NMT inhibitor and use thereof

Abstract

The present invention provides a novel sulfonamide derivative compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating NMT inhibition-related diseases, the composition comprising same as an active ingredient. The sulfonamide derivative compound of the present invention exhibits excellent inhibitory activity against NMT, and thus can be effectively used for the prevention and treatment of NMT inhibition-related diseases such as cancer, infectious diseases, viral diseases, and the like.

Description

NMT Inhibitors and Their Uses

[0001] The present application claims priority based on Korean Patent Application No. 10-2024-0163417 filed on November 15, 2024, and all contents disclosed in the specification and drawings of said application are incorporated into the present application.

[0002] The present invention relates to NMT inhibitors and their uses, and more specifically, to sulfonamide derivative compounds having NMT inhibitory activity and their uses.

[0003] NMT is an enzyme that adds a myristoyl group to glycine residues of specific proteins. This process affects various important cellular functions, such as signal transduction, apoptosis, and cell differentiation; in particular, these functions may be abnormally activated in cancer cells. Cancer cells often exhibit more active NMT than normal cells, which can contribute to their abnormal growth and metastasis. Therefore, inhibitors targeting NMT have the potential to slow or prevent cancer progression by inhibiting cancer cell growth and inducing apoptosis.

[0004] Previous studies have shown that cancer cells in various tissues exhibit higher NMT activity and expression levels compared to normal cells. It was found that NMT enzyme activity was higher in colon epithelial neoplasms than in normal-looking colon tissue, and that increased NMT activity occurs in the early stages of colon cancer. Significantly increased NMT expression and activity are observed in various tumor types, including colorectal cancer, gallbladder cancer, lung cancer, and breast tumors. Academic reports on the correlation between NMT expression and patient prognosis indicate that in acute myeloid leukemia (AML), higher NMT1 expression is associated with a poorer prognosis, and it is reported that high NMT levels are associated with lower survival rates in most solid tumors. Therefore, NMT inhibitors with novel mechanisms that block various anticancer signaling pathways through broad myristoylation inhibition could be applied not only to the treatment of primary cancers but also to cancer types that are ineffective or resistant to existing therapies.

[0005] The mechanism of action of NMT inhibitors involves blocking the myristoylation of target proteins, thereby preventing them from performing essential molecular biological functions such as intracellular protein transport and signaling, vesicle transport, protein stability, and the determination of protein localization on the cell membrane. In other words, inhibiting NMT function disrupts the metabolism and growth of cancer cells, ultimately playing a crucial role in their death. Consequently, inhibiting NMT blocks various downstream signaling pathways involved in oncogenesis and prevents signaling via bypass pathways, thereby maximizing the efficacy of anticancer drugs and enabling the avoidance of resistance caused by existing anticancer agents. Furthermore, since NMT-induced myristoylation is known to play a critical role in viral capsid protein assembly, it is established that inhibiting NMT can prevent viral infection and self-replication.

[0006] Therefore, NMT inhibitors can be used for various types of hematological and solid cancers. Specifically, hematological cancers include myeloma (e.g., multiple myeloma), leukemia (e.g., chronic lymphocytic leukemia, myeloid leukemia, and acute lymphoblastic leukemia), lymphoma (e.g., follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, etc.), and blastoma (e.g., neuroblastoma, retinoblastoma, glioblastoma, etc.); and solid cancers include brain cancer, lung cancer, breast cancer, prostate cancer, ovarian cancer, colon cancer, rectal cancer, gallbladder cancer, kidney cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, and liver cancer. Additionally, they can be used as treatments for infectious diseases caused by protozoa (e.g., malaria, candidiasis, leishmaniasis, etc.) and viral infections (e.g., rhinovirus, HIV, etc.).

[0007] The problem that the present invention aims to solve is to provide a sulfonamide derivative compound of a novel structure that exhibits excellent inhibitory activity against NMT.

[0008] In addition, the problem to be solved by the present invention is to provide a pharmaceutical composition for the prevention or treatment of NMT inhibition-related diseases comprising a sulfonamide derivative compound having the novel structure described above.

[0009] In addition, the problem to be solved by the present invention is to provide a method for preventing or treating NMT inhibition-related diseases, comprising administering a therapeutically effective amount of a sulfonamide derivative compound of the novel structure to an individual in need thereof.

[0010] In addition, the problem to be solved by the present invention is to provide a use of the sulfonamide derivative compound of the novel structure as an active ingredient in the manufacture of medicines for the prevention or treatment of NMT inhibition-related diseases.

[0011] The problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned technical problems will be clearly understood by those skilled in the art to which the present invention belongs from the description below.

[0012] To achieve the above-mentioned problem, according to one aspect of the present invention, a sulfonamide derivative compound represented by the following formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is provided.

[0013] <Chemical Formula 1>

[0014]

[0015] In the above formula,

[0016] A and B are independently C or N,

[0017] R 1 Silver is hydrogen, C 1-4 Straight-chain or branched-chain alkyl, -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b , -(CH2) x -OH, -(CH2) y -aryl, or a heteroaryl having one or two rings of 4 to 10 molecules containing one to three heteroatoms selected from N, O, and S, or a heterocyclil having one or two rings of 4 to 10 molecules containing one to three heteroatoms selected from N, O, and S, and R 1 is a singular or plural independent R 1-1 Whether replaced or not,

[0018] The above R 1-1 C 1-6Straight-chain or branched-chain alkyl, C 2-8 Alkenyl, C 1-4 Alkoxy, halogen, -(CH2) x -OH, -SR a , Oxo, -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b A heteroaryl comprising 1 to 3 heteroatoms selected from , N, O, and S, or a heterocyclil comprising 4 to 6 heteroatoms selected from N and O, wherein R 1-1 is a singular or plural independent R 1-2 Whether replaced or not,

[0019] The above R 1-2 is C 1-4 Straight-chain or branched-chain alkyl, C 1-4 Alkoxy, oxo, -(CH2) x -OH, acetyl, C 1-4 It is a alkylsulfonyl, or a quaternary to six-membered heterocyclile comprising one to two heteroatoms selected from N and O, and

[0020] R 2 is hydrogen, C 1-4 Straight-chain or branched-chain alkyl, C 3-8 Cycloalkyl, -(CH2) y -aryl, a heteroaryl having one or two rings of 5 to 10 molecules containing 1 to 3 Ns, or a partially unsaturated heterocyclil having two rings of 10 molecules containing 1 N, wherein R 2 is a singular or plural independent R 2-1 Whether replaced or not,

[0021] The above R 2-1 C 1-4It is a straight-chain or branched-chain alkyl, or nitro, and

[0022] R 3 is hydrogen, halogen, -(CH2) y -aryl, or a heteroaryl of one or two rings of 5 to 10 molecules containing 1 to 3 Ns, and the R 3 is a singular or plural independent R 3-1 Whether replaced or not,

[0023] The above R 3-1 C 1-4 Straight-chain or branched-chain alkyl, -(CH2) r -NR a R b , or is a heterocyclile of 4 to 7 groups containing 1 to 3 Ns, and

[0024] R 4 is absent, or hydrogen, C 1-4 Straight-chain or branched-chain alkyl, hydroxy, C 1-3 It is an alkoxy or aryl, and

[0025] R 5 is hydrogen, -(CH2) y - It is a heteroaryl or partially unsaturated heterocyclile of one or three rings comprising four to thirteen members, containing one to three heteroatoms selected from N, O, and S, and R 5 is a singular or plural independent R 5-1 Whether replaced or not,

[0026] The above R 5-1 C 1-4 Straight-chain or branched-chain alkyl, halogen, C 1-4 haloalkyl, -(CH2) x -OH, C 1-4 Alkoxy, cyano, -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a Rb or a saturated or partially unsaturated heterocyclile of one or two rings of 4 to 10 molecules comprising one to three heteroatoms selected from N and O, and said R 5-1 is a singular or plural independent R 5-2 Whether replaced or not,

[0027] The above R 5-2 is C 1-6 Straight-chain or branched-chain alkyl, halogen, C 1-4 haloalkyl, oxo, -(CH2) x -CN, -(CH2) x -OH, -(CH2) x -OR a , -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b , -(CH2) y - It is an aryl, or a 4- to 6-membered heterocyclile containing 1 to 2 Ns, and

[0028] R 6 is a heteroaryl of one or two rings of 4 to 10 molecules containing no, hydrogen, halogen, or 1 to 3 N, and R 6 is a singular or plural independent R 6-1 Whether replaced or not,

[0029] The above R 6-1 -(CH2) r -NR a R b And,

[0030] The above R a and R b is independently hydrogen, C 1-6 Straight-chain or branched-chain alkyl, -(CH2) x -OH, C1-4 Alkoxy, -(CH2) y -aryl, a 5- to 10-membered heteroaryl containing 1 to 2 Ns, or a saturated or partially unsaturated heterocyclile of 1 or 2 rings of 4 to 10 members containing 1 to 2 heteroatoms selected from N and O, or R a and R b N and R connected to a and R b A forms a ring and further comprises 0 to 1 heteroatom selected from N and O, forming a heterocyclile of 1 or 2 rings of 4 to 10, and

[0031] m is an integer from 1 to 3, and

[0032] n is an integer from 0 to 2, and

[0033] o is an integer from 0 to 2, and

[0034] p is an integer from 0 to 7, and

[0035] q is an integer from 0 to 3, and

[0036] r is an integer from 0 to 6, and

[0037] x is an integer from 0 to 6, and

[0038] y is an integer from 0 to 3.

[0039] According to another aspect of the present invention, a pharmaceutical composition for the prevention or treatment of NMT inhibition-related diseases is provided, comprising as an active ingredient a sulfonamide derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0040] According to another aspect of the present invention, a method for preventing or treating NMT inhibition-related diseases is provided, comprising administering a therapeutically effective amount of a sulfonamide derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0041] According to another aspect of the present invention, in the manufacture of a medicine for the prevention or treatment of NMT inhibition-related diseases, a sulfonamide derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is used as an active ingredient.

[0042] According to another aspect of the present invention, a pharmaceutical composition is provided comprising a sulfonamide derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0043] It has been confirmed that the novel sulfonamide derivative compounds of the present invention exhibit excellent inhibitory activity against NMT, and it has been revealed that they can be used for the prevention and treatment of diseases related to NMT inhibition.

[0044] Therefore, the sulfonamide derivative compounds of the present invention can be usefully used in the fields of medicine and pharmaceuticals for the prevention and treatment of NMT inhibition-related diseases such as cancer, infectious diseases, and viral diseases.

[0045] The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the composition of the invention described in the description of the invention or the claims.

[0046] The present invention provides a sulfonamide derivative compound represented by the following chemical formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0047] <Chemical Formula 1>

[0048]

[0049] In the above formula,

[0050] A and B are independently C or N,

[0051] R 1 Silver is hydrogen, C 1-4 Straight-chain or branched-chain alkyl, -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b , -(CH2) x -OH, -(CH2) y -aryl, or a heteroaryl having one or two rings of 4 to 10 molecules containing one to three heteroatoms selected from N, O, and S, or a heterocyclil having one or two rings of 4 to 10 molecules containing one to three heteroatoms selected from N, O, and S, and R 1 is a singular or plural independent R 1-1 Whether replaced or not,

[0052] The above R 1-1 C 1-6 Straight-chain or branched-chain alkyl, C 2-8 Alkenyl, C 1-4 Alkoxy, halogen, -(CH2) x -OH, -SR a , Oxo, -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R bA heteroaryl comprising 1 to 3 heteroatoms selected from , N, O, and S, or a heterocyclil comprising 4 to 6 heteroatoms selected from N and O, wherein R 1-1 is a singular or plural independent R 1-2 Whether replaced or not,

[0053] The above R 1-2 is C 1-4 Straight-chain or branched-chain alkyl, C 1-4 Alkoxy, oxo, -(CH2) x -OH, acetyl, C 1-4 It is a alkylsulfonyl, or a quaternary to six-membered heterocyclile comprising one to two heteroatoms selected from N and O, and

[0054] R 2 is hydrogen, C 1-4 Straight-chain or branched-chain alkyl, C 3-8 Cycloalkyl, -(CH2) y -aryl, a heteroaryl having one or two rings of 5 to 10 molecules containing 1 to 3 Ns, or a partially unsaturated heterocyclil having two rings of 10 molecules containing 1 N, wherein R 2 is a singular or plural independent R 2-1 Whether replaced or not,

[0055] The above R 2-1 C 1-4 It is a straight-chain or branched-chain alkyl, or nitro, and

[0056] R 3 is hydrogen, halogen, -(CH2) y -aryl, or a heteroaryl of one or two rings of 5 to 10 molecules containing 1 to 3 Ns, and the R 3 is a singular or plural independent R 3-1 Whether replaced or not,

[0057] The above R 3-1 C 1-4Straight-chain or branched-chain alkyl, -(CH2) r -NR a R b , or is a heterocyclile of 4 to 7 groups containing 1 to 3 Ns, and

[0058] R 4 is absent, or hydrogen, C 1-4 Straight-chain or branched-chain alkyl, hydroxy, C 1-3 It is an alkoxy or aryl, and

[0059] R 5 is hydrogen, -(CH2) y - It is a heteroaryl or partially unsaturated heterocyclile of one or three rings comprising four to thirteen members, containing one to three heteroatoms selected from N, O, and S, and R 5 is a singular or plural independent R 5-1 Whether replaced or not,

[0060] The above R 5-1 C 1-4 Straight-chain or branched-chain alkyl, halogen, C 1-4 haloalkyl, -(CH2) x -OH, C 1-4 Alkoxy, cyano, -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b or a saturated or partially unsaturated heterocyclile of one or two rings of 4 to 10 molecules comprising one to three heteroatoms selected from N and O, and said R 5-1 is a singular or plural independent R 5-2 Whether replaced or not,

[0061] The above R 5-2 is C 1-6 Straight-chain or branched-chain alkyl, halogen, C 1-4 haloalkyl, oxo, -(CH2)x -CN, -(CH2) x -OH, -(CH2) x -OR a , -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b , -(CH2) y - It is an aryl, or a 4- to 6-membered heterocyclile containing 1 to 2 Ns, and

[0062] R 6 is a heteroaryl of one or two rings of 4 to 10 molecules containing no, hydrogen, halogen, or 1 to 3 N, and R 6 is a singular or plural independent R 6-1 Whether replaced or not,

[0063] The above R 6-1 -(CH2) r -NR a R b And,

[0064] The above R a and R b is independently hydrogen, C 1-6 Straight-chain or branched-chain alkyl, -(CH2) x -OH, C 1-4 Alkoxy, -(CH2) y -aryl, a 5- to 10-membered heteroaryl containing 1 to 2 Ns, or a saturated or partially unsaturated heterocyclile of 1 or 2 rings of 4 to 10 members containing 1 to 2 heteroatoms selected from N and O, or R a and R b N and R connected to a and R bA forms a ring and further comprises 0 to 1 heteroatom selected from N and O, forming a heterocyclile of 1 or 2 rings of 4 to 10, and

[0065] m is an integer from 1 to 3, and

[0066] n is an integer from 0 to 2, and

[0067] o is an integer from 0 to 2, and

[0068] p is an integer from 0 to 7, and

[0069] q is an integer from 0 to 3, and

[0070] r is an integer from 0 to 6, and

[0071] x is an integer from 0 to 6, and

[0072] y is an integer from 0 to 3.

