-3-sulfonamide;

[0313] 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 (Example 32);

[0314] 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 (Example 36);

[0315] 5-Chloro-N-[3-fluoro-4-(2-{imidazo[1,2-b]pyridazin-3-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide;

[0316] N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxybenzene-1-sulfonamide (Example 13);

[0317] 5-Chloro-N-[3-fluoro-4-(2-{imidazo[1,2-b]pyridazin-7-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide;

[0318] 5-Chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidin-3-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 31);

[0319] 5-Chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Example 30);

[0320] N-{4-[2-(5-amino-1,6-naphthyridin-8-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide;

[0321] N-[4-(2-{7-aminopyrazolo[1,5-a]pyridin-3-yl}ethynyl)-3-fluoropyridin-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide;

[0322] 5-Chloro-N-[3-fluoro-4-(2-{5H-pyrrolo[2,3-b]pyrazin-2-yl}ethynyl)pyridin-2-yl]-2-

[0323] Methoxypyridine-3-sulfonamide;

[0324] 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-2-methoxybenzene-1-sulfonamide (Example 12);

[0325] N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-2,5-dichlorobenzene-1-sulfonamide (Example 15); and

[0326] 2,5-Dichloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]benzene-1-sulfonamide (Example 14).

[0327] According to the substituents present in the compound of the present invention, the compound may form esters, amides, carbamates and / or salts. Salts of the compounds of the present invention suitable for use in medicines are those in which the counterions are pharmaceutically acceptable. Such pharmaceutically acceptable salts are described in standard textbooks on salt formation, see, for example: P.Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA / Wiley-VCH, 2002), or SM Berge et al., "Pharmaceutical Salts", J.Pharm.Sci., 1977, 66, 1-19. However, salts with non-pharmaceutically acceptable counterions are within the scope of the present invention, for example, used as intermediates for preparing compounds of the present invention and pharmaceutically acceptable salts thereof and physiologically functional derivatives. The term "physiologically functional derivative" means a chemical derivative of a compound of the present invention having the same physiological function as the free compound of the present invention, for example, formed by being convertible in vivo. Esters, amides and carbamates are examples of physiologically functional derivatives.

[0328] Suitable salts according to the present invention include salts formed from organic or inorganic acids. In particular, suitable salts formed with acids according to the present invention include salts formed with mineral acids, strong organic carboxylic acids (such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids) or with organic sulfonic acids (such as (C 1-4 ) alkyl or aryl sulfonic acid). Pharmaceutically acceptable acid addition salts include those formed by: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxalic 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 glutamic acid, lysine and arginine. Other acids such as oxalic acid, although not pharmaceutically acceptable per se, can be used as intermediates for obtaining compounds of the present invention and pharmaceutically acceptable acid addition salts thereof.

[0329] Suitable salts according to the present invention also include those formed with organic or inorganic bases. Pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts, such as those of potassium and sodium; alkaline earth metal salts, such as those of calcium and magnesium; and salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucose, 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.

[0330] The compounds of the present invention may have suitable groups which can be converted into esters, amides or carbamates. G Typical ester and amide and carbamate groups formed by the group include OC(O)R G NR G C(O)R G NR G CO 2 R G 、OSO 2 R G and NR G SO 2 R G , where R G Selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl and C 3-8 Cycloalkyl C1-8 Alkyl, halogenated C 1-8 Alkyl, dihalogenated C 1-8 Alkyl, trihalogenated C 1-8 Alkyl, phenyl and phenyl C 1-4 More preferably, R G Selected from C 1-8 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and C 3-8 Cycloalkyl C 1-8 alkyl.

[0331] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they react or precipitate or crystallize. These complexes are referred to as "solvates". "Pharmaceutically acceptable solvates" means a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (e.g., water or ethanol). For example, a complex with water is referred to as a "hydrate". When a drug substance is incorporated into a solvent (e.g., water) in a stoichiometric or non-stoichiometric amount in a crystal lattice, a solvate (e.g., hydrate) is present. Since hydrates can be encountered at any stage of the drug preparation process or when storing a drug substance or dosage form, drug substances are routinely screened to determine the presence of hydrates. Solvates are described in S. Byrn et al., Pharmaceutical Research, 12 (7), 1995, 954-954 and Water-Insoluble Drug Formulation, 2nd edition, R. Liu, CRC Press, p. 553, which are incorporated herein by reference. Therefore, it will be appreciated by those skilled in the art that the compounds of the present invention and their esters, amides, carbamates and / or salts can therefore exist in the form of solvates, and these are also included within the scope of the present invention. Solvates of the compounds of the present invention suitable for use in medicines are those in which the associated solvent is pharmaceutically acceptable. For example, hydrates are examples of pharmaceutically acceptable solvates. However, solvates with non-pharmaceutically acceptable associated solvents can be used as intermediates for preparing compounds of the present invention and their pharmaceutically acceptable esters, amides, carbamates and / or salts.

[0332] When administered to a recipient, a compound that can be converted into a compound of the invention as described above or its active metabolite or residue is referred to as a "prodrug". A prodrug can be converted into an active form having a medical effect in vivo, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Volume 14 of the ACS Symposium Series (1976); "Design of Prodrugs", H. Bundgaard, ed., 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.

[0333] definition :

[0334] In the context of this application and the present invention, the following definitions apply:

[0335] As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine or bromine are preferred. Fluorine and chlorine are particularly preferred.

[0336] As used herein, "alkyl" used alone or as a suffix or prefix is ​​intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C 1-6 "Alkyl" means 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, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

[0337] As used herein, "alkenyl" or "alkylene" used alone or as a suffix or prefix is ​​intended to include straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. 1-6 "Alkenyl" or "C 1-6 "Alkylene" means an alkenyl or alkylene group having 1, 2, 3, 4, 5 or 6 carbon atoms. When the specific number of alkenyl or alkylene groups is an integer 0 (zero), the bond is intended to connect the group substituted on the alkenyl or alkylene group. For example, "-C 0"Alkylene OH" is equivalent to "-OH" (hydroxyl). As used herein, a group attached through an alkylene or alkenyl group is intended to be attached to the first carbon and the last carbon of the alkylene or alkenyl group. In the case of a methylene group, the first carbon and the last carbon are the same. Examples of alkylene or alkenyl groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene.

[0338] As used herein, the term "aryl" means phenyl or naphthyl.

[0339] As used herein, the term "cycloalkyl" refers to a saturated group in a ring system having the specified number of carbon atoms. 3-6 "Cycloalkyl" means a cycloalkyl group having 3, 4, 5 or 6 carbon atoms. The cycloalkyl group may be monocyclic, spirocyclic or bicyclic. The cycloalkyl group may have a bridge in the ring structure. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl. Other examples of monocyclic cycloalkyl groups are cyclohexyl, cycloheptyl and cyclooctyl. Examples of bridged cycloalkyl groups include bicyclo[2.2.1]hept-2-yl and adamantyl. Examples of spirocyclic cycloalkyl groups include spiro[5.5]undecyl and spiro[5.4]decyl. Preferably, the cycloalkyl group is monocyclic or spirocyclic, and the monocyclic or spirocyclic cycloalkyl group may be optionally bridged.

[0340] As used herein, the term "non-aromatic heterocyclic group" or "non-aromatic heterocycle" refers to a non-aromatic cyclic group of carbon atoms, wherein one to three carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. The non-aromatic heterocyclic group can be, for example, monocyclic, spirocyclic or bicyclic. The non-aromatic heterocyclic group can have a bridge, for example, in the ring structure. In a bicyclic heterocyclic group, one or more heteroatoms may be present in each ring or only in one ring. As described above, the heteroatoms in the non-aromatic heterocycle can be selected from S, O and N, and are preferably selected from O and N. The heterocyclic group containing a suitable nitrogen atom includes the corresponding N-oxide. The non-aromatic heterocyclic group can be partially saturated, i.e., contain one or more double bonds, but the number of bonds is not enough to form a completely delocalized electronic ring.

[0341] Examples of monocyclic non-aromatic heterocyclic groups (also referred to as monocyclic heterocycloalkyl rings) include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and azepanyl.

[0342] Examples of bridged non-aromatic heterocyclyl groups include morpholinyl and 1,4-diazabicyclo[2.2.2]octyl.

[0343] Examples of spirocyclic non-aromatic heterocyclic groups include 1,4-dioxaspiro[4.5]decyl, 6-azaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2-azaspiro[3.4]octyl, 1,1-dimethylethyl ester and 1,4,6-triazaspiro[4.4]nonane.