[0073] In one embodiment, the above chemical formula 1 may be the following chemical formula 1a.

[0074] <Chemical Formula 1a>

[0075]

[0076] In the above formula,

[0077] R 1 Silver is hydrogen, C 1-4 Straight-chain or branched-chain alkyl, -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b , -(CH2) x -OH, -(CH2) y-aryl, or a heteroaryl having one or two rings of 4 to 10 molecules containing one to three heteroatoms selected from N, O, and S, or a heterocyclil having one or two rings of 4 to 10 molecules containing one to three heteroatoms selected from N, O, and S, and R 1 is a singular or plural independent R 1-1 Whether replaced or not,

[0078] The above R 1-1 C 1-6 Straight-chain or branched-chain alkyl, C 2-8 Alkenyl, C 1-4 Alkoxy, halogen, -(CH2) x -OH, -SR a , Oxo, -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b A heteroaryl comprising 1 to 3 heteroatoms selected from , N, O, and S, or a heterocyclil comprising 4 to 6 heteroatoms selected from N and O, wherein R 1-1 is a singular or plural independent R 1-2 Whether replaced or not,

[0079] The above R 1-2 is C 1-4 Straight-chain or branched-chain alkyl, C 1-4 Alkoxy, oxo, -(CH2) x -OH, acetyl, C 1-4 It is a alkylsulfonyl, or a quaternary to six-membered heterocyclile comprising one to two heteroatoms selected from N and O, and

[0080] R 2 is hydrogen, C 1-4Straight-chain or branched-chain alkyl, C 3-8 Cycloalkyl, -(CH2) y -aryl, a heteroaryl having one or two rings of 5 to 10 molecules containing 1 to 3 Ns, or a partially unsaturated heterocyclil having two rings of 10 molecules containing 1 N, wherein R 2 is a singular or plural independent R 2-1 Whether replaced or not,

[0081] The above R 2-1 C 1-4 It is a straight-chain or branched-chain alkyl, or nitro, and

[0082] R 3 is hydrogen, halogen, -(CH2) y -aryl, or a heteroaryl of one or two rings of 5 to 10 molecules containing 1 to 3 Ns, and the R 3 is a singular or plural independent R 3-1 Whether replaced or not,

[0083] The above R 3-1 C 1-4 Straight-chain or branched-chain alkyl, -(CH2) r -NR a R b , or is a heterocyclile of 4 to 7 groups containing 1 to 3 Ns, and

[0084] R 4 is hydrogen, C 1-4 Straight-chain or branched-chain alkyl, hydroxy, C 1-3 It is an alkoxy or aryl, and

[0085] R 5 is hydrogen, -(CH2) y - It is a heteroaryl or partially unsaturated heterocyclile of one or three rings comprising four to thirteen members, containing one to three heteroatoms selected from N, O, and S, and R 5 is a singular or plural independent R 5-1 Whether replaced or not,

[0086] The above R 5-1 C 1-4 Straight-chain or branched-chain alkyl, halogen, C 1-4 haloalkyl, -(CH2) x -OH, C 1-4 Alkoxy, cyano, -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b or a saturated or partially unsaturated heterocyclile of one or two rings of 4 to 10 molecules comprising one to three heteroatoms selected from N and O, and said R 5-1 is a singular or plural independent R 5-2 Whether replaced or not,

[0087] The above R 5-2 is C 1-6 Straight-chain or branched-chain alkyl, halogen, C 1-4 haloalkyl, oxo, -(CH2) x -CN, -(CH2) x -OH, -(CH2) x -OR a , -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b , -(CH2) y - It is an aryl, or a 4- to 6-membered heterocyclile containing 1 to 2 Ns, and

[0088] R 6 is a heteroaryl of one or two rings of 4 to 10 molecules containing hydrogen, a halogen, or 1 to 3 Ns, and R 6is a singular or plural independent R 6-1 Whether replaced or not,

[0089] The above R 6-1 -(CH2) r -NR a R b And,

[0090] The above R a and R b is independently hydrogen, C 1-6 Straight-chain or branched-chain alkyl, -(CH2) x -OH, C 1-4 Alkoxy, -(CH2) y -aryl, a 5- to 10-membered heteroaryl containing 1 to 2 Ns, or a saturated or partially unsaturated heterocyclile of 1 or 2 rings of 4 to 10 members containing 1 to 2 heteroatoms selected from N and O, or R a and R b N and R connected to a and R b A forms a ring and further comprises 0 to 1 heteroatom selected from N and O, forming a heterocyclile of 1 or 2 rings of 4 to 10, and

[0091] m is an integer from 1 to 3, and

[0092] n is an integer from 0 to 2, and

[0093] o is an integer from 0 to 2, and

[0094] p is an integer from 0 to 7, and

[0095] q is an integer from 0 to 3, and

[0096] r is an integer from 0 to 6, and

[0097] x is an integer from 0 to 6, and

[0098] y is an integer from 0 to 3.

[0099] In one embodiment, the R 1Silver hydrogen, methyl, ethyl, propyl, isopropyl, 2-oxoethyl, -(CH2)C(O)OH, -(CH2)C(O)OCH3, -(CH2)3C(O)OH, -(CH2)6C(O)OH, -(CH2)6C(O)OCH3, -(CH2)C(O)NR a R b , -(CH2)2C(O)NH2, -(CH2)2NR a R b , -(CH2)3NR a R b , -(CH2)4NR a R b , -(CH2)5NR a R b , hydroxyethyl, hydroxypropaneyl, benzyl, phenethyl, pyrazolyl, thiazoleyl, isooxazoleyl, pyridineyl, pyrazolopyridineyl, indazoleyl, pyrazolopyrimidineyl, pyrazolopyridazineyl, pyrazolopyrazineyl, quinolineyl, isoquinolineyl, or tetrahydropyrazolopyridineyl, and R 1-1 is methyl, ethyl, propyl, isopropyl, isobutyl, methylpropyl, propenyl, methylpropenyl, methoxy, chloro, bromo, hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxydimethylpropyl, -SH, -SCH3, oxo, acetyl, C(O)C(CH3)3, C(O)OH, C(O)NH2, C(O)NH(CH3), C(O)N(CH3)2, C(O)N(CH3)(OCH3), C(O)NH(C6H5), -NH2, -(CH2)2NH2, oxazolyl, pyridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazineyl or morpholino, and R 1-2 is methyl, methoxy, oxo, hydroxy, hydroxymethyl, acetyl, methylsulfonyl, or morpholino, and R a and R b is independently hydrogen, methyl, ethyl, dimethylaminoethyl, hydroxyethyl, hydroxypropaneyl, phenyl, benzyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or isoindolinyl, or Ra and R b N and R connected to a and R b It may form a ring to form azetidinyl, pyrrolidineyl, piperidineyl, piperazineyl, morpholino, or octahydro-2H-pyrido[1,2-a]pyrazineyl.

[0100] In one embodiment, the R 2 is hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl, phenyl, pyrazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, or dihydroisoquinolineyl, and R 2-1 It can be methyl, ethyl, or nitro.

[0101] In one embodiment, R 3 is hydrogen, fluoro, phenyl, pyridinyl, indazoleyl, or imidazopyridinyl, and R 3-1 It may be methyl, methylaminomethyl, dimethylaminomethyl, or piperazine.

[0102] In one embodiment, the R 4 It may not be or may be hydrogen.

[0103] In one embodiment, the R 5 is hydrogen, phenyl, thiazoleyl, pyrazolyl, pyridineyl, pyrimidineyl, pyrazineyl, pyridazineyl, naphthaleneyl, thienopyrimidineyl, imidazopyridineyl, quinolineyl, dihydrocyclopentapyrimidineyl, hexahydrobisisoquinolineyl, tetrahydroquinazolinyl, or tetrahydrobenzofuro[3,2-c]pyridineyl, and R 5-1is methyl, ethyl, fluoro, chloro, trifluoromethyl, hydroxymethyl, hydroxypropyl, methoxy, cyano, -(CH2)2C(O)NH2, amino, aminomethyl, aminoethyl, C(O)OH, azetidineyl, pyrrolidineyl, piperidineyl, piperazineyl, diazepanyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[3.2.0]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[4.1.0]heptanyl, tetrahydropyridineyl, hexahydropyrrolo[3,4-c]pyrroleyl, diazapyrolo[2.5]octanyl, or Hexahydro-2H,6H-pyrazino[1,2-c][1,3]oxazine, and the above R 5-2 It may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, fluoro, trifluoromethyl, cyano, cyanomethyl, hydroxy, oxo, amino, methylamino, dimethylamino, ethylamino, aminomethyl, dimethylaminomethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, ethoxymethyl, oxopropyl, C(O)OH, C(O)OCH3, CH3C(O)OH, CH3C(O)OC2H5, C(O)NH2, C(O)NH(CH3), C(O)N(CH3)2, CH3C(O)NH2, CH3C(O)NH(CH3), CH3C(O)N(CH3)2, phenyl, benzyl, azetidineyl, pyrrolidineyl, or piperidineyl.

[0104] In one embodiment, the R 6 is absent or is hydrogen, fluoro, or imidazopyridine, and the above R 6-1 It can be methylaminomethyl.

[0105] In one embodiment, the R a and R bis independently hydrogen, methyl, ethyl, butyl, dimethylaminoethyl, hydroxy, hydroxyethyl, hydroxypropyl, methoxy, phenyl, benzyl, pyridine-4-yl, azetidine-3-yl, pyrrolidine-3-yl, tetrahydrofuran-3-yl, piperidine-3-yl, piperidine-4-yl, or isoindolin-5-yl, or R a and R b N and R connected to a and R b It may form a ring to form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazine-1-yl, morpholino, or octahydro-2H-pyrido[1,2-a]pyrazine-2-yl.

[0106] Specific examples of sulfonamide derivative compounds according to the present invention are as follows:

[0107] [1] 5-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0108] [2] 5-(3-((dimethylamino)methyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0109] [3] 5-(3-((dimethylamino)methyl)-1-methyl-1H-indazole-5-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0110] [4] 7-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0111] [5] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0112] [6] 8-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0113] [7] N-(3-isobutyl-1,5-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0114] [8] 6-(2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0115] [9] 6-(6-(piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0116]

[0010] 6-(6-(piperazine-1-yl)pyridine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0117]

[0011] 6-(6-(piperazine-1-yl)pyridazine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0118]

[0012] 6-(5-(piperazine-1-yl)pyridazine-3-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0119]

[0013] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0120]

[0014] N,N,1,5-tetramethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-3-carboxamide 2HCl,

[0121]

[0015] N-(2-methylpyridine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0122]

[0016] N-(2-isopropylpyridine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0123]

[0017] 1,5-dimethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-3-carboxamide 2HCl,

[0124]

[0018] N,1,5-trimethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-3-carboxamide 2HCl,

[0125]

[0019] (S)-6-(6-(2,4-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0126]

[0020] (S)-6-(6-(2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0127]

[0021] (R)-6-(6-(2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0128]

[0022] 6-(6-(4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0129]

[0023] (S)-6-(6-(3-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0130]

[0024] 6-(6-(1,4-diazepan-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0131]

[0025] 6-(6-(4-aminopiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0132]

[0026] 6-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0133]

[0027] 6-(6-(3-(dimethylamino)azetidine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0134]

[0028] (S)-6-(6-(2-methylpiperazine-1-yl)pyridine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0135]

[0029] (S)-6-(6-(2-methylpiperazine-1-yl)pyridazine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0136]

[0030] (S)-6-(2-(2-methylpiperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0137]

[0031] 6-(6-(1,2,3,6-tetrahydropyridine-4-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0138]

[0032] N-(2-ethylpyridine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0139]

[0033] N-(2-isobutylpyridine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0140]

[0034] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0141]

[0035] 6-(6-(4-methyl-1,4-diazepan-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0142]

[0036] 6-(6-(4-(dimethylamino)piperidine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0143]

[0037] (R)-6-(6-(3-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0144]

[0038] 6-(6-(4-(aminomethyl)piperidine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0145]

[0039] N-(1-methyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0146]

[0040] N-(3,5-dimethylisooxazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0147]

[0041] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(pyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfoamide,

[0148]

[0042] N-(2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0149]

[0043] 6-(6-((3S,5R)-3,5-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0150]

[0044] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(piperazine-1-yl)pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0151]

[0045] (R)-6-(6-(3,4-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0152]

[0046] N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-6-(6-((3S,5R)-3,4,5-trimethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0153]

[0047] 6-(6-(4-(azetidine-3-yl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0154]

[0048] 6-(2-(piperazine-1-yl)thieno[3,2-d]pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0155]

[0049] 6-(6-(4-methyl-1,4-diazepan-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0156]

[0050] 6-(6-(4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0157]

[0051] (R)-6-(6-(2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0158]

[0052] (R)-6-(6-(3-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0159]

[0053] 6-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0160]

[0054] 6-(6-(4-aminopiperidin-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0161]

[0055] N-(6-methylquinoline-5-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0162]

[0056] N-(1-ethyl-3,5-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0163]

[0057] 6-(6-(2,3-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0164]

[0058] 6-(6-(3-(trifluoromethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0165]

[0059] 6-(6-(3,3-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0166]

[0060] 6-(6-(3-aminopyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0167]

[0061] N-(3-methylisoquinoline-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0168]