[0344] As used herein, the term "heteroaryl" group means an aromatic cyclic group of carbon atoms, wherein one to three carbon atoms are replaced by one or more (e.g., 1, 2, 3 or 4; preferably 1, 2 or 3) heteroatoms independently selected from nitrogen, oxygen or sulfur. The heteroaryl group can be, for example, monocyclic or bicyclic. In a bicyclic heteroaryl group, one or more heteroatoms may be present in each ring or only in one ring. In a bicyclic heteroaryl group, both rings may be aromatic, or only one ring may be aromatic. As described above, the heteroatoms in the heteroaryl group may be selected from S, O and N, and are preferably selected from N and S.

[0345] Examples of monocyclic aromatic heterocyclyl groups (also referred to as monocyclic heteroaryl groups) include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, triazolyl, triazinyl, pyridazinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl groups.

[0346] Examples of bicyclic heterocyclyl groups in which one ring is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and benzazepanyl groups.

[0347] Examples of bicyclic aromatic heterocyclic groups (also referred to as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridinyl, pyridopyrimidinyl, isoquinolinyl, and benzobisoxazolyl.

[0348] Preferred examples of heteroaryl groups of the present invention include azophenyl (i.e., pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzimidazolyl, dihydroindole and the like.

[0349] As mentioned above, the compound of the present invention has the activity as a GCN2 inhibitor, and is an inhibitor of GCN2. Therefore, the present invention also provides a compound of the present invention or a composition comprising the compound of the present invention, which is used as a medicine or for treatment. For example, the present invention provides a compound of the present invention or a composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, which is used as a medicine or for treatment.

[0350] For the avoidance of doubt, as used herein, the terms "therapy," "treatment," and "treating" include both prevention and treatment of a condition, disease, or disorder. It also includes slowing, interrupting, controlling, or stopping the progression of a condition, disease, or disorder. It also includes preventing, curing, slowing, interrupting, controlling, or stopping the symptoms of a condition, disease, or disorder. For example, it includes preventing cancer metastasis, where the disease or disorder is cancer.

[0351] The compounds of the invention or compositions comprising the compounds of the invention can be used to treat diseases or conditions in which inhibition of GCN2 provides a therapeutic effect. Thus, the compounds of the invention can be used to treat or prevent diseases or conditions for which GCN2 inhibitors are useful.

[0352] The compounds of the invention are particularly useful for treating or preventing diseases or conditions in which inhibition of GCN2 provides a therapeutic benefit, such as diseases or conditions selected from cancer (eg, solid cancers and hematological cancers).

[0353] The present invention also provides a method for treating a subject suffering from a medical condition or disease. The method includes administering to the subject a therapeutically effective amount of a compound or composition of the present invention as described herein to treat the condition or disease. As described above, the compounds of the present invention can be used to treat a variety of diseases or conditions in which the inhibition of GCN2 provides a therapeutic effect. For example, the compounds described herein can be used to treat cancer (e.g., solid cancer and hematological cancer).

[0354] When a compound of the invention or a composition comprising a compound of the invention is used in therapy as a medicament for treating or preventing a disease or condition, such as in the therapeutic uses and methods described herein, the use or method may comprise the step of administering a therapeutically effective amount of a compound of the invention to a mammal (including a human) in need of such treatment or prevention.

[0355] The compounds of the present invention are particularly useful for treating or preventing cancer. In certain embodiments, the cancer is a solid tumor or a hematological cancer (eg, leukemia or multiple myeloma). In certain embodiments, the cancer is a cancer with a MYC mutation.

[0356] Examples of cancers for which the compounds of the invention are particularly useful for treating or preventing include, but are not limited to, colorectal cancer (e.g., colorectal 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 carcinoma), duodenal cancer, small intestine cancer, breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor), ovarian germ cell tumor, ovarian tumor of low malignant potential), testicular tumors, prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer), liver cancer (e.g., hepatoma, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid cancer), renal 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, uterine corpus cancer, uterine sarcoma), gestational choriocarcinoma, brain tumors (e.g., medulloblastoma, glioma, glioblastoma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (e.g., basal cell carcinoma, malignant melanoma), (melanoma)), sarcomas (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma, osteosarcoma), malignant bone tumors, bladder cancer, and hematologic cancers (e.g., multiple myeloma, smoldering myeloma, plasmacytoma, leukemias (e.g., acute myeloid leukemia, acute lymphocytic leukemia (including blast crisis of chronic leukemia)), non-Hodgkin lymphoma, malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disorders), and cancers of unknown primary nucleus).

[0357] The compounds of the present invention are also suitable for use as cancer growth inhibitors, cancer metastasis inhibitors, cell apoptosis promoters, and for preventing or treating precancerous lesions (eg, myelodysplastic syndrome of the bone marrow, monoclonal gammopathy of undetermined significance).

[0358] In one embodiment, the compounds of the invention are particularly useful for the treatment or prevention of osteosarcoma, acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, pancreatic cancer, colorectal cancer, melanoma and malignant lymphoma.

[0359] Examples of solid cancers for which the compounds of the invention are particularly useful for treating or preventing include, but are not limited to, colorectal cancer (e.g., colorectal 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 carcinoma), duodenal cancer, small intestine cancer, breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumors), ovarian germ cell tumors, ovarian tumors of low malignant potential), testicular tumors, prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone dependent prostate cancer, The cancers include, but are not limited to, prostate cancer (e.g., leukemia, prostate cancer, ovarian ...

[0360] Examples of hematological cancers for which the compounds of the invention are particularly useful for treating or preventing include, but are not limited to, multiple myeloma, smoldering myeloma, plasmacytoma, leukemias (e.g., acute myeloid leukemia, acute lymphocytic leukemia (including blast crisis of chronic leukemia)), non-Hodgkin's lymphoma, malignant lymphoma, Hodgkin's disease, and chronic myeloproliferative disorders.

[0361] In one embodiment, the compounds of the invention are particularly useful for treating or preventing 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 that the compounds of the invention are particularly useful for treating or preventing 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 leukemias (e.g., acute lymphoblastic leukemia and mixed cell leukemia).

[0362] The compounds of the invention are also useful in a condition selected from diabetic retinopathy, myocardial ischemia, diabetic cardiomyopathy, allergic airway inflammation, doxorubicin-induced cardiotoxicity and non-alcoholic fatty liver disease (NAFLD).

[0363] The present invention also provides a method for treating or preventing a disease or condition in which the inhibition of GCN2 provides a therapeutic effect in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound according to the present invention or a composition comprising a compound according to the present invention. Diseases and conditions that can be treated by the method of the present invention are preferably those described above.

[0364] The present invention also provides the use of a compound according to the invention in the preparation of a medicament for the treatment or prevention of a disease or condition in which inhibition of GCN2 provides a therapeutic effect. Diseases and conditions treatable by this use of the invention are preferably those described above.

[0365] Of course, the amount of active ingredient required to achieve a therapeutic effect will vary with the specific compound, the route of administration, the subject being treated, including its type, species, age, weight, sex and medical condition. The subject, the renal and liver function of the subject, the specific disorder or disease being treated and its severity. A physician, veterinarian or clinician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0366] When used for the effect shown, oral doses of the present invention will be between about 0.01mg / kg body weight every day (mg / kg / day) to about 100mg / kg / day, preferably 0.01mg / kg body weight. For adults, body weight every day (mg / kg / day) to 10mg / kg / day, most preferably 0.1 to 5.0mg / kg / day. For oral administration, mebendazole is preferably provided in the form of a pharmaceutical composition of a tablet or other presentation form provided in discrete units, and the discrete units contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500mg of mebendazole for the dosage of the patient to be treated and symptomatic adjustment. Medicine generally comprises an active ingredient of about 0.01mg to about 500mg, preferably an active ingredient of about 1mg to about 100mg. During constant rate infusion, intravenously, the most preferred dosage range is about 0.1 to about 10mg / kg / minute. Advantageously, the compounds of the present invention can be administered in a single daily dose, or the total daily dose can be administered twice, three or four times a day. In addition, the compounds of the present invention can be administered in intranasal form via topical use of a suitable intranasal carrier, or via transdermal routes using those forms of transdermal skin patches well known to those of ordinary skill in the art. In order to be administered in the form of a transdermal delivery system, the dosage administration is of course continuous rather than intermittent throughout the dosage regimen.

[0367] Although it is possible to administer the active ingredient alone, it is preferred that the active ingredient is present in a pharmaceutical formulation or composition. Therefore, the present invention provides a pharmaceutical preparation or composition comprising a compound according to the present invention and a pharmaceutically acceptable diluent, excipient or carrier (collectively referred to herein as "carrier" material). The pharmaceutical composition and preparation of the present invention can take the form of a pharmaceutical composition or preparation as described below.

[0368] Pharmaceutical compositions according to the present invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion] and intraarticular), inhalation (including fine particle powders or mists that can be produced by various types of metered dose pressurized aerosols), nebulizer or insufflator, rectal, intraperitoneal and topical (including dermal, buccal, sublingual and intraocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient.

[0369] The composition can be conveniently present in unit dosage form and can be prepared by any method well known in the pharmaceutical field. All methods include the step of combining the active ingredient with a carrier constituting one or more auxiliary ingredients. Generally speaking, the composition is prepared by uniformly and closely combining the active ingredient with a liquid carrier or a finely dispersed solid carrier or both, and then, if necessary, molding the product into a desired composition.

[0370] Compositions of the invention suitable for oral administration may be in the form of discrete units such as capsules, sachets, pills or tablets each containing a predetermined amount of active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids, such as elixirs, tinctures, suspensions or syrups; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. The active ingredient may also be presented as a bolus, electuary or paste.

[0371] Tablets can be prepared by optionally compressing or molding with one or more auxiliary ingredients. Can be prepared by compressing in a suitable machine the active ingredient (such as powder or granules) in a free-flowing form optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersant. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and can be formulated to provide a slow or controlled release of the active ingredient therein. The compound of the present invention can be applied, for example, in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by using a suitable pharmaceutical composition comprising the compounds of the present invention, or, particularly in the case of extended release, by using devices such as subcutaneous implants or osmotic pumps.

[0372] Exemplary compositions for oral administration include suspensions, which may include, for example, microcrystalline cellulose for imparting volume, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavorings, such as those known in the art; and immediate release tablets, which may include, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants, such as those known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax, etc. Disintegrants include, but are not limited to starch, methylcellulose, agar, bentonite, xanthan gum, etc. The compounds of the present invention may also be delivered orally by sublingual and / or buccal administration. Molded tablets, compressed tablets, or freeze-dried tablets are exemplary forms that can be used. Exemplary compositions include compositions of one or more compounds of the present invention formulated with fast-dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrin. Such compositions may also include high molecular weight excipients such as cellulose (avicel) or polyethylene glycol (PEG). Such compositions may also include excipients that contribute to mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez) and controlled release agents such as polyacrylic acid copolymers (e.g., Carbopol 1934). For ease of manufacture and use, lubricants, glidants, flavorings, colorants and stabilizers may also be added. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. For oral administration in liquid form, oral drug components may be mixed with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc.

[0373] The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (cephalin) or phosphatidylcholine (lecithin).

[0374] Compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The composition may be present in unit dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under freeze drying (lyophilization) conditions that require only the addition of a sterile liquid carrier (e.g., saline or water for injection) immediately before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the aforementioned types. Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may include, for example, suitable nontoxic, parenterally acceptable diluents or solvents (such as 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution), or other suitable dispersants or wetting agents and suspending agents (including synthetic monoglycerides or diglycerides) and fatty acids (including oleic acid) or

[0375] Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and / or other solubilizing or dispersing agents as are known in the art.

[0376] Compositions for rectal administration may be in the form of a suppository with a conventional carrier such as cocoa butter, synthetic glycerides or polyethylene glycols. Such carriers are generally solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug.

[0377] Compositions for topical administration in the mouth (e.g., buccal or sublingual) include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, as well as lozenges comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as (Mineral oil gelled with polyethylene).

[0378] Preferred unit dosage compositions are those containing an effective dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0379] It should be understood that in addition to the ingredients particularly mentioned above, the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavoring agents.

[0380] Although the compounds of the present invention can be used as the sole active ingredient in a drug, the compounds can also be used in combination with one or more other therapeutic agents. The present invention also provides a PYY analogue according to the present invention for use simultaneously, sequentially or separately with another therapeutic agent. Such other therapeutic agents can be other compounds according to the present invention, or they can be different therapeutic agents, such as another GCN2 inhibitor. The other therapeutic agent can also be a therapeutic agent for treating or preventing a disease or condition in which the inhibition of GCN2 provides a therapeutic effect, such as a disease or condition selected from cancer (e.g., solid cancer and hematological cancer) and autoimmune diseases, particularly cancer diseases or conditions.

[0381] Thus, in one embodiment, the additional therapeutic agent may be a different therapeutic agent for treating or preventing cancer, for example, it may be a chemotherapeutic agent selected from the group consisting of L-asparaginase (ASNase), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib or marizomib), immunomodulatory drugs (e.g., thalidomide, lenalidomide and pomalidomide), SINE compounds (e.g., selinexor), monoclonal antibodies (e.g., rituximab, daratumumab, isatuximab, Herceptin and Avastin), alkylating agents, alkylating agents, Base sulfonates, aziridine, ethyleneimine and methylmelamine, polyacetyl, camptothecin, bryostatin, callystatin, CC-1065, nostoc, caudatum, duocarmycin, acanthocyanin, spatholobiline, spatholobiline, spongestatin, nitrogen mustard, antibiotics, enediyne antibiotics, danemycin, bisphosphonates, ramycin, chromophores of enediyne antibiotics, actinomycin, anthramycin, azaserine, bleomycin, actinomycin C, carabicin, carmine, carmomycin, chromomycin , actinomycin D, daunomycin, detoxibicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, mexilomycin, mitomycin, mycophenolic acid, nogamycin, olive mycin, peplomycin, porfibrinocin, puromycin, tri-iron doxorubicin, rhodorubicin, streptomycin, streptozotocin, tuberculocidin, ubenimex, netastatin, zorubicin, antimetabolites, erlotinib, vemurafenib, crizotinib, sorafenib, ibrutinib, enzalutamide, folic acid analogs, purine analogs, androgen folic acid supplements such as folinic acid, acetylglucosyl ester, aldehyde phosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, amustine, bisantrene, edatrexate, phosphamide, colcemid, diazocine, ilonic acid, elliptin, epothilone, ethoxyquin, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansinoids, mitoxantrone, mitoxantrone, monopyridamole, diamine nitracrine, pentostatin, methamine nitrogen mustard, pirarubicin, losoxantrone, 2-ethylhydrazide of alginate, procarbazine, polysaccharide complex (JHS Natural Products, Eugene, OR), razoxane, rhizobactin, sizolan, spirogermanium, tenuisporic acid, triazoquinone; 2,2',2"-trichlorotriethylamine, trichothecenes (especially T-2 toxin, verrucosporin A, baculosporin A, and serpentin), ethyl carbamate, vindesine, dacarbazine, mannomustine, dibromomannitol, dibromodulanol, pipobroman, cytosine, arabinoside ("Ara-C" ), cyclophosphamide, thiotepa, taxanes, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum analogs, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, vinorelbine, mitoxantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan (Camptosar, CPT-11), topoisomerase inhibitor RFS 2000, difluoromethylornithine, asparaginase, retinoids, capecitabine, combretin, leucovorin, oxaliplatin, inhibitors of PKC-α, Raf, H-Ras, EGFR and VEGF-A that reduce cell proliferation, and pharmaceutically acceptable salts, acids or derivatives thereof, and combinations thereof.

[0382] In another embodiment, the additional therapeutic agent may be a checkpoint inhibitor, such as an agent or antibody that inhibits one or more of CTLA4, PD-1, PD-L1, LAG-3, B7-H3, B7-H4, TIM3, VISTA, and KIR.

[0383] In certain embodiments, the compounds of the present invention are administered in combination with L-asparaginase (ASNase). Such combined therapy can be used to treat cancer, particularly for the treatment of acute lymphocytic leukemia (including the blast crisis of chronic leukemia) and non-Hodgkin's lymphoma. Such combined therapy can also be used to treat cancer tumors that are resistant or tolerant to asparaginase, for example, selected from acute lymphocytic leukemia (including the blast crisis of chronic leukemia) and non-Hodgkin's lymphoma.

[0384] In certain embodiments, the compounds of the invention are administered in combination with a proteasome inhibitor, such as bortezomib, carfilzomib, ixazomib, marizomib, or oprezomib. Such combination therapy may be used to treat cancer, particularly hematological cancers such as Hodgkin's lymphoma, multiple myeloma, smoldering myeloma, and premalignant conditions, monoclonal gammopathy of undetermined significance.

[0385] In embodiments in which the compounds of the present invention are used in combination with other agents for treating or preventing diseases or conditions in which the inhibition of GCN2 provides a therapeutic effect, the individual components of such combinations may be administered separately at different times during the course of treatment or simultaneously in separate or single combination forms. Therefore, the present invention should be understood to cover all such simultaneous or alternating treatment regimens. It should be understood that the scope of the combination of the compounds of the present invention and other agents for treating or preventing diseases or conditions in which the inhibition of GCN2 provides a therapeutic effect includes in principle any combination of any pharmaceutical composition for treating a disease or condition in which the inhibition of GCN2 provides a therapeutic effect.