[0062] N-(1,3-dimethylisoquinoline-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0169]

[0063] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(2,4,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0170]

[0064] N-(2,6-dimethylpyridine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0171]

[0065] 5-fluoro-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0172]

[0066] 6-(5-fluoro-2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0173]

[0067] 6-(5-methyl-2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0174]

[0068] 6-(6-((3R,5S)-3,5-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0175]

[0069] 6-(6-(2,3-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0176]

[0070] 6-(2-(piperazine-1-yl)thiazole-5-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0177]

[0071] 6-(2-(piperazine-1-yl)thiazole-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0178]

[0072] 6-(6-(3,3-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0179]

[0073] 6-(6-(1,4-diazepan-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0180]

[0074] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(2,5,7-trimethylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0181]

[0075] N-(2-methylquinoline-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0182]

[0076] N-(6-chloro-2-methylpyrazolo[1,5-a]pyrimidine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0183]

[0077] N-(2-methylpyrazolo[1,5-b]pyridazine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0184]

[0078] N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1',2',3,3',4,4'-hexahydro-[6,7'-bis-isoquinoline]-2(1H)-sulfonamide,

[0185]

[0079] 6-(3-((methylamino)methyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0186]

[0080] N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-((3R,5S)-3,4,5-trimethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0187]

[0081] 5-fluoro-6-(6-(piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0188]

[0082] 6-(2-(piperazine-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0189]

[0083] 6-(2-(piperazine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0190]

[0084] 6-(6-(3,6-diazabicyclo[3.2.0]heptane-3-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0191]

[0085] 6-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0192]

[0086] 8-fluoro-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0193]

[0087] N-(2,4-dimethylthiazole-5-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0194]

[0088] N-(2-methylpyrazolo[1,5-a]pyrimidine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0195]

[0089] 5-(3-((methylamino)methyl)imidazo[1,2-a]pyridine-8-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0196]

[0090] 8-fluoro-6-(1-(piperidin-4-yl)-1H-pyrazole-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0197]

[0091] 6-(6-(1,4-diazepan-1-yl)pyrazine-2-yl)-8-fluoro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0198]

[0092] 6-(6-(4,7-diazaspyro[2.5]octan-4-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0199]

[0093] 6-(4-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0200]

[0094] 6-(2-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0201]

[0095] N-(2-methylpyrazolo[1,5-a]pyrazine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0202]

[0096] 6-(5-cyano-2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0203]

[0097] 6-(5-cyano-4-(piperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0204]

[0098] 6-(3-((methylamino)methyl)imidazo[1,2-a]pyridine-8-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0205]

[0099] 6-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridine-6-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0206]

[0100] 6-(5-chloro-2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0207]

[0101] 6-(5-methoxy-2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0208]

[0102] (S)-6-(6-(3-aminopyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0209]

[0103] (R)-6-(6-(3-aminopyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0210]

[0104] (S)-6-(6-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0211]

[0105] (R)-6-(6-(3-(methylamino)pyrrolidine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0212]

[0106] 6-(3-cyano-6-(piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0213]

[0107] 6-(3-(piperazine-1-yl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0214]

[0108] 6-(6-(3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0215]

[0109] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0216]

[0110] 6-(6-(2-cyanopiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0217]

[0111] 6-(6-(3-cyanopiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0218]

[0112] 6-(3-((methylamino)methyl)quinoline-6-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0219]

[0113] (S)-6-(6-(2-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0220]

[0114] (R)-6-(6-(3-(methoxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0221]

[0115] (S)-6-(6-(2-methyl-1,4-diazepan-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0222]

[0116] 6-(6-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0223]

[0117] 6-(3-(2-oxopiperazine-1-yl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0224]

[0118] N-(2,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0225]

[0119] N-(5-isobutyl-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0226]

[0120] N-(5-isopropyl-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0227]

[0121] N-(5-bromo-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0228]

[0122] 6-(6-(pyrrolidin-3-ylamino)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0229]

[0123] (S)-6-(6-(pyrrolidin-3-ylamino)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0230]

[0124] 5-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindoline-2-sulfonamide,

[0231]

[0125] (R)-6-(6-(3-isopropylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0232]

[0126] 6-(3-cyano-2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0233]

[0127] N-(3-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0234]

[0128] 6-(3-((methylamino)methyl)imidazo[1,2-a]pyridine-6-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0235]

[0129] (R)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0236]

[0130] (R)-6-(6-(2-isopropylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0237]

[0131] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0238]

[0132] 6-(6-((methylamino)methyl)naphthalene-1-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0239]

[0133] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0240]

[0134] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-5-(2-(piperazine-1-yl)pyridin-4-yl)isoindoline-2-sulfonamide,

[0241]

[0135] 8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0242]

[0136] 5-fluoro-N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0243]

[0137] N-(2,4-dimethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0244]

[0138] N-(1,3-dimethyl-5-(2-methylprop-1-en-1-yl)-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0245]

[0139] N-(1,3-dimethyl-5-(prop-1-en-2-yl)-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0246]

[0140] 5-(6-((3R,5S)-3,5-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindolin-2-sulfonamide,

[0247]

[0141] (R)-5-(6-(2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindoline-2-sulfonamide,

[0248]

[0142] 5-(6-(1,4-diazepan-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindoline-2-sulfonamide,

[0249]

[0143] (R)-5-(6-(3-aminopyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindolin-2-sulfonamide,

[0250]

[0144] 5-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindoline-2-sulfonamide,

[0251]

[0145] 5-(6-(4-aminopiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindole-2-sulfonamide,

[0252]

[0146] (R)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0253]

[0147] Methyl (R)-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylate,

[0254]

[0148] N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-6-(3-(piperazine-1-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0255]

[0149] 8-fluoro-6-(3-(piperazine-1-yl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0256]

[0150] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyrazine-2-yl)-8-fluoro-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0257]

[0151] 8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-6-(3-(piperazine-1-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0258]

[0152] (R)-8-fluoro-6-(6-(3-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0259]

[0153] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyrazine-2-yl)-8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0260]

[0154] (R)-8-fluoro-6-(6-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0261]

[0155] 8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-6-(2-(piperazine-1-yl)thieno[3,2-d]pyrimidine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0262]

[0156] N-(1,3-dimethylisoquinoline-4-yl)-8-fluoro-6-(3-(piperazine-1-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0263]

[0157] (R)-5-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindoline-2-sulfonamide,

[0264]

[0158] (R)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0265]

[0159] (R)-6-(3-(2-ethylpiperazine-1-yl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0266]

[0160] (R)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0267]

[0161] 6-(6-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0268]

[0162] 6-(6-((3R,4S)-4-amino-3-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0269]

[0163] 6-(6-((3S,4R)-4-amino-3-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0270]

[0164] (S)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0271]

[0165] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0272]

[0166] 6-(6-(2-(hydroxymethyl)-2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0273]

[0167] (R)-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylic acid,

[0274]

[0168] Methyl (S)-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylate,

[0275]

[0169] (R)-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxamide,

[0276]

[0170] (R)-N-methyl-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxamide,

[0277]

[0171] (R)-N,N-dimethyl-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxamide,

[0278]

[0172] (S)-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylic acid,

[0279]

[0173] N-(1,3-dimethyl-5-phenyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0280]

[0174] N-(1,3-dimethyl-5-(pyridin-3-yl)-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0281]

[0175] N-(3-acetyl-1,5-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0282]

[0176] N-(3-(1-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0283]

[0177] (R)-5-(6-(2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)isoindoline-2-sulfonamide,

[0284]

[0178] (R)-5-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)isoindoline-2-sulfonamide,

[0285]

[0179] 5-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)isoindolin-2-sulfonamide,

[0286]

[0180] (R)-5-(6-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)isoindolin-2-sulfonamide,

[0287]

[0181] Methyl 2-((dimethylamino)methyl)-4-(2-(N-(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)benzoate,

[0288]

[0182] 6-(3-((dimethylamino)methyl)-4-(hydroxymethyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0289]

[0183] (S)-6-(3-(1-amino-3-hydroxypropyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl,

[0290]

[0184] (R)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0291]

[0185] (S)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0292]

[0186] (S)-6-(6-(3-(methoxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0293]

[0187] 6-(6-(4-(methylamino)piperidine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0294]

[0188] 6-(6-(4-amino-3,3-difluoropiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0295]

[0189] 6-(6-((3R,4S)-4-amino-3-fluoropiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0296]

[0190] 2-((dimethylamino)methyl)-4-(2-(N-(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)benzoic acid,

[0297]

[0191] (S)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0298]

[0192] (S)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0299]

[0193] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0300]

[0194] (R)-6-(6-(2-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0301]

[0195] (R)-6-(3-(1-amino-3-hydroxypropyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0302]

[0196] 6-(3-(aminomethyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0303]

[0197] 6-(3-(2-(methylamino)ethyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0304]

[0198] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0305]

[0199] (R)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0306]

[0200] (R)-N-(1,3-dimethylisoquinoline-4-yl)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0307]

[0201] (R)-N-(1,3-dimethylisoquinoline-4-yl)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0308]

[0202] 8-(3-((methylamino)methyl)imidazo[1,2-a]pyridine-6-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0309]

[0203] N,N,2,6-tetramethyl-5-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)nicotinamide,

[0310]

[0204] N-(1,3-dimethyl-5-(pyridin-4-yl)-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0311]

[0205] N-(1,3-dimethyl-5-(5-methylpyridine-3-yl)-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0312]

[0206] Methyl (R)-1-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylate,

[0313]

[0207] Methyl (S)-1-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylate,

[0314]

[0208] (S)-N,N-dimethyl-4-(6-(2-(N-(1,3,5--dimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxamide,

[0315]

[0209] N-methoxy-N,1,3-trimethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-5-carboxamide,

[0316]

[0210] (R)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0317]

[0211] (R)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0318]

[0212] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0319]

[0213] (S)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0320]

[0214] (S)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0321]

[0215] (R)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0322]

[0216] (S)-N-(1,3-dimethylisoquinoline-4-yl)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0323]

[0217] (R)-N-(1,3-dimethylisoquinoline-4-yl)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0324]

[0218] (S)-6-(6-(3-isopropylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0325]

[0219] (R)-6-(6-(3-ethylpiperazine-1-yl)pyridine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0326]

[0220] 6-(6-(2,5-diazabicyclo[4.1.0]heptane-2-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0327]

[0221] (S)-6-(6-(2-isobutylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0328]

[0222] (R)-6-(6-(3-isobutylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0329]

[0223] (R)-6-(6-(2-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0330]

[0224] (R)-6-(6-(2-propylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0331]

[0225] (R)-6-(6-(2-phenylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0332]

[0226] (R)-6-(6-(2-benzylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0333]

[0227] (R)-6-(2-(3-ethylpiperazine-1-yl)thieno[3,2-d]pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0334]

[0228] (S)-6-(2-(3-ethylpiperazine-1-yl)thieno[3,2-d]pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0335]

[0229] N-(1,3-dimethyl-5-pivaloyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0336]

[0230] N-(5-acetyl-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0337]

[0231] N-(5-(1-hydroxy-2,2-dimethylpropyl)-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0338]

[0232] N-(5-(1-hydroxyethyl)-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0339]

[0233] N,N,1,3-tetramethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-5-carboxamide 2HCl,

[0340]

[0234] 1,3-dimethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-5-carboxamide 2HCl,

[0341]

[0235] 1,3-dimethyl-N-phenyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-5-carboxamide 2HCl,

[0342]

[0236] (R)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0343]

[0237] (R)-6-(6-(3-benzylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0344]

[0238] 6-(6-((2S,5R)-2,5-diethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0345]

[0239] (S)-6-(6-(2-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0346]

[0240] (R)-6-(6-(3-(cyanomethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0347]

[0241] (R)-6-(6-(2-(cyanomethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0348]

[0242] (S)-6-(6-(2-(cyanomethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0349]

[0243] 6-(3-(1-(methylamino)ethyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0350]

[0244] 6-(3-(1-(methylamino)-2-phenylethyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0351]

[0245] (S)-6-(3-(3-hydroxy-1-(methylamino)propyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0352]

[0246] (R)-N-(1,3-dimethylisoquinoline-4-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0353]

[0247] (S)-N-(1,3-dimethylisoquinoline-4-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0354]

[0248] (R)-6-(4-(3-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0355]

[0249] (S)-6-(6-(3-ethylpiperazine-1-yl)pyridine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0356]

[0250] (S)-6-(4-(3-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0357]

[0251] (S)-6-(4-(2-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0358]

[0252] (R)-6-(4-(2-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0359]

[0253] (R)-6-(2-(3-ethylpiperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0360]

[0254] (S)-6-(2-(3-ethylpiperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0361]

[0255] (R)-6-(6-(3-ethylpiperazine-1-yl)pyridine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0362]

[0256] (S)-6-(6-(3-ethylpiperazine-1-yl)pyridine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0363]

[0257] (R)-6-(4-(3-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0364]

[0258] (S)-6-(4-(3-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0365]

[0259] N-methyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0366]

[0260] N-(3-ethyl-1,5-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0367]

[0261] (S)-3-amino-3-(3-(2-(N-(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)propanamide,

[0368]

[0262] (S)-3-amino-N-methyl-3-(3-(2-(N-(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)propanamide,

[0369]

[0263] N-ethyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0370]

[0264] 6-(6-((3R)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0371]

[0265] 6-(6-((2R,5R)-2-(hydroxymethyl)-5-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0372]

[0266] (R)-6-(6-(3-butylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0373]

[0267] (S)-6-(6-(3-butylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0374]

[0268] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-methyl-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0375]

[0269] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0376]

[0270] N-ethyl-N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0377]

[0271] N-methyl-N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0378]

[0272] (S)-6-(6-(3-(ethoxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0379]

[0273] (R)-6-(6-(3-propylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0380]

[0274] (S)-6-(6-(3-propylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0381]

[0275] N-benzyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0382]

[0276] N-(2-hydroxyethyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0383]

[0277] N-cyclopentyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0384]

[0278] N-isopropyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0385]

[0279] N-(4-nitrophenyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0386]

[0280] (R)-N-ethyl-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0387]

[0281] (R)-N-(3-ethyl-1,5-dimethyl-1H-pyrazol-4-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0388]

[0282] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-b]pyridazine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0389]

[0283] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0390]