[0386] When used in combination with the compounds of the invention, the aforementioned additional therapeutic agents can be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

[0387] The compounds of the invention as described above may also be used in combination with radiation therapy to treat cancer.

[0388] In addition, the compounds of the present invention can be used in combination with non-drug therapies. Specifically, the compounds of the present invention or the combination agents of the present invention can be used in combination with, for example, non-drug therapies such as (1) surgery, (2) chemotherapy for hypertension using angiotensin II, etc., 30 (3) gene therapy, (4) hyperthermia therapy, (5) cryotherapy; (6) laser ablation; (7) radiotherapy; (8) dietary therapy (e.g., amino acid restricted diet), etc.

[0389] For example, by using the compound of the present invention or the combination agent of the present invention before or after the above-mentioned surgical procedures, etc., or before or after a combination treatment of two or three of these, effects such as suppressing the expression of resistance, prolonging disease-free survival, suppressing cancer metastasis or recurrence, and prolonging life span can be achieved.

[0390] In addition, treatment using the compound of the present invention or the combination agent of the present invention can be combined with supportive therapy, such as (i) administration of antibiotics (e.g., β-lactam system such as cefotiam, etc., macrolide system such as clarithromycin, etc.) for complications of various infectious diseases, (ii) administration of intravenous nutrition solutions, amino acid preparations, multivitamin preparations to improve malnutrition, (iii) administration of morphine to relieve pain, (iv) administration of drugs to improve side effects such as nausea, vomiting, anorexia, diarrhea, leukopenia, thrombocytopenia, decreased hemoglobin concentration, hair loss, liver disease, kidney disease, DIC, fever, etc., and (v) administration of drugs for suppressing multidrug resistance of cancer, etc.

[0391] The compounds of the invention as described above may also be used, optionally in labeled form, 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.

[0392] In addition to their uses in therapeutic drugs, the compounds according to the present invention can also be used as pharmacological tools in the development and standardization of in vitro and in vivo test systems for evaluating other compounds with similar activity. In addition, the compounds of the present invention can be used as molecular probes to identify and / or locate their target of action, such as targets in the airway, and as diagnostic tools for in vivo, in vitro or in vitro diagnosis of diseases or conditions, or as synthetic precursors for such probes. The molecular probes of the present invention may include reactive markers (i.e. compounds of the present invention, in which one or more constituent atoms are enriched with radioactive substances or detectable isotopes by other means), and fluorescent compounds well known to those skilled in the art.

[0393] The following examples illustrate the invention.

[0394] List of abbreviations :

[0395] anh.-anhydrous

[0396] ACN-Acetonitrile

[0397] BOC-tert-Butyloxycarbonyl

[0398] CDCl 3- -Deuterated chloroform

[0399] CD 3 OD-deuterated methanol

[0400] DCM-dichloromethane

[0401] DIPEA-N,N-Diisopropylethylamine

[0402] DMAP-4-dimethylaminopyridine

[0403] DMSO-Dimethyl sulfoxide

[0404] DMSO-d 6 -Deuterated dimethyl sulfoxide

[0405] EA-ethyl acetate

[0406] eq. or Equiv-equivalent

[0407] FC-Flash Chromatography

[0408] 1 H NMR - Proton Nuclear Magnetic Resonance

[0409] HPLC - High Performance Liquid Chromatography

[0410] MeOH - methanol

[0411] MS - Mass Spectrometry

[0412] NCS-N-chlorosuccinimide

[0413] rt - room temperature

[0414] RT - retention time

[0415] sat.-saturated

[0416] TEA-Triethylamine

[0417] THF-Tetrahydrofuran

[0418] TMS-Trimethylsilyl

[0419] Y-yield

[0420] Description of analytical method :

[0421] All measurements were made on a Bruker Avance III HD 400 MHz or Bruker Fourier 300 MHz NMR spectrometer. 1 In H NMR spectroscopy, exchangeable protons may or may not be observed.

[0422] LCMS (method A )

[0423] Equipment: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQPlus

[0424] Chromatographic column: 2.6 μm XB-C18 (4.6×50 mm), 110A, column number 00B-4496-E0.

[0425] Reagents: - Formic acid ≥98%, Sigma-Aldrich

[0426] -Acetonitrile for HPLC UV / gradient grade, Baker

[0427] -μQ-Water for LCMS

[0428] HPLC conditions: - Wavelength range: (190-340) nm ± 4 nm

[0429] -Flow rate: 1.0ml / min

[0430] - Column temperature: 25℃

[0431] -Autosampler temperature: 20℃

[0432] -Analysis time: 6 minutes

[0433] - Elution: Gradient

[0434] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.0 70 30 1.0 3.35 45 55 1.0 3.75 45 55 1.0 3.90 5 95 1.0 4.75 5 95 1.0 5.00 70 30 1.0 6.00 70 30 1.0

[0435] Mobile phase A: 0.1% v / v formic acid in water

[0436] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0437] Solution for syringe washing: 20% MeOH

[0438] MS conditions: -Mass range: 100-1000 m / z

[0439] -Ionization: Alternating

[0440] - Scanning speed: 12000amu / s

[0441] LCMS (Method B) :

[0442] Equipment: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQPlus

[0443] Chromatographic column: 2.6 μm XB-C18 (4.6×50 mm), 110A, column number 00B-4496-E0.

[0444] Reagents: - Formic acid ≥98%, Sigma-Aldrich

[0445] -Acetonitrile for HPLC UV / gradient grade, Baker

[0446] -μQ-Water for LCMS

[0447] HPLC conditions: - Wavelength range: (190-340) nm ± 4 nm

[0448] -Flow rate: 1.0ml / min

[0449] - Column temperature: 25℃

[0450] -Autosampler temperature: 20℃

[0451] -Injection volume: 2.0 μl

[0452] -Analysis time: 6 minutes

[0453] - Elution: Gradient

[0454] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.0 70 30 1.0 3.35 20 80 1.0 3.75 20 80 1.0 3.90 5 95 1.0 4.75 5 95 1.0 5.00 70 30 1.0 6.00 70 30 1.0

[0455] Mobile phase A: 0.1% v / v formic acid in water

[0456] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0457] Solution for syringe washing: 20% MeOH

[0458] MS conditions: -Mass range: 100-1000 m / z

[0459] -Ionization: Alternating

[0460] - Scanning speed: 12000amu / s

[0461] LCMS (Method C) :

[0462] Equipment: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQPlus

[0463] Chromatographic column: 2.6 μm XB-C18 (4.6×50 mm), 110A, column number 00B-4496-E0.

[0464] Reagents: - Formic acid ≥98%, Sigma-Aldrich

[0465] -Acetonitrile for HPLC UV / gradient grade, Baker

[0466] -μQ-Water for LCMS

[0467] HPLC conditions: - Wavelength range: (190-340) nm ± 4 nm

[0468] -Flow rate: 1.0ml / min

[0469] - Column temperature: 25℃

[0470] -Autosampler temperature: 20℃

[0471] -Injection volume: 2.0 μl

[0472] -Analysis time: 6 minutes

[0473] - Elution: Gradient

[0474] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.0 80 20 1.0 3.35 20 80 1.0 3.75 20 80 1.0 3.90 5 95 1.0 4.75 5 95 1.0 5.00 80 20 1.0 6.00 80 20 1.0

[0475] Mobile phase A: 0.1% v / v formic acid in water

[0476] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0477] Solution for syringe washing: 20% MeOH

[0478] MS conditions: -Mass range: 100-1000 m / z

[0479] -Ionization: Alternating

[0480] - Scanning speed: 12000amu / s

[0481] LCMS (Method D) :

[0482] Equipment: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQPlus

[0483] Chromatographic column: 2.6 μm XB-C18 (4.6×50 mm), 110A, column number 00B-4496-E0.

[0484] Reagents: - Formic acid ≥98%, Sigma-Aldrich

[0485] -Acetonitrile for HPLC UV / gradient grade, Baker

[0486] -μQ-Water for LCMS

[0487] HPLC conditions: - Wavelength range: (190-340) nm ± 4 nm

[0488] -Flow rate: 1.0ml / min

[0489] - Column temperature: 25℃

[0490] -Autosampler temperature: 20℃

[0491] -Injection volume: 2.0 μl

[0492] -Analysis time: 6 minutes

[0493] - Elution: Gradient

[0494] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.0 60 40 1.0 3.35 20 80 1.0 3.75 20 80 1.0 3.90 5 95 1.0 4.75 5 95 1.0 5.00 60 40 1.0 6.00 60 40 1.0

[0495] Mobile phase A: 0.1% v / v formic acid in water

[0496] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0497] Solution for syringe washing: 20% MeOH

[0498] MS conditions: -Mass range: 100-1000 m / z

[0499] -Ionization: Alternating

[0500] - Scanning speed: 12000amu / s

[0501] LCMS (Method E)

[0502] Equipment: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQPlus

[0503] Chromatographic column: 2.6μm XB-C18 (4.6×50mm), 110A, column number 00B-4496-E0, internal column number 019

[0504] Reagents: - Formic acid ≥98%, Sigma-Aldrich

[0505] -Acetonitrile for HPLC UV / gradient grade, Baker

[0506] -μQ-Water for LCMS

[0507] HPLC conditions: - Wavelength range: (190-340) nm ± 4 nm

[0508] -Flow rate: 1.0ml / min

[0509] - Column temperature: 25℃

[0510] -Autosampler temperature: 20℃

[0511] -Analysis time: 6 minutes

[0512] - Elution: Gradient

[0513] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.0 70 30 1.0 3.35 40 60 1.0 3.75 40 60 1.0 3.90 5 95 1.0 4.75 5 95 1.0 5.00 70 30 1.0 6.00 70 30 1.0

[0514] Mobile phase A: 0.1% v / v formic acid in water

[0515] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0516] Solution for syringe washing: 20% MeOH

[0517] MS conditions: -Mass range: 100-1000 m / z

[0518] -Ionization: Alternating

[0519] - Scanning speed: 12000amu / s

[0520] LCMS (Method F)

[0521] Equipment: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC-mass spectrometer

[0522] Chromatographic column: 2.6μm XB-C18 (4.6×50mm), 110A, column number 00B-4496-E0, internal column number 036

[0523] Reagents: - Ammonium hydroxide solution 28%-30%, Sigma-Aldrich

[0524] -Acetonitrile for HPLC UV / gradient grade, Baker

[0525] -μQ-Water for LCMS

[0526] HPLC conditions: - Wavelength range: (190-350) nm ± 4 nm

[0527] -Flow rate: 1.0ml / min

[0528] - Column temperature: 25℃

[0529] -Autosampler temperature: 20℃

[0530] -Analysis time: 6 minutes

[0531] - Elution: Gradient

[0532]

[0533]

[0534] Mobile phase C: 0.05% ammonium hydroxide aqueous solution (28.0%-30.0% NH 3 base)

[0535] Mobile phase D: acetonitrile

[0536] Solution for syringe washing: 20% MeOH

[0537] MS conditions: -Mass range: 100-1000 m / z

[0538] -Ionization: Alternating

[0539] - Scanning speed: 12000amu / s

[0540] LCMS (Method G)

[0541] Equipment: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC-mass spectrometer

[0542] Chromatographic column: 2.6μm XB-C18 (4.6×50mm), 110A, column number 00B-4496-E0, internal column number 036

[0543] Reagents: - Ammonium hydroxide solution 28%-30%, Sigma-Aldrich

[0544] -Acetonitrile for HPLC UV / gradient grade, Baker

[0545] -μQ-Water for LCMS

[0546] HPLC conditions: - Wavelength range: (190-350) nm ± 4 nm

[0547] -Flow rate: 1.0ml / min

[0548] - Column temperature: 25℃

[0549] -Autosampler temperature: 20℃

[0550] -Analysis time: 6 minutes

[0551] - Elution: Gradient

[0552] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.00 90 10 1.0 3.35 60 40 1.0 3.75 60 40 1.0 3.90 5 95 1.0 4.75 5 95 1.0 5.00 90 10 1.0 6.00 90 10 1.0

[0553] Mobile phase C: 0.05% ammonium hydroxide aqueous solution (28.0%-30.0% NH 3 base)

[0554] Mobile phase D: acetonitrile

[0555] Solution for syringe washing: 20% MeOH

[0556] MS conditions: -Mass range: 100-1000 m / z

[0557] -Ionization: Alternating

[0558] - Scanning speed: 12000amu / s

[0559] LCMS (Method H)

[0560] Equipment: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQPlus

[0561] Chromatographic column: 2.6μm XB-C18 (4.6×50mm), 110A, column number 00B-4496-E0, internal column number 019

[0562] Reagents: - Formic acid ≥98%, Sigma-Aldrich

[0563] -Acetonitrile for HPLC UV / gradient grade, Baker

[0564] -μQ-Water for LCMS

[0565] HPLC conditions: - Wavelength range: (190-340) nm ± 4 nm

[0566] -Flow rate: 1.0ml / min

[0567] - Column temperature: 25℃

[0568] -Autosampler temperature: 20℃

[0569] -Injection volume: 2.0 μl

[0570] -Analysis time: 6 minutes

[0571] - Elution: Gradient

[0572] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.00 60 40 1.0 3.35 40 60 1.0 3.75 40 60 1.0 3.90 5 95 1.0 4.75 5 95 1.0 5.00 60 40 1.0 6.00 60 40 1.0

[0573] Mobile phase A: 0.1% v / v formic acid in water

[0574] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0575] Solution for syringe washing: 20% MeOH

[0576] MS conditions: -Mass range: 100-1000 m / z

[0577] -Ionization: Alternating

[0578] - Scanning speed: 12000amu / s

[0579] Example 1: N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxy Pyridine-3-sulfonamide

[0580]

[0581] Step 1: tert-Butyl N-(5-bromopyrimidin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0582]

[0583] To a stirred solution of 2-amino-5-bromopyrimidine (5.1 g, 0.029 mol, 1 eq.) and DMAP (0.72 g, 0.006 mol, 0.2 eq.) in anhydrous THF (204 ml) was added di-tert-butyl dicarbonate (15.99 g, 0.073 mol, 2.5 eq.). The mixture was stirred at room temperature overnight and quenched with water (150 ml). The resulting mixture was extracted with EA (3×100 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), purified by Na 2 SO 4 Drying, filtration and evaporation gave the crude product as a brown solid (11.62 g) which was used in the next step without purification.

[0584] 1 H NMR (300 MHz, CDCl 3 )δ:8.80(s,2H),1.49(s,18H)

[0585] MS m / z: [M+H] + 373.85

[0586] Step 2: N-[(tert-Butyloxy)carbonyl]-N-{5-[2-(trimethylsilyl)ethynyl]pyrimidin-2-yl}amino tert-Butyl formate

[0587]

[0588] To a stirred solution of crude tert-butyl N-(5-bromopyrimidin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (Step 1, 11.62 g, 0.031 mol, 1 eq) in ACN (140 ml) was added TMS acetylene (13.26 ml, 9.15 g, 0.093 mol, 3 eq), copper(I) iodide (1.18 g, 0.006 mol, 0.2 eq) and TEA (13 ml, 9.43 g, 0.093 mol, 3 eq) in a glass pressure reactor. Argon was bubbled through the mixture for 15 min, and PdCl was added. 2 (PPh 3 ) 2 (2.18 g, 0.003 mol, 0.1 eq.). The reactor was sealed and the mixture was stirred at 80 °C overnight. The mixture was filtered through a pad of celite and the volatiles 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 washed with additional EA (4 x 100 ml). The combined organic phases were filtered through a pad of Na 2SO 4 Drying, filtration and evaporation gave the crude product as a brown solid (16.7 g) which was used further without purification.

[0589] 1 H NMR (300 MHz, CDCl 3 )δ: 8.78(s,2H),1.47(s,18H),0.30(s,9H)

[0590] MS m / z: [M+H] + 392.10

[0591] Step 3: tert-Butyl N-(5-ethynylpyrimidin-2-yl)carbamate

[0592]

[0593] To 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 K 2 CO 3 (14.82 g, 0.107 mol, 3 eq.). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EA (300 ml) and concentrated under reduced pressure. The residue was purified by FC (SiO 2 The residue was purified by HPLC (0.1% CO, hexane / EA 100:0→0:100) to give the product as a tan solid (1.48 g, Y: 23% over 3 steps).