[0284] (R)-N-(2-ethyl-5,6-dimethylpyridine-3-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0391]

[0285] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methoxy-5,6-dimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0392]

[0286] (R)-N-(5,6-dimethyl-2-(methylthio)pyridine-3-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0393]

[0287] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-mercapto-5,6-dimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0394]

[0288] 2-((6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0395]

[0289] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-propyl-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0396]

[0290] N-phenethyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0397]

[0291] 6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0398]

[0292] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0399]

[0293] 6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0400]

[0294] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0401]

[0295] (S)-6-(6-(3-acetylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0402]

[0296] (R)-6-(6-(3-acetylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0403]

[0297] 6-(6-((3R)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0404]

[0298] 6-(6-((3R)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0405]

[0299] N-cyclopropyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0406]

[0300] N-(2-(piperazine-1-yl)ethyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0407]

[0301] (S)-6-(6-(3-(2-hydroxypropane-2-yl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0408]

[0302] 2-(4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetamide,

[0409]

[0303] N-methyl-2-(4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetamide,

[0410]

[0304] N,N-dimethyl-2-(4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetamide,

[0411]

[0305] 6-(6-(3-(2-oxopropyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0412]

[0306] N-(2-(3-aminoazetidine-1-yl)-2-oxoethyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0413]

[0307] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(pyrrolidin-3-ylmethyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0414]

[0308] N-methyl-2-((6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0415]

[0309] 6-(6-(3-(2-hydroxypropyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0416]

[0310] N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-(3-(2-hydroxylophil)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0417]

[0311] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0418]

[0312] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0419]

[0313] N-(5-aminopentyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0420]

[0314] N-(4-aminobutyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0421]

[0315] N-(2-aminoethyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0422]

[0316] N-(3-hydroxybenzyl)-2-((6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0423]

[0317] (R)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0424]

[0318] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(2-propylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0425]

[0319] (R)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0426]

[0320] N-(3-aminopropyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0427]

[0321] (R)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0428]

[0322] 6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0429]

[0323] 6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0430]

[0324] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3R)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0431]

[0325] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3R)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0432]

[0326] N-(2-hydroxypropyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0433]

[0327] N-(oxazole-5-ylmethyl)-2-((6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0434]

[0328] (R)-6-(6-(3-((dimethylamino)methyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0435]

[0329] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0436]

[0330] (R)-6-(6-(2-cyclopropylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0437]

[0331] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(2-isobutylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0438]

[0332] 6-(6-(azetidine-3-ylamino)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0439]

[0333] (R)-6-(6-(pyrrolidin-3-ylamino)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0440]

[0334] 6-(6-(piperidin-4-ylamino)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0441]

[0335] (R)-6-(6-(3-cyclopropylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0442]

[0336] N-(2-methyl-2H-indazole-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0443]

[0337] (R)-N-(2-(3-(dimethylamino)azetidine-1-yl)-2-oxoethyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0444]

[0338] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-methoxyethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0445]

[0339] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0446]

[0340] (R)-N-(azetidine-3-yl)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0447]

[0341] N-(2-(dimethylamino)ethyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0448]

[0342] N-(3-(dimethylamino)propyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0449]

[0343] (R)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0450]

[0344] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(1-methylazetidine-3-yl)acetamide,

[0451]

[0345] (R)-N-(azetidine-3-ylmethyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0452]

[0346] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0453]

[0347] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-8-fluoro-6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0454]

[0348] (R)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-6-(6-(3-(methylamino)pyrrolidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0455]

[0349] (R)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-(3-(methylamino)pyrrolidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0456]

[0350] (S)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-(3-isopropylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0457]

[0351] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0458]

[0352] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0459]

[0353] (S)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-6-(6-(3-isopropylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0460]

[0354] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3S)-3-(1-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0461]

[0355] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0462]

[0356] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0463]

[0357] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0464]

[0358] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(hydroxymethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0465]

[0359] (R)-N-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycine,

[0466]

[0360] N-(2-aminoethyl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(piperidin-1-yl)pyrazin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0467]

[0361] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0468]

[0362] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(hexahydro-2H,6H-pyrazino[1,2-c][1,3]oxazine-2-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0469]

[0363] 2-(4-(6-(2-(N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetic acid,

[0470]

[0364] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-8-fluoro-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0471]

[0365] (R)-N-(3-ethyl-1,5-dimethyl-1H-pyrazol-4-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0472]

[0366] (R)-6-(6-(3-(aminomethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0473]

[0367] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(3-isopropyl-1,5-dimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0474]

[0368] (R)-N-(1,5-dimethyl-3-propyl-1H-pyrazol-4-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0475]

[0369] 6-(6-((3R,4S)-4-amino-3-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0476]

[0370] (R)-6-(6-(ethyl(pyrrolidin-3-yl)amino)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0477]

[0371] (R)-6-(6-(3-(ethylamino)pyrrolidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0478]

[0372] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2-hydroxyethyl)(pyrrolidin-3-yl)amino)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0479]

[0373] (R)-6-(6-(3-(aminomethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0480]

[0374] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-morpholino-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0481]

[0375] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(pyridine-4-yl)acetamide,

[0482]

[0376] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0483]

[0377] N-(2-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-2-oxoethyl)-6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0484]

[0378] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0485]

[0379] Methyl (R)-N-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycinate,

[0486]

[0380] (R)-N-(2-(dimethylamino)ethyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0487]

[0381] (R)-N-(3-(dimethylamino)propyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0488]

[0382] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(4-(piperazine-1-yl)pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0489]

[0383] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(4-(piperazine-1-yl)pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0490]

[0384] 6-(4-(piperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0491]

[0385] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(4-(piperazine-1-yl)thieno[3,2-d]pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0492]

[0386] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(4-(piperazine-1-yl)thieno[3,2-d]pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0493]

[0387] 6-(4-(piperazine-1-yl)thieno[3,2-d]pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0494]

[0388] 6-(5-chloro-4-(piperazine-1-yl)pyrimidine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0495]

[0389] 6-(5-chloro-4-(piperazine-1-yl)pyrimidine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0496]

[0390] 6-(5-chloro-4-(piperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0497]

[0391] 6-(6-((3R,4S)-3-amino-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0498]

[0392] 6-(6-((3S,4R)-3-amino-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0499]

[0393] 6-(6-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0500]

[0394] 6-(6-((3S,4S)-3-amino-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0501]

[0395] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(2-methylpiperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0502]

[0396] (S)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0503]

[0397] (S)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0504]

[0398] (S)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0505]

[0399] (R)-N-(1,3-dihydroxypropane-2-yl)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0506]

[0400] N-(1-chloro-3-hydroxypropane-2-yl)-2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0507]

[0401] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(3-hydroxypropyl)acetamide,

[0508]

[0402] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0509]

[0403] (S)-6-(5-(2-ethylpiperazine-1-yl)pyridine-3-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0510]

[0404] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(5-(piperazine-1-yl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0511]

[0405] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(2-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0512]

[0406] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(2-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0513]

[0407] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0514]

[0408] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0515]

[0409] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(2-hydroxyethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0516]

[0410] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(2-hydroxyethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0517]

[0411] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(2-hydroxyethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0518]

[0412] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(2-hydroxyethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0519]

[0413] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0520]

[0414] 6-(6-((3R,4R)-3-(dimethylamino)-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0521]

[0415] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(2-hydroxyethyl)acetamide,

[0522]

[0416] N-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-L-proline,

[0523]

[0417] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0524]

[0418] Methyl (R)-5-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-2,2-dimethylpentanoate,

[0525]

[0419] N-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-D-proline,

[0526]

[0420] N-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-L-serine,

[0527]

[0421] (R)-5-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-2,2-dimethylpentanoic acid,

[0528]

[0422] (R)-6-(5-(3-ethylpiperazine-1-yl)pyridine-3-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0529]

[0423] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0530]

[0424] (R)-2-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-7,8-dihydro-1,6-naphthiridine-6(5H)-sulfonamide,

[0531]

[0425] N-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-D-serine,

[0532]

[0426] N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-((3R,4R)-4-hydroxy-3-(methylamino)piperidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0533]

[0427] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-methylpiperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0534]

[0428] N-(2,3-dihydroxypropyl)-2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0535]

[0429] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-yl)pyrazine-2-yl)3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0536]

[0430] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(1-methylpiperidine-4-yl)acetamide,

[0537]

[0431] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-(2-hydroxyethyl)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0538]

[0432] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2S,4R)-2-(hydroxymethyl)-4-(methylamino)pyrrolidin-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0539]

[0433] (R)-6-(6-(3-ethylpiperazine-1-yl)pyridazine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0540]

[0434] (R)-6-(5-(3-ethylpiperazine-1-yl)pyridazine-3-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0541]

[0435] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0542]

[0436] (R)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0543]

[0437] Ethyl 2-((2S,6R)-6-ethyl-4-(6-(2-(N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetate,

[0544]

[0438] 2-((2S,6R)-6-ethyl-4-(6-(2-(N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetic acid,

[0545]

[0439] (R)-2-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-sulfonamide,

[0546]

[0440] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydro-2,7-naphthiridine-2(1H)-sulfonamide,

[0547]

[0441] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-(2-hydroxyethyl)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0548]

[0442] (S)-N-(3-(dimethylamino)propyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0549]

[0443] (S)-N-(3-(dimethylamino)propyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0550]

[0444] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(piperidin-4-yl)pyrazin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0551]

[0445] N-(2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-6-(6-(piperidin-4-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0552]

[0446] (R)-2-(2-((6-(6-(R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamido)-3-hydroxypropanamide,

[0553]

[0447] (R)-N-(2-(dimethylamino)ethyl)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0554]

[0448] (R)-N-(2-([1,4'-bipiperidin]-1'-yl)-2-oxoethyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0555]

[0449] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(2-(piperidine-1-yl)ethyl)acetamide,

[0556]

[0450] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2S,5S)-5-(hydroxymethyl)-2-methylpiperazine-1-yl)pyrazine-2-yl)3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0557]

[0451] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2R,5S)-5-(hydroxymethyl)-2-methylpiperazine-1-i)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0558]

[0452] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-(2-hydroxyethyl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0559]

[0453] N-(3-(dimethylamino)propyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0560]

[0454] 6-(6-((3R,5R)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0561]

[0455] (S)-2-((N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0562]

[0456] 2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-i)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0563]

[0457] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(methylamino)piperidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0564]

[0458] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(methylamino)piperidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0565]

[0459] 6-(6-((R)-3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-((S)-3-(methylamino)pyrrolidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0566]

[0460] 6-(6-((R)-3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-((R)-3-(methylamino)pyrrolidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0567]

[0461] N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-2-oxoethyl)-6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0568]

[0462] 2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-((R)-1-methylpyrrolidine-3-yl)acetamide,

[0569]

[0463] 2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-((S)-1-methylpyrrolidine-3-yl)acetamide,

[0570]

[0464] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2S,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-yl)pyrazine-2-yl)3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0571]

[0465] (S)-2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0572]

[0466] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0573]

[0467] (R)-N-(2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0574]

[0468] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3R,5S)-3-methyl-5-(methylamino)piperidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0575]

[0469] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3S,5R)-3-methyl-5-(methylamino)piperidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0576]

[0470] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3S,5S)-3-methyl-5-(methylamino)piperidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0577]

[0471] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3R,5R)-3-methyl-5-(methylamino)piperidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0578]

[0472] 2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(2-oxopyrrolidine-3-yl)acetamide,

[0579]

[0473] 2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(2-oxotetrahydrofuran-3-yl)acetamide,

[0580]

[0474] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-morpholinopiperidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0581]

[0475] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(octahydro-2H-pyrido[1,2-a]pyrazine-2-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0582]

[0476] (R)-N-(2-(4-(dimethylamino)piperidin-1-yl)-2-oxoethyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0583]

[0477] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-8-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0584]

[0478] (R)-3-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)propanamide,

[0585]

[0479] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(3-morphopropyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0586]

[0480] (R)-4-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)butanoic acid,

[0587]

[0481] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0588]

[0482] 6-(6-((3S,4S)-3-(dimethylamino)-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0589]

[0483] (R)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-oxo-2-(3-(piperazine-1-yl)azetidine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0590]

[0484] (R)-2-((6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(isoindoline-5-yl)acetamide,

[0591]

[0485] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(4-(4-methylpiperazine-1-yl)phenyl)acetamide,

[0592]

[0486] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(4-(4-morpholinopiperidine-1-yl)phenyl)acetamide,

[0593]

[0487] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(3-(4-methylpiperazine-1-yl)benzyl)acetamide,

[0594]

[0488] (R)-N-(2-(4-(azetidine-3-yl)piperazine-1-yl)-2-oxoethyl)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0595]

[0489] 2-((2S,6R)-6-ethyl-4-(6-(2-(N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetamide,

[0596]

[0490] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(((R)-1-methylpyrrolidine-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0597]

[0491] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(((S)-1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0598]

[0492] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(2-oxomidazolidine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0599]

[0493] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-methyl-2-oxomidazolidine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0600]

[0494] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0601]

[0495] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(4-methylpiperazine-1-yl)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0602]

[0496] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-(1-methylazetidin-3-yl)piperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0603]

[0497] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-((3R,4S)-3-(hydroxymethyl)-4-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0604]

[0498] N-(2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-6-(2-((3R,4S)-3-(hydroxymethyl)-4-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0605]

[0499] (3S,4R)-1-(6-(2-(N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)-N,N-dimethyl-4-(methylamino)pyrrolidine-3-carboxamide,

[0606]

[0500] N-(3-(dimethylamino)propyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0607]

[0501] 6-(6-((3S,5R)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0608]

[0502] 6-(6-((3S,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0609]

[0503] N-(2-(3-(dimethylamino)azetidine-1-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0610]

[0504] (S)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-(3-(hydroxymethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0611]

[0505] (S)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-(3-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0612]

[0506] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0613]

[0507] N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0614]

[0508] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(4-hydroxypiperidine-1-yl)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0615]

[0509] 2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(1-(2-hydroxyethyl)piperidine-3-yl)acetamide,

[0616]

[0510] 6-(6-((R)-3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(((R)-pyrrolidine-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0617]

[0511] 6-(6-((R)-3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(((S)-pyrrolidin-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0618]

[0512] (R)-N-(azetidine-3-ylmethyl)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0619]

[0513] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-methylpiperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0620]

[0514] N-(2-([1,4'-bipiperidin]-1'-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0621]

[0515] N-(2-(dimethylamino)ethyl)-2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0622]

[0516] N-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycine,

[0623]

[0517] (S)-2-((N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-(3-(hydroxymethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0624]

[0518] (S)-2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0625]

[0519] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0626]

[0520] N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-((S)-3-(hydroxymethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-((S)-3-(methylamino)pyrrolidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0627]

[0521] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((S)-3-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-((S)-3-(methylamino)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0628]

[0522] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-((S)-3-(methylamino)pyrrolidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0629]

[0523] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-((S)-3-(hydroxymethyl)-4-methylpiperazine-1-yl)piperidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0630]

[0524] N-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-D-serine,

[0631]

[0525] N-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-L-serine,

[0632]

[0526] (R)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-oxo-2-(4-(piperidin-4-yl)piperazine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0633]

[0527] N-(2,3-dihydroxypropyl)-2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0634]

[0528] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-(1-methylazetidin-3-yl)piperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0635]

[0529] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0636]

[0530] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(4-methylpiperazine-1-yl)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0637]

[0531] N-(1,3-dihydroxypropane-2-yl)-2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0638]

[0532] 6-(6-((3R,4R)-3-(dimethylamino)-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0639]

[0533] (R)-2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0640]

[0534] 2-((6-(2-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0641]

[0535] (R)-2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0642]

[0536] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0643]

[0537] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0644]

[0538] N-(1,3-dihydroxy-2-(hydroxymethyl)propane-2-yl)-2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0645]

[0539] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0646]

[0540] (R)-2-((6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0647]

[0541] N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0648]

[0542] 2-((6-(2-((3R,4R)-3-(dimethylamino)-4-hydroxypiperidin-1-yl)pyridin-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0649]

[0543] 2-((N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide,

[0650]

[0544] N-(2-(3-(dimethylamino)azetidine-1-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0651]

[0545] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-N-(2-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0652]

[0546] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0653]

[0547] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-morpholinozetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0654]

[0548] N-(2-(3-(4-acetylpiperazine-1-yl)azetidine-1-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0655]

[0549] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-oxo-2-(3-(3-oxopiperazine-1-yl)azetidine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0656]

[0550] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(4-(methylsulfonyl)piperazine-1-yl)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0657]

[0551] N-(2-(4-(4-acetylpiperazine-1-yl)piperidin-1-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0658]

[0552] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-morpholinopiperidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0659]

[0553] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-oxo-2-(4-(3-oxopiperazine-1-yl)piperidine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide,

[0660]

[0554] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(2-morpholinoethyl)acetamide,

[0661]

[0555] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-8-fluoro-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, and

[0662]

[0556] N-(2-(3-(dimethylamino)azetidine-1-yl)-2-oxoethyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide.

[0663] In defining compounds of Formula 1 throughout this specification, the following definitions apply unless otherwise stated.

[0664] As used herein, the term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon, C 1-10　 Alkyl is preferred. For example, the alkyl includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0665] The term “alkenyl” as used in this specification refers to a straight-chain or branched-chain unsaturated hydrocarbon having at least one carbon-carbon double bond, preferably comprising 1 to 10 carbon atoms, but not limited thereto.

[0666] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated single or fused cyclic hydrocarbon, C 3-10 It refers to monocyclic, bicyclic, or tricyclic functional groups. Examples of monocyclic functional groups among cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexinyl, etc. Bicyclic functional groups among cycloalkyls include bicycloalkyl and spiro functional groups, and specific examples include bicyclo[1.1.1]fentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, etc.

[0667] As used herein, the terms “hydroxy” or “hydroxy” are defined as -OH, and the term “alkoxy” means an alkyloxy, which is a radical in which a hydrogen atom of the hydroxyl group is substituted with 1 to 10 alkyls, unless otherwise defined.

[0668] As used herein, the terms "halogen" or "halo" mean fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0669] The terms “haloalkyl” and “haloalkoxy” as used in this specification mean an alkyl or alkoxy substituted with one or more halogen atoms.

[0670] As used in this specification, the term "heteroatom" means N, O, or S.

[0671] As used in this specification, the term “oxo” means =O.

[0672] As used herein, the term "aryl" means aromatic hydrocarbon and includes polycyclic aromatic ring systems in which a carbocyclic aromatic ring or a heteroaryl ring is fused with one or more other rings. Preferably, C 5-12 aryl, more preferably C 5-10 It is an aryl. For example, the aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, etc. Additionally, it includes a group in which a heteroaryl ring is fused to a cycloalkyl or non-aromatic heterocyclic ring, for example, indanyl or tetrahydrobenzopyranyl, etc.

[0673] As used herein, the terms “heteroaryl” or “aromatic heterocycle” refer to an aromatic hydrocarbon comprising one to three heteroatoms selected from N, O, and S as a reducer. The heteroaryl group may be a single or fused ring (bicyclic). The heteroaryl group may include 3 to 20, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 4 to 9, 4 to 8, 4 to 7, or 4 to 6 ring atoms. For example, the above heteroaryls include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, furanyl, benzofuranyl, thiophenyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, etc.

[0674] In addition, heteroaryls include groups in which a heteroaryl ring is fused to a cycloalkyl or non-aromatic heterocyclic ring, e.g., dihydrocyclopentapyrazinyl.

[0675] Arylalkyl, alkylaryl, and heteroarylalkyl refer to groups formed by combining an aryl and an alkyl or a heteroaryl and an alkyl as defined above, and include, for example, benzyl, phenethyl, thiopheneethyl, pyrimidinemethyl, but are not limited thereto.

[0676] As used herein, the terms “heterocyclile” or “heterocycloalkyl” refer to saturated or partially unsaturated cyclic hydrocarbons comprising one to three heteroatoms selected from N, O, and S as reducers. The heterocyclile ring group may be monocyclic, bicyclic, or tricyclic. The bicyclic heterocyclile may be a spiro, bridged, and fused ring group. The heterocyclile group may comprise 3 to 20, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 4 to 9, 4 to 8, 4 to 7, or 4 to 6 ring atoms.

[0677] Non-limiting examples of monocyclic heterocyclils include aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, dihydrooxadiazolyl, tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isooxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, oxathiolanil, dithiolanil, thiomopolinyl, azephanil, diazephanil, oxazephanil, thiazephanil, piperidinyl, tetrahydropyranyl, thianil, piperazinyl, mopolino, and dioxanyl.

[0678] Since the compound represented by Formula 1 according to the present invention can be prepared and used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt to enhance in vivo absorption or increase solubility, the above prodrug, hydrate, solvate, and pharmaceutically acceptable salt also fall within the scope of the present invention. Furthermore, the compound represented by Formula 1 has a chiral carbon, so stereoisomers exist, and such stereoisomers are also included within the scope of the present invention.

[0679] As used herein, the term "prodrug" refers to a substance that is modified into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be able to achieve bioavailability by oral administration, whereas the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. For example, the prodrug may be an in vivo hydrolyzable ester of a compound according to the present invention and a pharmaceutically acceptable salt thereof. Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group that is converted by metabolism to expose an active site.

[0680] The term “hydrate” as used in this specification means a compound of the present invention or a salt thereof containing stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

[0681] As used herein, the term "solvate" means a compound of the present invention or a salt thereof comprising stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. Preferred solvents thereof include volatile, non-toxic, and / or solvents suitable for administration to humans.

[0682] As used herein, the term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but differs structurally or stereochemically. Such isomers include structural isomers such as tautomers, and stereoisomers such as R or S isomers having an asymmetric carbon center, geometric isomers (trans, cis), and diastereomers. All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0683] If the compound of Formula 1 has an optical isomer, a stereoisomer, a regioisomer, or a rotamer, these are also included in the compound of Formula 1 and can be obtained as a single product according to synthesis and separation methods known in themselves. For example, if the compound of Formula 1 contains an optical isomer, the optical isomer separated from this compound is also included in the compound of Formula 1. The optical isomer can be prepared according to methods known in themselves.

[0684] The term “pharmaceuticalally acceptable salt” as used in this specification refers to a form of salt of a compound that does not cause severe irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutical salt includes acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromide, hydroiodide, etc.; organic carboxylic acids like tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; and sulfonic acids like methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, etc., and organic salts such as dicyclohexylamine, N-methyl-D-glucarmine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine, etc. The compound of Formula 1 according to the present invention can be converted into its salt by conventional methods.

[0685] The present invention also provides a method for preparing the compound of Formula 1. The synthesis methods of Examples 1 to 556 have been exemplified as methods for preparing the compound of Formula 1 according to the present invention, but the synthesis methods of Examples 1 to 556 do not limit the method for preparing the compound of Formula 1 according to the present invention. The synthesis methods of Examples 1 to 556 are merely examples, and it is obvious that they can be easily modified by a person skilled in the art depending on specific substituents.

[0686] The present invention also provides a pharmaceutical composition for the prevention or treatment of NMT inhibition-related diseases, comprising as an active ingredient a sulfonamide derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0687] The present invention also provides a method for preventing or treating NMT inhibition-related diseases, comprising administering a therapeutically effective amount of a sulfonamide derivative compound represented by Formula 1, its hydrate, its solvate, or its pharmaceutically acceptable salt to an individual in need thereof.

[0688] The present invention also provides for the use of a sulfonamide derivative compound represented by Formula 1, its hydrate, its solvate, or its pharmaceutically acceptable salt as an active ingredient in the manufacture of a medicine for the prevention or treatment of NMT inhibition-related diseases.

[0689] NMT inhibitory activity (IC) for the sulfonamide derivative compounds of the present invention 50 As a result of measuring ), it was confirmed that it not only exhibits excellent inhibitory activity against NMT but also exhibits excellent cytotoxicity in various cancer cell lines, revealing that it can be used for the prevention and treatment of NMT inhibition-related diseases.

[0690] In one embodiment, the NMT inhibition-related disease may be any one selected from the group consisting of myeloma, leukemia, lymphoma, blastoma, solid tumor, protozoal infection, and viral infection.

[0691] In one embodiment, the NMT inhibition-related disease is a myeloma that is multiple myeloma; one or more leukemias selected from the group consisting of chronic lymphocytic leukemia, myeloid leukemia, and acute lymphoblastic leukemia; one or more lymphomas selected from the group consisting of follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and Burkitt lymphoma; one or more blastomas selected from the group consisting of neuroblastoma, retinoblastoma, and glioblastoma; one or more solid tumors selected from the group consisting of brain cancer, lung cancer, breast cancer, prostate cancer, ovarian cancer, colon cancer, rectal cancer, gallbladder cancer, kidney cancer, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, and liver cancer; one or more protozoal infections selected from the group consisting of malaria, candidiasis, and leishmaniasis; It may be one or more selected from the group consisting of one or more viral infections selected from the group consisting of rhinovirus and HIV.

[0692] The present invention also provides a pharmaceutical composition or formulation comprising a sulfonamide derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0693] The above additive may include pharmaceutically acceptable carriers such as commonly used excipients, disintegrants, sweeteners, lubricants, or flavorings, and may be formulated according to conventional methods into oral preparations such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or into parenteral preparations such as topical liquids, topical suspensions, topical emulsions, gels (ointments, etc.), inhalants, sprays, or injections. The above preparations may be formulated in various forms, for example, as single-dose or multi-dose administration forms. In the case of oral tablets, carriers such as lactose or corn starch and lubricants such as magnesium stearate may typically be added. In the case of oral capsules, lactose and / or dried corn starch may be used as diluents. If an oral aqueous suspension is required, the active ingredient may be combined with an emulsifier and / or suspending agent. If necessary, specific sweeteners and / or flavorings may be added. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, a sterile solution of the active ingredient is typically prepared, and the pH of the solution must be appropriately adjusted and buffered. For intravenous administration, the total concentration of the solute must be adjusted to impart isotonicity to the formulation. The composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline solution with a pH of 7.4.

[0694] The individual to which the pharmaceutical composition of the present invention is administered may be, for example, a human, monkey, cow, horse, sheep, pig, chicken, turkey, cat, dog, mouse, rat, rabbit, or guinea pig, for example, a mammal, for example, a human, but is not limited thereto.

[0695] In addition, the pharmaceutical composition of the present invention may be administered orally or parenterally. In the case of parenteral administration, it may be administered via routes such as skin, transdermal, ocular, abdominal cavity, rectum or vein, muscle, subcutaneous, intrauterine dura mater, intracerebroventricular injection, or local administration. Ocular local administration includes, for example, direct administration into the eye, or administration around the eye, behind the eye, subretinal, central retinal, outside the fovea, subconjunctival, intravitreous, intracameral, or suprachoroidal. The pharmaceutical composition may also be administered through an insertion device.

[0696] The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and body weight, the severity of the disease, the form of the active ingredient, the route of administration, and the duration, and can be appropriately adjusted according to the patient. For example, the active ingredient may be administered at a dose of 0.0001 to 1000 mg / kg per day, preferably 0.001 to 100 mg / kg, and the administration may be divided into one dose or several doses per day. In addition, the pharmaceutical composition of the present invention may contain the active ingredient at a weight percentage of 0.001 to 90% relative to the total weight of the composition.

[0697]

[0698] The present invention will be explained in more detail below through manufacturing examples, examples, and experimental examples. However, the following manufacturing examples, examples, and experimental examples are intended to illustrate the present invention and do not limit the scope of the present invention.

[0699]

[0700] Preparation Example 1. 5-Bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0701] Step 1: 5-Bromo-3,4-Dihydroisoquinoline-2(1H)-sulfonyl chloride

[0702] 5-Bromo-1,2,3,4-tetrahydroisoquinoline (213 mg, 1.0 mmol) was dissolved in DCM, and the temperature was lowered to 0 °C. Then, triethylamine (280 μL, 2.0 mmol) was added, and sulfuryl chloride (2 mL, 1.0 eq, 1 M in DCM) was slowly added. The mixture was stirred at 0 °C for 4 hours, and DCM (100 mL) was added to the reaction mixture for extraction. The organic layer was washed with water (50 mL x 2) and dried with anhydrous MgSO4. After filtration, the solution was concentrated under reduced pressure to obtain the target compound, 5-bromo-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride (310 mg, crude). The compound was used in the following reaction without further purification.