[0594] 1 H NMR (300 MHz, CDCl 3 )δ: 8.71(s,2H),8.20(s,1H),3.31(s,1H),1.58(s,9H)

[0595] MS m / z: [M+H] + 219.95

[0596] Step 4: 3-(Benzylsulfanyl)-5-chloro-2-methoxypyridine

[0597]

[0598] 5-Chloro-2-methoxy-3-bromopyridine (8.0 g, 35 mmol, 1 eq.), benzyl mercaptan (8.5 ml, 71 mmol, 2 eq.) and DIPEA (15.7 ml, 89 mmol, 2.5 eq.) were dissolved in dioxane (160 ml.) After degassing with argon for 10 min, Xantphos (4.2 g, 7.1 mmol, 0.2 eq.) and Pd 2 (dba) 3 (3.29 g, 3.6 mmol, 0.1 eq.), and the resulting mixture was heated at 100°C overnight. Then, the insoluble matter was filtered off, the solvent was evaporated in vacuo, and the residue was diluted with EA and washed with water. The organic phase was washed with MgSO 4 Dry, filter and evaporate under reduced pressure. 2 The crude product was purified by HPLC (5% EA in hexane) to give a crystalline product (6.1 g, Y: 62%).

[0599] 1 H NMR (300 MHz, CDCl 3 )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)

[0600] MS m / z: [M+H] + 265.90

[0601] Step 5: 5-Chloro-2-methoxypyridine-3-sulfonyl chloride

[0602]

[0603] NCS (15 g, 112 mmol, 6 eq) was added slowly to a pre-cooled (5 °C) solution of 3-(benzylsulfanyl)-5-chloro-2-methoxypyridine (step 4, 5 g, 18.8 mmol, 1 eq) in water (20 ml) and acetic acid (40 ml) over 30 min. The mixture was stirred at 5-10 °C for 2 h and at room temperature for 1 h. Then, the mixture was diluted with water, ethyl acetate was added and basified to pH = 7 with sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a crude residue. The product was extracted with warm hexane and filtered from the cooled solution to give the title product (3.64 g, Y: 73.1%).

[0604] 1 H NMR (300 MHz, CDCl 3 )δ: 8.45(d,J=2.5Hz,1H),8.24(d,J=2.5Hz,1H),4.21(s,3H)

[0605] Step 6: 3-Fluoro-4-iodopyridin-2-amine

[0606]

[0607] 2,3-Difluoro-4-iodopyridine (1.14 g, 4.74 mmol, 1 eq.) and acetamidine hydrochloride (0.538 g, 5.69 mmol, 1.2 eq.) were combined and aqueous NaOH (0.474 g, 11.9 mmol, 2.5 eq. in 2 mL H 2 O) and DMSO (11.5 mL). The reaction mixture was stirred at 130 °C overnight. After 22 h, the reaction mixture was filtered through a silica pad, the filtrate was concentrated in vacuo and filtered through FC (SiO 2 , hexane / EA 100:0→50:50) to give the desired product (0.307 g, Y: 27.2%) as a solid.

[0608] 1 H NMR (300 MHz, CDCl 3 )δ: 7.52(d,J=5.4Hz,1H),7.03(dd,J=5.4,3.9Hz,1H),4.83(s,2H)

[0609] MS m / z: [M+H] + 238.65

[0610] Step 7: 5-Chloro-N-(3-fluoro-4-iodopyridin-2-yl)-2-methoxypyridine-3-sulfonamide

[0611]

[0612] To a suspension of NaH (60% in oil, 1.02 g, 2.52 mmol, 4 eq.) in anhydrous THF (4.5 ml) at 0°C was added 3-fluoro-4-iodopyridin-2-amine (step 6, 150 mg, 0.63 mmol, 1 eq.) and the reaction mixture was stirred at room temperature for 1 h. It was then cooled to 0°C and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (step 5, 168 mg, 0.69 mmol, 1.1 eq.) 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 NaHCO 3 The combined organic layers were washed with MgSO 4 Drying, filtration and concentration in vacuo gave the desired product (234 mg, Y: 84.0%) as a brown solid.

[0613] 1H NMR (300 MHz, DMSO-d 6 )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)

[0614] MS m / z: [M+H] + 443.70

[0615] Step 8: N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridin- Pyridine-3-sulfonamide

[0616]

[0617] Under argon atmosphere, 5-chloro-N-(3-fluoro-4-iodopyridin-2-yl)-2-methoxypyridine-3-sulfonamide (Step 7, 100 mg, 0.230 mmol, 1 eq), tert-butyl N-(5-ethynylpyrimidin-2-yl)carbamate (Step 3, 59 mg, 0.27 mmol, 1.2 eq) and Cs 2 CO 3 (294 mg, 0.900 mmol, 4 equiv) To a stirred solution of anhydrous DMSO (3 mL) was added PdCl 2 [P(Cy) 3 ] 2 (12 mg, 0.020 mmol, 0.07 eq.), and the reaction mixture was stirred in a microwave first at 120 ° C. for 1 h, and then at 150 ° C. for 1 h. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo and purified by preparative HPLC to give 20.5 mg of a beige solid. The solid product was treated with NaHCO 3 The saturated solution (4 mL) was treated with H 2 O (4 mL) and dried in vacuo to give the product as a beige solid as a free base (15.8 mg, Y: 16.1%).

[0618] 1 H NMR (400 MHz, DMSO-d 6 )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)

[0619] LCMS (Method A) RT: 2.653 min

[0620] MS m / z: [MH] - 432.77

[0621] Example 2: N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-chloropyridin-2-yl}-5-chloro-2-methoxy Pyridine-3-sulfonamide

[0622]

[0623] Step 1: 5-Chloro-N-(3-chloro-4-iodopyridin-2-yl)-2-methoxypyridine-3-sulfonamide

[0624] To a suspension of NaH (60% in mineral oil, 44 mg, 1.1 mmol, 4 eq.) in anhydrous THF (4.2 ml) cooled to 0°C was added 3-chloro-4-iodopyridin-2-amine (70 mg, 0.28 mmol, 1 eq.). The mixture was stirred at room temperature for 1 h, and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (Example 1, Step 5; 70 mg, 0.29 mmol, 1.05 eq.) was added. The reaction was allowed to continue overnight at room temperature. MeOH (4 ml) was added, and the mixture was evaporated to give the crude product, which was purified by FC (SiO 2 , DCM / MeOH 100:0→90:10) to give the desired product (59 mg, Y: 47%) as a pale yellow solid.

[0625] 1 H NMR (300MHz, CD 3 OD)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)

[0626] MS m / z: [M+H] + 459.70

[0627] Step 2: N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-chloropyridin-2-yl}-5-chloro-2-methoxypyridin- Pyridine-3-sulfonamide

[0628]

[0629] Under argon atmosphere, 5-chloro-N-(3-chloro-4-iodopyridin-2-yl)-2-methoxypyridine-3-sulfonamide (Step 1, 59 mg, 0.13 mmol, 1 eq), tert-butyl N-(5-ethynylpyrimidin-2-yl)carbamate (Example 1, Step 3; 34 mg, 0.15 mmol, 1.2 eq) and Cs 2 CO 3 (167 mg, 0.510 mmol, 4 equiv) was added to a stirred solution of PdCl in anhydrous DMSO (2 mL). 2 [P(Cy) 3 ]2 (7 mg, 0.01 mmol, 0.07 equiv), and the reaction mixture was stirred in a microwave first at 120 ° C for 1 h, and then at 150 ° C for 1 h. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo and purified by preparative HPLC to give 13 mg of a brown solid. The solid product was treated with NaHCO 3 The saturated solution (2 mL) was treated with H 2 O (2 mL) and dried in vacuo to give the product as a brown solid as a free base (5.2 mg, Y: 9.0%).

[0630] 1 H NMR (300 MHz, DMSO-d 6 )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)

[0631] LCMS (Method A) RT: 2.793 min

[0632] MS m / z: [MH] - 448.66

[0633] Example 3: 5-Chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridine-2-yl 2-methoxypyridine-3-sulfonamide

[0634]

[0635] Step 1: 5-[2-(Trimethylsilyl)ethynyl]-1H-pyrazolo[3,4-b]pyridine

[0636]

[0637] To a stirred solution of 3-bromo-1H-pyrazolo[3,4-b]pyridine (0.5 g, 2.32 mmol, 1 eq) in ACN (25 ml) was added TMS acetylene (0.72 ml, 5.1 mmol, 2.2 eq), copper(I) iodide (0.09 g, 0.46 mmol, 0.2 eq) and TEA (1.31 ml, 13.9 mmol, 6 eq) in a glass pressure reactor. Argon was passed through the mixture for 15 min, and PdCl was added. 2 (PPh 3 ) 2 (0.16 g, 0.23 mmol, 0.1 eq.). The reactor was sealed and the mixture was stirred at 80 °C overnight. The mixture was then filtered through celite and the ACN was evaporated to give a 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 washed with Na 2 SO4 Dry, filter and evaporate. The residue is purified by column chromatography (SiO 2 , EA / hexane 2:8) to give the title product (0.29 g, 59%) as a yellow solid.