[0703] Step 2: 5-Bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0704] The 5-bromo-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride (115 mg, 0.37 mmol) obtained in Step 1 was dissolved in anhydrous THF (4 mL), followed by the addition of diisopropylethylamine (0.26 mL, 1.48 mmol). 1,3,5-trimethylpyrazole-4-amine (47 mg, 0.37 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate (50 mL). The organic layer was washed with water (25 mL x 2) and dried with anhydrous MgSO4. The residue obtained by vacuum concentration was purified by MPLC to obtain the target compound 5-bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (83 mg, 56%).

[0705]

[0706] Preparation Example 2. 6-Bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0707] Step 1: 2-((1H-imidazole-1-yl)sulfonyl)-6-bromo-1,2,3,4-tetrahydroisoquinoline

[0708] 6-bromo-1,2,3,4-tetrahydroisoquinoline (7.02 g, 33.12 mmol) was completely dissolved in acetonitrile (138 mL), and 1-imidazole-1-ylsulfonyl-3-methyl-imidazole-1-ium trifluoromethanesulfonate (10 g, 27.60 mmol) was added. The mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure. After adding water to the reaction mixture, it was extracted with ethyl acetate and washed with salt water. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the target compound 2-((1H-imidazole-1-yl)sulfonyl)-6-bromo-1,2,3,4-tetrahydroisoquinoline (4.50 g, 48%).

[0709] Step 2: 1-((6-bromo-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-3-methyl-1H-imidazole-3-um trifluoromethanesulfonate

[0710] The 2-((1H-imidazole-1-yl)sulfonyl)-6-bromo-1,2,3,4-tetrahydroisoquinoline (13.7 g, 40.0 mmol) obtained in Step 1 was dissolved in DCM (200 mL), and the temperature was lowered to 0°C. Methyl trifluoromethanesulfonate (4.5 mL, 40.0 mmol) was slowly added. After stirring at 0°C for 1 hour, the temperature was raised to room temperature and stirred for an additional 2 hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether was added to the solid produced at this time, and after ultrasonic grinding, the mixture was filtered to obtain the target compound 1-((6-bromo-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-3-methyl-1H-imidazole-3-um trifluoromethanesulfonate (16.3 g, 80%).

[0711] Step 3: 6-Bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0712] 1,3,5-trimethylpyrazole-4-amine (2.0 g, 16.0 mmol) and 1-((6-bromo-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (8.1 g, 16.0 mmol) obtained in Step 2 were dissolved in acetonitrile (80 mL) and stirred at 90 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added. It was extracted with ethyl acetate and washed with salt water. The residue obtained by drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure was purified by MPLC to obtain the target compound 6-bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (6.4 g, 100%).

[0713]

[0714] Preparation Example 3. 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0715] 6-bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (400 mg, 10 mmol), bis(pinacollato)diborone (305 mg, 1.2 mmol), PdCl2(dppf).DCM (41 mg, 0.05 mmol), and potassium acetate (295 mg, 3.0 mmol) obtained in Preparation Example 2 were placed in a reaction vessel, and 1,4-dioxane (10 mL) was added. The reaction mixture was degassed using nitrogen for 5 minutes, the temperature was raised to 100 °C, and the mixture was stirred for 18 hours. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate. Diethyl ether was added to the residue obtained under reduced pressure concentration, and the resulting precipitate was removed by filtering through a Celite pad. The target compound 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (408 mg, quant.) was obtained by washing with diethyl ether and concentrating under reduced pressure. The compound was used in the following reaction without further purification.

[0716]

[0717] Preparation Example 4. 7-Bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0718] Step 1: 2-oxo-N-(1,3,5-trimethylpyrazole-4-yl)oxazolidine-3-sulfonamide

[0719] Chlorosulfonyl isocyanite (0.96 mL, 11 mmol) was added to DCM (35 mL) at 0 °C. Subsequently, 2-chloroethanol (0.74 mL, 11 mmol) was slowly added, and the mixture was stirred at 0 °C for 45 minutes. Next, diisopropylethylamine (5.3 mL, 30 mmol) was added, followed by the slow addition of 1,3,5-trimethylpyrazole-4-amine (1.25 g, 10 mmol) dissolved in DCM (15 mL). The reaction mixture was stirred at 0 °C for 1 hour, followed by stirring at room temperature for 24 hours. The reaction mixture was extracted by adding dichloromethane (50 mL), and the organic layer was washed with water (50 mL x 2). The organic layer was then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Diethyl ether was added to solidify the mixture, followed by filtration. The target compound 2-oxo-N-(1,3,5-trimethylpyrazole-4-yl)oxazolidine-3-sulfonamide (1.1 g, 40%) was obtained by washing with diethyl ether and drying under reduced pressure.

[0720] Step 2: 7-Bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0721] The 2-oxo-N-(1,3,5-trimethylpyrazole-4-yl)oxazolidin-3-sulfonamide (412 mg, 1.5 mmol) and 7-bromo-1,2,3,4-tetrahydroisoquinoline (318 mg, 1.5 mmol) obtained in Step 1 were dissolved in MeCN (10 mL), and then diisopropylethylamine (1.3 mL, 7.5 mmol) was added. The temperature was raised to 90 °C and stirred for 24 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by MPLC (0% MeOH in DCM to 10% MeOH in DCM) to obtain the target compound 7-bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (120 mg, 20%).

[0722]

[0723] Preparation Example 5. 8-Bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0724] The target compound (0.38 g, 47%) was obtained by applying the method of Preparation Example 2 using 8-bromo-1,2,3,4-tetrahydroisoquinoline (0.53 g, 2.48 mmol) and 1-imidazole-1-ilsulfonyl-3-methyl-imidazole-1-um trifluoromethanesulfonate (0.75 g, 2.07 mmol).

[0725]

[0726] Preparation Example 6. 6-Bromo-N-(3-isobutyl-1,5-dimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0727] Step 1: 1,5-dimethyl-3-(2-methylprop-1-enyl)pyrazol

[0728] THF (135 mL) was added to isopropyltriphenylphosphonium iodide (21.8 g, 50.35 mmol) and the temperature was lowered to -20 °C. Then, 1.6 M n-butyllithium (32 mL, 50 mmol) was slowly added dropwise and stirred at -20 °C for 1 hour. Next, dimethylpyrazole-3-carbaldehyde (5.0 g, 50 mmol) dissolved in THF (225 mL) was slowly added. The temperature of the reaction mixture was slowly raised to room temperature and stirred for 18 hours. The reaction was terminated by adding saturated NH4Cl (200 mL) to the reaction mixture, and extraction was performed by adding ethyl acetate (200 mL x 3). The organic layer was washed with water and dried with anhydrous magnesium sulfate. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by MPLC (0% EA in hex to 60% EA in Hex) to obtain the target compound (2.5 g, 41%).

[0729] Step 2: 3-Isobutyl-1,5-Dimethyl-Pyrazole

[0730] 1,5-dimethyl-3-(2-methylprop-1-enyl)pyrazole (5.86 g, 39 mmol) obtained in Step 1 was dissolved in MeOH (180 mL), and 10% Pd / C (1.8 g) was added. The reaction mixture was stirred for 8 hours under a hydrogen balloon at room temperature. After filtering using a Celite pad, it was washed with methanol. Diethyl ether was added to the residue obtained under reduced pressure concentration, and the mixture was filtered using a Celite pad. The filtrate was concentrated under reduced pressure to obtain the target compound (5.0 g, 84%).

[0731] Step 3: 3-Isobutyl-1,5-dimethyl-4-nitro-pyrazol

[0732] The temperature was lowered to 0 ℃, and sulfuric acid (13.6 mL, 250 mmol) was slowly added to the 3-isobutyl-1,5-dimethyl-pyrazole (3.82 g, 25 mmol) obtained in Step 2. Subsequently, nitric acid (10.5 mL, 250 mmol) was slowly added. The temperature was raised to 100 ℃ and stirred for 3 hours. The reaction was terminated by adding ice, and the aqueous layer was basicized by adding an aqueous sodium hydroxide solution. Extraction was performed by adding ethyl acetate (150 mL x 3), and the organic layer was washed with water. The target compound (3.8 g, 77%) was obtained by drying with anhydrous magnesium sulfate, filtering, and applying reduced pressure.

[0733] Step 4: 3-Isobutyl-1,5-dimethyl-pyrazol-4-amine

[0734] The target compound (2.9 g, 91%) was obtained using the method of Step 2 of Preparation Example 6 with the 3-isobutyl-1,5-dimethyl-pyrazole-4-amine (3.75 g, 19 mmol) obtained in Step 3.

[0735] Step 5: 6-Bromo-3,4-Dihydro-1H-isoquinoline-2-sulfonyl chloride

[0736] 6-Bromo-1,2,3,4-tetrahydroisoquinoline (213 mg, 1.0 mmol) was dissolved in DCM (8 mL), and triethylamine (0.28 mL, 2 mmol) was added. The temperature was lowered to -40 °C, and SO2Cl2 dissolved in dichloromethane (2 mL, 2 mmol, 1 M in DCM) was slowly added. The reaction mixture was stirred for 4 hours between -60 °C and -40 °C. DCM (50 mL) was added, and the mixture was washed with water (25 mL x 2). The target compound (220 mg, crude) was obtained by drying with anhydrous magnesium sulfate, filtering, and applying reduced pressure. The compound was used in the following reaction without further purification.

[0737] Step 6: 6-Bromo-N-(3-isobutyl-1,5-dimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0738] 6-bromo-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride (217 mg, 0.7 mmol) obtained in Step 5 was dissolved in THF (4 mL), and DIPEA (0.37 mL, 2.1 mmol) was added. Subsequently, 3-isobutyl-1,5-dimethyl-pyrazole-4-amine (117 mg, 0.7 mmol) obtained in Step 4 was dissolved in THF (2 mL) and slowly added, and the mixture was stirred at room temperature for 15 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by MPLC (100% Hex to 100% EtOAc) to obtain the target compound (130 mg, 42%).

[0739]

[0740] Preparation Example 7. 4-((6-bromo-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N,N,1,5-tetramethyl-1H-pyrazol-3-carboxamide

[0741] Step 1: 1,5-dimethyl-1H-pyrazole-3-carboxylic acid

[0742] Ethyl 1,5-dimethylpyrazole-3-carboxylate (2.52 g, 15 mmol) was dissolved in MeOH (50 mL), and a solution of LiOH monohydrate (3.15 g, 75 mmol) dissolved in water (25 mL) was added. The reaction mixture was stirred at room temperature for 15 hours. After concentration under reduced pressure, water (25 mL) and 1N HCl were added to acidify the mixture to pH 2. The resulting solid was stirred at room temperature for 15 minutes, filtered, and washed with water. The target compound (1.40, 66%) was obtained by drying under reduced pressure.

[0743] Step 2: 1,5-dimethyl-4-nitro-1H-pyrazole-3-carboxylic acid

[0744] The target compound (1.4 g, 75%) was obtained by applying the method of Step 3 of Preparation Example 6 to 1,5-dimethylpyrazole-3-carboxylic acid (1.4 g, 10 mmol).

[0745] Step 3: N,N,1,5-tetramethyl-4-nitro-1H-pyrazol-3-carboxamide

[0746] The 1,5-dimethyl-4-nitro-1H-pyrazole-3-carboxylic acid (277 mg, 1.5 mmol) obtained in Step 2 was dissolved in DMF (8 mL), and DIPEA (1.3 mL, 7.5 mmol) was added. The temperature was lowered to 0°C, and HATU (860 mg, 2.25 mmol) was added and stirred for 15 minutes. Subsequently, dimethylamine hydrochloride (245 mg, 3.0 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and it was washed with water (50 mL x 2). The organic layer was dried with anhydrous magnesium sulfate and filtered. The residue obtained by vacuum concentration was purified by MPLC (100% DCM to 10% MeOH in DCM) to obtain the target compound (160 mg, 50%).

[0747] Step 4: 4-amino-N,N,1,5-tetramethyl-1H-pyrazol-3-carboxamide

[0748] The target compound (110 mg, 85%) was obtained by applying the method of Step 2 of Preparation Example 6 to the N,N,1,5-tetramethyl-4-nitro-1H-pyrazole-3-carboxamide (150 mg, 0.7 mmol) obtained in Step 3.

[0749] Step 5: 4-((6-Bromo-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N,N,1,5-tetramethyl-1H-pyrazol-3-carboxamide

[0750] The target compound (100 mg, 31%) was obtained by applying the method of Step 6 of Preparation Example 6 to 6-bromo-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride (218 mg, 0.8 mmol) obtained in Step 5 of Preparation Example 6 and 4-amino-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide (128 mg, 0.7 mmol) obtained in Step 4.

[0751]

[0752] Preparation Example 8. 4-((6-bromo-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1,5-dimethyl-1H-pyrazol-3-carboxamide

[0753] The target compound (57 mg, 31%) was obtained by sequentially applying the method of Step 3 of Preparation Example 7, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 1,5-dimethyl-4-nitro-1H-pyrazole-3-carboxylic acid (277 mg, 1.5 mmol) and ammonium chloride (160 mg, 3.0 mmol) obtained in Step 2 of Preparation Example 7.

[0754]

[0755] Preparation Example 9. 4-((6-bromo-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N,1,5-trimethyl-1H-pyrazol-3-carboxamide

[0756] The target compound (108 mg, 48%) was obtained by sequentially applying the method of Step 3 of Preparation Example 7, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 1,5-dimethyl-4-nitro-1H-pyrazole-3-carboxylic acid (277 mg, 1.5 mmol) and methylamine hydrochloride (203 mg, 3.0 mmol) obtained in Step 2 of Preparation Example 7.

[0757]

[0758] Preparation Example 10. 6-Bromo-N-(1-methyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0759] Step 1: 1-Methyl-4-Nitro-Pyrazole

[0760] 4-nitro-1H-pyrazole (850 mg, 7.5 mmol) was dissolved in DMF (4 mL), followed by the sequential addition of K2CO3 (1.25 g, 9.0 mmol) and iodomethane (0.56 mL, 9.0 mmol). The reaction mixture was stirred at room temperature for 15 hours. Extraction was performed by adding ethyl acetate EtOAc (50 mL), followed by washing with water (25 mL x 3). The organic layer was dried with anhydrous magnesium sulfate and filtered. The residue obtained by vacuum concentration was purified by MPLC (100% Hexane to 50% EtOAc in Hex) to obtain the target compound (900 mg, 94%).

[0761] Step 2: 1-methylpyrazole-4-amine

[0762] The target compound (680 mg, quant) was obtained by applying the method of Step 2 of Preparation Example 6 to the 1-methyl-4-nitro-pyrazole (890 mg, 7.0 mmol) obtained in Step 1.

[0763] Step 3: 6-Bromo-N-(1-methyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0764] The target compound (148 mg, 79%) was obtained by applying the method of Step 3 of Preparation Example 2 to 1-methylpyrazole-4-amine (50 mg, 1.022 mmol) obtained in Step 2 and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (255 mg, 0.50 mmol) obtained in Step 2 of Preparation Example 2.

[0765]

[0766] Preparation Example 11. 6-Bromo-N-(1-ethyl-3,5-dimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0767] The target compound (86%, Step 3) was obtained by sequentially applying the method of Step 1 of Preparation Example 10, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 3,5-dimethyl-4-nitro-1H-pyrazole (500 mg, 3.54 mmol) and ethyl iodide (0.57 mL, 7.08 mmol).

[0768]

[0769] Preparation Example 12. 6-Bromo-5-fluoro-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0770] 6-bromo-5-fluoro-1,2,3,4-tetrahydroisoquinoline (2.0 g, 8.69 mmol) was prepared by applying the same method as in Preparation Example 2 to obtain the target compound (23%, 3-step yield).

[0771]

[0772] Preparation Example 13. 6-Bromo-8-fluoro-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0773] 6-bromo-8-fluoro-1,2,3,4-tetrahydroisoquinoline (0.50 g, 1.38 mmol) was used to obtain the target compound (51%, 3-step yield) by applying the same method as in Preparation Example 2.

[0774]

[0775] Preparation Example 14. 6-Bromo-N-(5-isobutyl-1,3-dimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0776] Step 1: 4,5-Dibromo-1,3-dimethyl-pyrazole

[0777] 1,3-dimethylpyrazole (961 mg, 10 mmol) was dissolved in acetic acid (25 mL), and NaOAc (2.46 g, 30 mmol) was added all at once. At room temperature, Br2 (1.6 mL, 31 mmol) was slowly added, the temperature was raised to 80 °C, and the mixture was stirred for 24 hours. Extraction was performed by adding ethyl acetate EtOAc (150 mL), followed by washing with water (100 mL x 3). The organic layer was dried with anhydrous magnesium sulfate and filtered. The residue obtained by vacuum concentration was purified by MPLC (100% Hex to 30% EtOAc in Hex) to obtain the target compound (2.3 g, 90%).

[0778] Step 2: 5-Bromo-1,3-dimethyl-4-nitro-pyrazole

[0779] The target compound (828 mg, 94%) was obtained by applying the method of Step 3 of Preparation Example 6 to the 4,5-dibromo-1,3-dimethyl-pyrazole (1.015 g, 4.0 mmol) obtained in Step 1.

[0780] Step 3: 1,3-dimethyl-5-(2-methylprop-1-enyl)-4-nitro-pyrazol

[0781] 5-bromo-1,3-dimethyl-4-nitro-pyrazole (330 mg, 1.5 mmol) obtained in Step 2 was dissolved in 1,4-daeoxane (6 mL), and Na2CO3 (476 mg, 4.5 mmol) and Pd(PPh3)4 (87 mg, 0.075 mmol) dissolved in water (1.5 mL) were added. The reaction mixture was degassed for 10 minutes, and 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (330 mg, 1.8 mmol) was added. The temperature was raised to 100 °C and stirred for 15 hours. The reaction mixture was filtered using a Celite pad and washed with ethyl acetate (200 mL). The organic layer was washed with water (100 mL x 2) and dried with anhydrous magnesium sulfate. The residue obtained by vacuum concentration after filtration was purified by MPLC (100% Hexane to 30% EtOAc in Hex) to obtain the target compound (40 mg, 13%).

[0782] Step 4: 6-Bromo-N-(5-isobutyl-1,3-dimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0783] The target compound (73 mg, 82%) was obtained by sequentially applying the method of Step 2 of Preparation Example 6 and Step 3 of Preparation Example 2 to the 1,3-dimethyl-5-(2-methylprop-1-enyl)-4-nitro-pyrazole (40 mg, 0.20 mmol) obtained in Step 3.

[0784]

[0785] Preparation Example 15. 6-Bromo-N-(5-isopropyl-1,3-dimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0786] The target compound (170 mg, 79%) was obtained by sequentially applying the method of Step 3 of Preparation Example 14, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 5-bromo-1,3-dimethyl-4-nitro-pyrazole (330 mg, 1.5 mmol) and 2-isoprofenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (303 mg, 1.8 mmol) obtained in Step 2 of Preparation Example 14.

[0787]

[0788] Preparation Example 16. 5-Bromo-1,3-dimethyl-1H-pyrazol-4-amine

[0789] 5-bromo-1,3-dimethyl-4-nitro-pyrazole (330 mg, 1.5 mmol) obtained in Step 2 of Preparation Example 14 was dissolved in ethanol (13 mL) and water (2 mL), and NH4Cl (803 mg, 15 mmol) and Fe (418 mg, 7.5 mmol) were added. The temperature was raised to 90 °C and stirred for 3 hours. The mixture was filtered using a Celite pad and washed with ethyl acetate. After concentration under reduced pressure, ethyl acetate (75 mL) was added. The mixture was washed with water (25 mL x 3), and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the target compound (230 mg, 80%) was obtained by concentrating under reduced pressure.

[0790]

[0791] Preparation Example 17. 6-Bromo-N-(1,3-dimethyl-5-(2-methylprop-1-en-1-yl)-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0792] The target compound (57 mg, 32%) was obtained by sequentially applying the method of Step 3 of Preparation Example 16 and Preparation Example 2 to the 1,3-dimethyl-5-(2-methylprop-1-enyl)-4-nitro-pyrazole (147 mg, 0.75 mmol) obtained in Step 3 of Preparation Example 14.

[0793]

[0794] Preparation Example 18. 6-Bromo-N-(1,3-dimethyl-5-(prop-1-en-2-yl)-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0795] The target compound (78 mg, 61%) was obtained by sequentially applying the method of Step 3 of Preparation Example 2 and Preparation Example 16 to 5-isoprofenyl-1,3-dimethyl-4-nitro-pyrazole (100 mg, 0.55 mmol) obtained in the preparation process of Preparation Example 15.

[0796]

[0797] Preparation Example 19. N-(3-acetyl-1,5-dimethyl-1H-pyrazole-4-yl)-6-bromo-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0798] Step 1: N-methoxy-N,1,5-trimethyl-pyrazol-3-carboxamide

[0799] 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (1.4 g, 10 mmol) obtained in Step 1 of Preparation Example 7 was dissolved in DCM (50 mL), and DMF (3 drops) was added. Then, oxalyl chloride (1.7 mL, 20 mmol) was slowly added, and after stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure. CHCl3 (50 mL) was added, and N,O-dimethylhydroxylamine hydrochloride (1.46 g, 15 mmol) was additionally added. The temperature was lowered to 0 °C, and pyridine (3 mL, 37 mmol) was slowly added. After stirring at room temperature for 15 hours, DCM (100 mL) was added. The mixture was washed with water (100 mL x 2) and dried with anhydrous magnesium sulfate. The residue obtained by vacuum concentration after filtration was purified by MPLC (100% DCM to 10% MeOH in DCM) to obtain the target compound (1.59 g, 86%).

[0800] Step 2: 1-(1,5-dimethylpyrazole-3-yl)ethanol

[0801] N-methoxy-N,1,5-trimethyl-pyrazole-3-carboxamide (733 mg, 4.0 mmol) obtained in Step 1 was dissolved in anhydrous THF (40 mL), and the temperature was lowered to -10 °C. Subsequently, 3 M methyl magnesium bromide (6.7 mL, 20 mmol) was slowly added, and the mixture was stirred for 2 hours. The reaction mixture was terminated by slowly adding saturated NH4Cl (50 mL), and the mixture was extracted by adding ethyl acetate (75 mL x 2). The organic layer was washed with water (50 mL) and dried with anhydrous magnesium sulfate. The residue obtained by vacuum concentration after filtration was purified by MPLC (100% Hex to 70% EtOAc in Hex) to obtain the target compound (470 mg, 85%).

[0802] Step 3: 1-(1,5-dimethyl-4-nitro-1H-pyrazole-3-yl)ethane-1-one

[0803] 1-(1,5-dimethylpyrazole-3-yl)ethanol (553 mg, 4.0 mmol) obtained in Step 2 was dissolved in Ac2O (15 mL), and conc. HNO3 (2.7 mL, 40 mmol) was slowly added. The reaction mixture was stirred at 70 °C for 3 hours. Extraction was performed by adding ethyl acetate (150 mL), and the organic layer was washed with water (50 mL x 2). Subsequently, the mixture was dried with anhydrous magnesium sulfate and filtered. The residue obtained by concentration under reduced pressure was purified by MPLC (100% Hex to 100% EtOAc) to obtain the target compound (543 mg, 74%).

[0804] Step 4: 1-(4-amino-1,5-dimethyl-1H-pyrazole-3-yl)ethane-1-one

[0805] The target compound (170 mg, 79%) was obtained by sequentially applying the method of Step 2 of Preparation Example 6 and Step 3 of Preparation Example 2 to the 1-(1,5-dimethyl-4-nitro-1H-pyrazole-3-yl)ethane-1-one (110 mg, 0.6 mmol) obtained in Step 3.

[0806]

[0807] Preparation Example 20. 6-Bromo-N-(1,5-dimethyl-3-pivaloyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0808] N-methoxy-N,1,5-trimethyl-pyrazole-3-carboxamide (550 mg, 3.0 mmol) obtained in Step 1 of Preparation Example 19 and 1.7 M tert-butyllithium (4.5 mL, 7.5 mmol) were sequentially applied to the methods of Steps 2, 3, and 4 of Preparation Example 19 to obtain the target compound (27%, Step 4 yield).

[0809]

[0810] Preparation Example 21. 6-Bromo-N-(1,3-dimethyl-5-phenyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0811] The target compound (39%, 3-step yield) was obtained by sequentially applying the method of Step 3 of Preparation Example 14, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 5-bromo-1,3-dimethyl-4-nitro-pyrazole (220 mg, 1.0 mmol) and benzeneboronic acid (147 mg, 1.2 mmol) obtained in Step 2 of Preparation Example 14.

[0812]

[0813] Preparation Example 22. 6-Bromo-N-(1,3-dimethyl-5-(pyridine-3-yl)-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0814] The target compound (24%, 3-step yield) was obtained by sequentially applying the method of Step 3 of Preparation Example 14, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 5-bromo-1,3-dimethyl-4-nitro-pyrazole (220 mg, 1.0 mmol) and 3-pyridylboronic acid (148 mg, 1.2 mmol) obtained in Step 2 of Preparation Example 14.

[0815]

[0816] Preparation Example 23. 6-Bromo-N-(1,3-dimethyl-5-(pyridine-4-yl)-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0817] The target compound (26%, 3-step yield) was obtained by sequentially applying the method of Step 3 of Preparation Example 14, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 5-bromo-1,3-dimethyl-4-nitro-pyrazole (220 mg, 1.0 mmol) and 4-pyridylboronic acid (148 mg, 1.2 mmol) obtained in Step 2 of Preparation Example 14.

[0818]

[0819] Preparation Example 24. 6-Bromo-N-(1,3-dimethyl-5-(5-methylpyridine-3-yl)-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0820] The target compound (16%, 3-step yield) was obtained by sequentially applying the method of Step 3 of Preparation Example 14, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 5-bromo-1,3-dimethyl-4-nitro-pyrazole (220 mg, 1.0 mmol) and (5-methyl-3-pyridyl)boronic acid (165 mg, 1.2 mmol) obtained in Step 2 of Preparation Example 14.

[0821]

[0822] Preparation Example 25. 4-((6-bromo-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-methoxy-N,1,3-trimethyl-1H-pyrazol-5-carboxamide

[0823] Ethyl 2,5-dimethylpyrazole-3-carboxylate (20.18 g, 120 mmol) was sequentially applied using the method of Step 1 of Preparation Example 7, Step 2 of Preparation Example 7, Step 1 of Preparation Example 19, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to obtain the target compound (43%, 5-step yield).

[0824]

[0825] Preparation Example 26. N-(5-acetyl-1,3-dimethyl-1H-pyrazole-4-yl)-6-bromo-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0826] The target compound (26%, 5-step yield) was obtained by sequentially applying the method of Step 1, Step 2, Step 3 of Preparation Example 19, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 2,5-dimethylpyrazole-3-carboxylic acid (3.5 g, 25 mmol) obtained during the synthesis process of Preparation Example 25.

[0827]

[0828] Preparation Example 27. 6-Bromo-N-(1,3-dimethyl-5-pivaloyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0829] N-methoxy-N,2,5-trimethyl-pyrazole-3-carboxamide (1.01 g, 5.5 mmol) and 1.7 M t-BuLi (8 mL, 13.75 mmol) obtained during the synthesis process of Preparation Example 25 were sequentially applied to Step 2 and Step 3 of Preparation Example 19, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to obtain the target compound (35%, 4-step yield).

[0830]

[0831] Preparation Example 28. 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0832] The target compound (0.45 g, 85%) was obtained by applying the method of Preparation Example 3 to the 8-bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.47 g, 1.22 mmol) obtained in Preparation Example 5.

[0833]

[0834] Preparation Example 29. 6-Bromo-5-fluoro-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0835] The target compound (137 mg, 41%) was obtained by applying the method of Preparation Example 3 to the 6-bromo-5-fluoro-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.30 g, 0.72 mmol) obtained in Preparation Example 12.

[0836]

[0837] Preparation Example 30. 6-Bromo-8-fluoro-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0838] The target compound (150 mg, 67%) was obtained by applying the method of Preparation Example 3 to the 6-bromo-8-fluoro-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.20 g, 0.48 mmol) obtained in Preparation Example 13.

[0839]

[0840] Preparation Example 31. 6-Bromo-N-(3,5-dimethylisooxazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0841] The target compound (185 mg, 95%) was obtained by applying the method of Step 3 of Preparation Example 2 to 3,5-dimethylisooxazole-4-amine (56 mg, 0.5 mmol) and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (255 mg, 0.5 mmol) obtained in Step 2 of Preparation Example 2.