[0638] 1 H NMR (300 MHz, CDCl 3 )δ: 8.79(s,1H),8.28(s,1H),7.28(s,1H),0.31(s,9H)

[0639] MS m / z: [M+H] + 215.95

[0640] Step 2: 5-ethynyl-1H-pyrazolo[3,4-b]pyridine

[0641]

[0642] To a solution of 5-[2-(trimethylsilyl)ethynyl]-1H-pyrazolo[3,4-b]pyridine (Step 1, 0.29 g, 1.3 mmol, 1 eq) in methanol (6 ml) was added K 2 CO 3 (0.55 g, 4 mmol, 3 eq.), and the resulting mixture was stirred at room temperature for 1.5 h under an argon atmosphere. The methanol was evaporated in vacuo, and the residue was triturated with water. The formed crystalline product was filtered and washed with water to give the desired product (0.126 g, Y: 68%).

[0643] 1 H NMR (300 MHz, DMSO-d 6 )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)

[0644] MS m / z: [M+H] + 144.00

[0645] Step 3: 5-chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]- 2-Methoxypyridine-3-sulfonamide

[0646]

[0647] Under argon atmosphere, 5-chloro-N-(3-fluoro-4-iodopyridin-2-yl)-2-methoxypyridine-3-sulfonamide (Example 1, Step 7, 50 mg, 0.11 mmol, 1 eq), 5-ethynyl-1H-pyrazolo[3,4-b]pyridine (Step 2, 19 mg, 0.14 mmol, 1.2 eq) and Cs 2 CO 3 (147 mg, 0.450 mmol, 4 equiv) was added to a stirred solution of PdCl in anhydrous DMSO (2 mL). 2 [P(Cy) 3 ] 2 (6 mg, 0.01 mmol, 0.07 eq.), and the reaction mixture was heated in a microwave at 120 ° C for 1 h. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo and purified by preparative HPLC to give 15.8 mg of a beige solid. The solid product was washed with saturated NaHCO 3 The solution (3 mL) was treated with H 2 O (3 mL) and dried in vacuo to give the product (14.1 mg, Y: 27.3%) as a beige solid.

[0648] 1 H NMR (300MHz, CD 3 OD)δ: 14.02(s,1H),8.74(m,1H),8.60(d,J=1.9Hz,1H),8.45(d,J=1.9Hz,1H),8.22(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)

[0649] LCMS (Method B) RT: 2.443 min

[0650] MS m / z: [MH] - 456.74

[0651] Synthesis of the intermediate of Example 10: N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3,5-difluoropyridine-2- 5-Chloro-2-methoxypyridine-3-sulfonamide

[0652]

[0653] Step 1: 3,5-difluoro-4-iodopyridin-2-amine

[0654] At -78 ° C, n-butyl lithium (36 ml, 1.6 M hexane solution, 57 mmol, 2.5 eq) was added dropwise to a solution of 2-amino-3,5-difluoropyridine (3.8 g, 23 mmol, 1 eq) in THF (87 ml). The mixture was stirred at this temperature for 1.5 hours, and then a solution of iodine (17.4 g, 69 mmol, 3 eq) in THF (27 ml) was added. The mixture was stirred at -78 ° C for 15 min and then allowed to warm to room temperature. Saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0-15% ethyl acetate in hexane) to give the title compound (3.4 g, 62% yield).

[0655] 1 H NMR (300 MHz, CDCl 3 )δ:7.71(s,1H),4.56(s,2H)

[0656] MS m / z: [M+H] + 256.90

[0657] Step 2: 5-Chloro-N-(3,5-difluoro-4-iodopyridin-2-yl)-2-methoxypyridine-3-sulfonamide

[0658] At 0-5 ℃, 2-methoxy-3-sulfonyl chloride-5-chloropyridine (1.2 g, 4.6 mmol, 1.2 equivalents) was added to a solution of 2-amino-3,5-difluoro-4-iodopyridine (1 g, 4.0 mmol, 1 equivalent) in anhydrous pyridine (15 ml) in batches, and the resulting mixture was stirred overnight at ambient temperature. The reaction progress was monitored by UPLC. MeOH and all volatiles were then evaporated in vacuo. The crude residue was purified by FC using 5% or 10% MeOH in DCM as eluent to give the desired compound (0.11 g, 24% yield).

[0659] 1 H NMR (300 MHz, DMSO-d 6 )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)

[0660] MS m / z: [M+H] + 461.70

[0661] Embodiment 4-11

[0662] Examples 4-11 were synthesized using methods similar to those described above for Examples 1-3.

[0663]

[0664]

[0665] Examples 12-17 were also synthesized using methods similar to those described above for Examples 1-3.

[0666]

[0667]

[0668] Example 18: 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

[0669]

[0670] Step 1: 5-Chloro-N-{2-fluoro-3-[2-(trimethylsilyl)ethynyl]phenyl}-2-methoxypyridine-3-yl Sulfonamide

[0671]

[0672] In a 200 ml glass pressure reactor, 5-chloro-N-(3-fluoro-4-iodopyridin-2-yl)-2-methoxypyridine-3-sulfonamide (Example 1, Step 7, 4.103 g, 8.971 mmol, 1.0 equiv), ethynyl(trimethyl)silane (2.481 ml, 17.946 mmol, 2.0 equiv), CuI (0.342 g, 1.796 mmol, 0.2 equiv) and triethylamine (6.878 ml, 49.347 mmol, 5.5 equiv) were mixed with anhydrous dimethylformamide (39.8 ml, 10.0 volumes). Argon was bubbled through the mixture for 15 minutes, and bis(triphenylphosphine)palladium(II) dichloride (0.316 g, 0.449 mmol, 0.05 equiv) was added. The mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and filtered through a celite pad and washed with MeOH. The filtrate was concentrated and the residue was purified by FC (silica gel, hexane / ethyl acetate, 100:0 to 80:20) to give 5-chloro-N-{3-fluoro-4-[2-(trimethylsilyl)ethynyl]pyridin-2-yl}-2-methoxypyridine-3-sulfonamide (2.79 g, 6.74 mmol, 71%) as a yellow solid.

[0673] 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)

[0674] MS m / z: [M+H] + 413.85

[0675] Step 2: 5-Chloro-N-(3-ethynyl-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide

[0676]

[0677] To a solution of 5-chloro-N-{3-fluoro-4-[2-(trimethylsilyl)ethynyl]pyridin-2-yl}-2-methoxypyridine-3-sulfonamide (2.79 g, 6.403 mmol, 0.95 equiv) in anhydrous methanol (22.32 ml, 8.0 volumes) and anhydrous tetrahydrofuran (11.16 ml, 4.0 volumes) at room temperature was added potassium fluoride (0.43 g, 7.402 mmol, 1.098 equiv). The mixture was stirred at room temperature for 1 hour and the volatiles were evaporated. The residue was triturated with diethyl ether and dried to give 5-chloro-N-(4-ethynyl-3-fluoropyridin-2-yl)-2-methoxypyridine-3-sulfonamide (2.34 g, 6.847 mmol, 97%) as a light brown solid.

[0678] 1 H NMR (300 MHz, DMSO-d 6 )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).

[0679] MS m / z: [M+H] + 341.85

[0680] Step 3: 5-Chloro-N-[3-fluoro-4-(2-{1-methyl-1H-imidazo[4,5-c]pyridin-7-yl}ethynyl)pyrrolidone [2-pyridin-2-yl]-2-methoxypyridine-3-sulfonamide

[0681]

[0682] 5-Chloro-N-(4-ethynyl-3-fluoropyridin-2-yl)-2-methoxypyridine-3-sulfonamide (84 mg, 0.25 mmol, 1 eq) was dissolved in DMF (4 ml), followed by the addition of 7-bromo-1-methyl-1H-imidazo[4,5-c]pyridine (55 mg, 0.26 mmol, 1.05 eq), CuI (9 mg, 0.05 mmol, 0.2 eq) and triethylamine (0.19 ml, 1.35 mmol, 5.5 eq). The solution was degassed with argon for 15 min, and Pd(P(Cy) 3 ) 2Cl 2 (18 mg, 0.025 mmol, 0.1 equiv). The vial was sealed and heated to 80 °C overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (33 mg, 27%) as a white solid.

[0683] 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)

[0684] LCMS (Method C) RT: 2.097 min, MS m / z: [M+H] + 472.97

[0685] Examples 19-38 were synthesized using methods similar to those described above for Example 18.

[0686]

[0687]

[0688]

[0689] Biological and pharmacokinetic testing

[0690] (a) GCN2 enzyme inhibition (10 μM and 300 μM assay)

[0691] Assay Protocol Overview :

[0692] The inhibitory activity of the example compounds on the GCN2 enzyme was measured using the LanthaScreen TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer) kinase activity assay distributed by ThermoFisher Scientific as described below.

[0693] All experiments were performed using the full length human GCN2 enzyme (UniProt accession number Q9P2K8) (Carna Bioscience).The TR-FRET pair consisted of GFP-eIF2α and LanthaScreen terbium-labeled anti-peIF2α (pSer52) antibody.

[0694] Each example compound was dissolved in DMSO (0.15 mM) and dispensed in 384-well plates using a D300 dispenser (Tecan) using logarithmic dilution mode to a final concentration range of 3000-0.13 nM in duplicate. Complete inhibition (3000 nM commercial reference inhibitor) and DMSO vehicle control wells were also included on the same plate. All volumes were normalized to a final DMSO concentration of 2% of the reaction volume. Next, 5 μL of H was added to each well of the plate. 2 O.

[0695] Prepare the enzyme mix to obtain the following concentrations:

[0696] ·GCN2-30nM

[0697] Unloaded tRNA - 0.3nM

[0698] HEPES (pH = 7.0) - 100 mM

[0699] MgCl 2 -20mM; MnCl 2 -10mM

[0700] The mixture was applied by adding 5 μL to each well of the plate. The enzyme and test compound were then incubated for 20 min at room temperature while shaking at 450 rpm.

[0701] Prepare the substrate mix to obtain the following concentrations:

[0702] GFP-eIF2α-240nM

[0703] ATP - 900 μM or 30 μM

[0704] HEPES (pH = 7.0) - 50 mM

[0705] MgCl 2 -10mM

[0706] ·MnCl 2 -5mM.

[0707] Apply the mixture by adding 5 μL to each well of the plate. Therefore, the final concentrations of 15 μL of reaction mixture are as follows:

[0708] ·GCN2-10nM

[0709] Unloaded tRNA - 0.1nM

[0710] GFP-eIF2α-80nM

[0711] ATP - 300 μM or 10 μM

[0712] HEPES (1M, pH=7.0) - 50 mM

[0713] MgCl 2 -10mM

[0714] ·MnCl 2 -5mM.

[0715] The reaction was allowed to proceed for 30 min at room temperature while shaking at 450 rpm.

[0716] Prepare the antibody mix to obtain the following concentrations:

[0717] ·Na 2 EDTA·2H 2 O-40 mM in TR-FRET dilution buffer (Life technologies)

[0718] • Tb - anti-peIF2a antibody - 4 nM.

[0719] The mixture was applied by adding 15 μL to each well. The plate was then incubated for 60 min at room temperature while shaking at 450 rpm and then read using a Tecan Spark reader using a specific TR-FRET filter.

[0720] GFP / Tb fluorescence results were analyzed using GraphPad Prism to determine the IC of each example compound using a 4-parameter model. 50 : Log(inhibitor) vs. response - variable slope. IC is calculated in the usual way 50 and K i Values. The assays were performed 1 to 15 times. Where applicable, the results in the following tables are the average results of replicate assays of the compounds in question.

[0721] result :

[0722] Table 1 :

[0723]

[0724]

[0725] The results in Table 1 show that the compounds of the present invention are potent inhibitors of GCN2.

[0726] (b) Kinetic solubility

[0727] Assay Protocol Overview :

[0728] Kinetic solubility assay studies solubility based on the amount of material retained in solution after the precipitation process. The compounds used for kinetic solubility testing were prepared as 10mM stock solutions in DMSO. The assay was performed using a Multiscreen vacuum manifold. The buffer of interest (PBS buffer at pH=7.4 was used in the standard protocol) was spiked with the stock solution and incubated at room temperature for 90 minutes. Thereafter, the solution / suspension was filtered. Based on the prepared calibration curve, the concentration of each compound was determined using UV-VIS spectrophotometry. The assay was performed in triplicate.

[0729] Buffer of interest: 0.24 g KH 2 PO 4 , 1.44 g Na 2 HPO 4 , 0.2 g KCl and 8 g NaCl, dissolved in 1 L distilled H 2 O; adjust the pH to an appropriate value (pH 7.4).

[0730] 190 μl of the buffer of interest is distributed into the wells of a 96-well filter plate, followed by 10 μl of the compound (10 mM stock solution in DMSO). Using BioSan, Plate Shaker-Thermostat, PST-60HL-4, the plate is gently shaken at 500 rpm for 90 minutes at room temperature. After 90 minutes, the plate is filtered using a vacuum manifold and a vacuum pump. 100 μl of each filtrate and 100 μl of acetonitrile are transferred to a 96-well UV-visible light transparent plate, and the UV-visible light absorption spectrum is measured from 250-500 nm (interval range 10 nm) using a Biotek Synergy 2 multi-plate reader. The amount of the test compound is calculated using a calibration curve prepared by serially diluting the compound in equal amounts of DMSO and acetonitrile.

[0731] result :

[0732]

[0733]

[0734] Comparison data 1

[0735] The inhibitory activity and kinetic solubility of certain comparative compounds against the GCN2 enzyme were measured using the above assay and compared with the compounds of the present invention. The results are shown below.

[0736]

[0737] Comparative Example 1 is disclosed in Fujimoto, J. et al. (2019) ACS Med. Chem. Lett 10 (1), 1498-1503, where it is named as compound 6e. In Nakamura et al. (2018), PNAS, 115 (33), 7776-7785, it is named as GCN2iB. Comparative Example 2 is disclosed in WO 2018 / 030466, where it is named as Example Compound 123. Comparative Example 3 is disclosed in WO 2018 / 030466, where it is named as Reference Compound 120.

[0738] It can be seen that the compound of Example 1 is superior to the comparative compound because it has 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 compounds of the present invention (such as Example 1), has extremely poor activity against GCN2.

[0739] Comparison data 2

[0740] The inhibitory activity and kinetic solubility of another comparative compound against the GCN2 enzyme were measured using the above assay and compared with the compounds of the present invention. The results are shown below.

[0741]

[0742] Comparative Example 4 is disclosed in WO 2018 / 030466, where it is named Example Compound 5. It can be seen that the compound of Example 3 is superior to the comparative compound because it has strong GCN2 inhibitory activity and good kinetic solubility as measured in the assay.

[0743] Kinase selectivity assay :

[0744] Using KINOMEscan TM The screening platform tests compounds for activity against off-target kinases using a novel and proprietary active site-directed competition binding assay to quantitatively measure the interaction of test compounds with hundreds of human kinases and disease-associated mutation variants. KINOMEscan TM The assay does not require ATP and therefore reports true thermodynamic interaction affinities.

[0745] For most assays, kinase-tagged T7 phage strains were grown in parallel in 24-well plates in E. coli hosts derived from BL21 strains. E. coli were grown to logarithmic phase and infected with T7 phage from frozen stocks (multiplicity of infection = 0.4) and incubated with shaking at 32°C until lysis (90-150 minutes). The lysate was centrifuged (6,000 x g) and filtered (0.2 μm) to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently labeled with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded 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 is assembled by combining kinase, liganded affinity beads and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6mM DTT). The test compound is prepared as a 40x stock solution in 100% DMSO and directly diluted for determination. All reactions are carried out in a final volume of 0.02ml in a polypropylene 384-well plate. The assay plate is shaken and incubated for 1 hour at room temperature, and the affinity beads are washed with washing buffer (1x PBS, 0.05% Tween20). The beads are then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand), and shaken and incubated for 30 minutes at room temperature. The kinase concentration in the eluate is measured by qPCR.

[0746] result :

[0747]

[0748] For comparison, the equivalent findings of Comparative Example 1 as reported in Nakamura et al. (2018), PNAS, 115(33), 7776-7785 (wherein it was named GCN2iB) are as follows:

[0749]

Claims

1. A compound of the following formula, or a pharmaceutically acceptable salt thereof:

2. The compound according to claim 1, wherein the compound is N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide.

3. A pharmaceutical composition comprising a compound according to claim 1 or 2 and at least one pharmaceutically acceptable carrier or excipient.

4. The pharmaceutical composition of claim 3, wherein the composition further comprises at least one other therapeutic agent.

5. The pharmaceutical composition according to claim 4, wherein the other therapeutic agent is an L-asparaginase or a proteasome inhibitor.

6. Use of the compound according to claim 1 or 2 or the composition according to any one of claims 3 to 5 in the preparation of a GCN2 inhibitor drug.

7. The use according to claim 6, wherein the medicament is for treating or preventing a disease or condition selected from solid cancer and hematological cancer.

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