[0842]

[0843] Preparation Example 32. 6-Bromo-N-(1-methyl-1H-pyrazole-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0844] The target compound (62 mg, 32%) was obtained by applying the method of Step 3 of Preparation Example 2 to 1-methylpyrazole-3-amine (50 mg, 1.022 mmol) and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (255 mg, 0.5 mmol) obtained in Step 2 of Preparation Example 2.

[0845]

[0846] Preparation Example 33. 6-Bromo-N-(2,4-dimethylthiazole-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0847] Step 1: tert-butyl N-(2,4-dimethylthiazole-5-yl)carbamate

[0848] 2,4-dimethylthiazole-5-carboxylic acid (1.0 g, 6.36 mmol) was dissolved in tert-BuOH (15 mL), and diphenylazidophosphate (1.85 mL, 8.58 mmol) was added. Then, triethylamine (2.2 mL, 15.9 mmol) was added, the temperature was raised to 85 °C, and the mixture was stirred for 15 hours. The residue obtained by concentration under reduced pressure was purified by MPLC (100% Hex to 60% EtOAc in Hex) to obtain the target compound (1.05 g, 72%).

[0849] Step 2: 2,4-Dimethylthiazole-5-amine hydrochloride

[0850] The tert-butyl N-(2,4-dimethylthiazole-5-yl)carbamate (1.0 g, 4.6 mmol) obtained in Step 1 was dissolved in DCM (45 mL), and then 4 M HCl (5.8 mL, 23 mmol) was added. After stirring at room temperature for 8 hours, the solution was concentrated under reduced pressure to obtain the target compound (1.0 g, crude).

[0851] Step 3: 6-Bromo-N-(2,4-dimethylthiazole-5-yl)-3,4-dihydro-1H-isoquinoline-2-sulfonamide

[0852] 2,4-dimethylthiazole-5-amine hydrochloride (101 mg, 0.5 mmol) obtained in Step 2 was added to MeCN (3 mL), followed by the addition of triethylamine (140 μL, 2.0 mmol). After stirring for 5 minutes, 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (253 mg, 0.5 mmol) obtained in Step 2 of Preparation Example 2 was added, and the mixture was stirred at 90 °C for 15 hours. The residue obtained by concentration under reduced pressure was purified by MPLC (100% Hex to 100% EtOAc) to obtain the target compound (80 mg, 40%).

[0853]

[0854] Preparation Example 34. 6-Bromo-N-(2-methylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0855] Step 1: 2-methyl-3-nitro-pyridine

[0856] Diethylpropanedioneate (1.28 g, 8.0 mmol) was dissolved in NMP (8 mL), and then NaOtBu (847 mg, 8.8 mmol) was slowly added. The reaction mixture was stirred at room temperature for 15 minutes. Then, 2-chloro-3-nitro-pyridine (635 mg, 4.0 mmol) dissolved in NMP (2 mL) was slowly added over 10 minutes. The temperature was raised to 50 °C and stirred for 3 hours. Then, 6 M H2SO4 (8 mL, 48 mmol) was slowly added. The temperature was raised to 100 °C and stirred for 12 hours. The temperature of the reaction mixture was lowered to 0 °C and ethyl acetate (100 mL) was added. Subsequently, the reaction mixture was alkalized with a 50% KOH solution. The resulting solid was removed using a filter with a Celite pad and washed with water. Extracted with ethyl acetate (50 mL x 2) and washed with water (50 mL). After drying with anhydrous magnesium sulfate and filtering, the residue obtained by concentrating under reduced pressure was purified by MPLC (100% Hex to 50% EtOAc in Hex) to obtain the target compound (400 mg, 72%).

[0857] Step 2: 2-Methylpyridine-3-amine

[0858] The target compound (28%, 2-step yield) was obtained by sequentially applying the method of Step 2 of Preparation Example 6 and Step 3 of Preparation Example 2 to the 2-methyl-3-nitro-pyridine (400 mg, 2.9 mmol) obtained in Step 1.

[0859]

[0860] Preparation Example 35. 6-Bromo-N-(2-isopropylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0861] The target compound (34%, 3-step yield) was obtained by sequentially applying the method of Step 3 of Preparation Example 14, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 2-chloro-3-nitro-pyridine (635 mg, 4.0 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 6.0 mmol).

[0862]

[0863] Preparation Example 36. 6-Bromo-N-(2,4,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0864] The target compound (45%, 3-step yield) was obtained by sequentially applying the method of Step 3 of Preparation Example 6, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 2,4,6-trimethylpyridine (1.21 g, 10 mmol).

[0865]

[0866] Preparation Example 37. 6-Bromo-N-(2,6-dimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0867] The target compound (150 mg, 75%) was obtained by applying the method of Step 3 of Preparation Example 2 to 2,6-dimethylpyridine-3-amine (62 mg, 0.5 mmol) and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (255 mg, 0.5 mmol) obtained in Step 2 of Preparation Example 2.

[0868]

[0869] Preparation Example 38. 6-Bromo-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0870] Step 1: 2,5-Dibromo-6-methyl-pyridine-3-amine

[0871] 5-bromo-6-methyl-pyridine-3-amine (561 mg, 3.0 mmol) was dissolved in DMF (10 mL) and the temperature was lowered to 0°C. Then, NBS (640 mg, 3.6 mmol) was added, the temperature was raised to room temperature, and the mixture was stirred for 8 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and it was washed with water (50 mL x 2). The residue obtained by drying with anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure was purified by MPLC (100% Hex to 50% EtOAc in Hex) to obtain the target compound (610 mg, 76%).

[0872] Step 2: 2,5,6-trimethylpyridine-3-amine

[0873] 2,5-dibromo-6-methyl-pyridine-3-amine (266 mg, 1.0 mmol) obtained in Step 1 was dissolved in 1,4-dioxane (8 mL) and water (2.0 mL), and K3PO4 (1.06 g, 5.0 mmol) and PdCl2 (dppf).DCM (83 mg, 0.1 mmol) were added. The mixture was degassed using nitrogen for 5 minutes, and trimethylboroxine (377 mg, 3.0 mmol) was added. The temperature was raised to 100 °C and stirred for 15 hours. Ethyl acetate (100 mL) was added, the mixture was dried with anhydrous magnesium sulfate, filtered using a Celite pad, and the residue obtained by concentration under reduced pressure was purified by MPLC (100% Hex to 50% EtOAc in Hex) to obtain the target compound (137 mg, quant).

[0874] Step 3: 6-Bromo-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0875] The target compound (62 mg, 30%) was obtained by applying the method of Step 3 of Preparation Example 2 to 2,5,6-trimethylpyridine-3-amine (70 mg, 0.51 mmol) obtained in Step 2 and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (255 mg, 0.5 mmol) obtained in Step 2 of Preparation Example 2.

[0876]

[0877] Preparation Example 39. 5-((6-bromo-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N,N,2,6-tetramethylnicotinamide

[0878] Step 1: 3-Bromo-2,6-dimethyl-5-nitro-pyridine

[0879] The target compound (830 mg, 71%) was obtained by applying the method of Step 1 of Preparation Example 34 to 3-bromo-2-chloro-6-methyl-5-nitro-pyridine (1.25 g, 5.0 mmol).

[0880] Step 2: 2,6-dimethyl-5-nitro-pyridine-3-carboxylic acid

[0881] 3-bromo-2,6-dimethyl-5-nitro-pyridine (347 mg, 1.5 mmol) obtained in Step 1 was added to DMF (15 mL) and water (1 mL), and Pd(PPh3)4 (174 mg, 0.15 mmol), KI (250 mg, 1.5 mmol), and KOAc (590 mg, 6.0 mmol) were additionally added. The mixture was degassed using nitrogen for 10 minutes, and CO gas was introduced under reduced pressure. (Repeated 5 times) The reaction mixture was stirred for 15 hours under CO gas at 100 °C. It was concentrated under reduced pressure, and after adding 1N NaOH (10 mL), extracted with ethyl acetate (25 mL x 2). The aqueous layer was adjusted to pH ~1 by adding 1N HCl and extracted with ethyl acetate (25 mL x 3). The organic layer was washed with water and dried with anhydrous magnesium sulfate. After filtering, it was concentrated under reduced pressure, and the resulting solid was filtered through a Celite pad after adding diethyl ether (100 mL). The target compound (150 mg, 51%) was obtained by reducing pressure concentration.

[0882] Step 3: 5-((6-Bromo-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N,N,2,6-tetramethylnicotinamide

[0883] Step: The target compound (16%, 3-step yield) was obtained by sequentially applying the method of Step 3 of Preparation Example 7, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to the 2,6-dimethyl-5-nitro-pyridine-3-carboxylic acid (148 mg, 0.75 mmol) and dimethylamine hydrochloride (184 mg, 2.25 mmol) obtained in Step 2.

[0884]

[0885] Preparation Example 40. 6-Bromo-N-(6-methylquinoline-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0886] The target compound (100 mg, 14%) was obtained by applying the method of Step 3 of Preparation Example 2 to 6-methylquinoline-5-amine (80 mg, 0.5 mmol) and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (255 mg, 0.5 mmol) obtained in Step 2 of Preparation Example 2.

[0887]

[0888] Preparation Example 41. 6-Bromo-N-(3-methylisoquinoline-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0889] Step 1: 3-Bromoisoquinoline-4-amine

[0890] Aminoquinoline (289 mg, 2.0 mmol) and NBS (427 mg, 2.4 mmol) were subjected to the method of Step 1 of Preparation Example 38 to obtain the target compound 3-bromoisoquinoline-4-amine (193 mg, 43%) and the byproduct 1,3-dibromoisoquinoline-4-amine (141 mg, 23%).

[0891] Step 2: 6-Bromo-N-(3-methylisoquinoline-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0892] The 3-bromoisoquinoline-4-amine (178 mg, 0.8 mmol) obtained in Step 1 was sequentially subjected to the method of Step 2 of Preparation Example 38 and Step 3 of Preparation Example 2 to obtain the target compound (5%, 2-step yield).

[0893]

[0894] Preparation Example 42. 6-Bromo-N-(1,3-dimethylisoquinoline-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0895] The target compound (21%, 2-step yield) was obtained by sequentially applying the method of Step 2 of Preparation Example 38 and Step 3 of Preparation Example 2 to the byproduct 1,3-dibromoisoquinoline-4-amine (136 mg, 0.45 mmol) obtained in the synthesis process of Step 1 of Preparation Example 41.

[0896]

[0897] Preparation Example 43. 6-Bromo-N-(2-methylquinoline-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0898] The target compound (155 mg, 70%) was obtained by applying the method of Step 3 of Preparation Example 2 to 2-methylquinoline-3-amine (80 mg, 0.51 mmol) and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (256 mg, 0.51 mmol) obtained in Step 2 of Preparation Example 2.

[0899]

[0900] Preparation Example 44. 6-Bromo-N-(3-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0901] Step 1: 4-acetylisochromen-1,3-dione

[0902] 2-(carboxymethyl)benzoic acid (24.3 g, 135 mmol) was added to acetic anhydride (120 mL), and the temperature was lowered to 0 °C. Pyridine (55 mL, 675 mmol) was slowly added, and the temperature was raised to room temperature and stirred for 15 hours. Diethyl ether (500 mL) was added to the reaction mixture, and the resulting solid was removed by filtering. The mixture was concentrated under reduced pressure to obtain the target compound (18.2 g, 66%).

[0903] Step 2: 3-methyl-2H-isoquinoline-1-one

[0904] NH4OH (15 mL) was added to the 4-acetylisochromen-1,3-dione (3.2 g, 15.67 mmol) obtained in Step 1, and the mixture was stirred at 100 °C for 8 hours. The temperature was lowered to room temperature, and cold water (30 mL) was added to terminate the reaction. The resulting solid was filtered and washed with water. It was dried under reduced pressure to obtain the target compound (1.7 g, 68%).

[0905] Step 3: 3-methyl-4-nitroisoquinoline-1(2H)-one

[0906] After lowering the temperature to 0°C, the 3-methyl-2H-isoquinoline-1-one (400 mg, 2.5 mmol) obtained in Step 2 was dissolved in conc. acetic acid (5 mL). Then, nitric acid (1.7 mL, 25 mmol) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Then, the temperature was slowly raised to room temperature and stirred for 4 hours. Ice (100 g) was added to terminate the reaction, and the resulting solid was filtered and washed with water. The target compound (375 mg, 72%) was obtained by drying under reduced pressure.

[0907] Step 4: 6-Bromo-N-(3-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0908] The 3-methyl-4-nitroisoquinoline-1(2H)-one (123 mg, 0.6 mmol) obtained in Step 3 was sequentially subjected to the method of Step 2 of Preparation Example 6 and Step 3 of Preparation Example 2 to obtain the target compound (35%, 2-step yield).

[0909]

[0910] Preparation Example 45. 6-Bromo-N-(1-isopropyl-3-methylisoquinoline-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0911] Step 1: 1-chloro-3-methyl-4-nitro-isoquinoline

[0912] 3-methyl-4-nitroisoquinoline-1(2H)-one (256 mg, 1.25 mmol) obtained in Step 3 of Preparation Example 44 was dissolved in POCl3 (6 mL) and stirred at 100 °C for 4 hours. After concentration under reduced pressure, ethyl acetate (100 mL) was added. The organic layer was washed with 1N NaOH (25 mL) and then washed with water (50 mL). The mixture was dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain the target compound (270 mg, 96%).

[0913] Step 2: 1-Isopropenyl-3-methyl-4-nitro-isoquinoline

[0914] The target compound (47%, 3-step yield) was obtained by sequentially applying the method of Step 3 of Preparation Example 14, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 to 1-chloro-3-methyl-4-nitro-isoquinoline (190 mg, 0.85 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (173 mg, 1.025 mmol) obtained in Step 1.

[0915]

[0916] Preparation Example 46. 6-Bromo-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0917] Step 1: Ethyl 2-methylpyrazolo[1,5-a]pyridine-3-carboxylate

[0918] Pyridine-1-ium-1-amine iodide (22.2 g, 100 mmol) and ethyl bute-2-innoate (14 mL, 120 mmol) were added to DMF (100 mL). After lowering the temperature to 0 °C, potassium carbonate (27.64 g, 200 mmol) was added. The temperature was slowly raised to room temperature and stirred for 5 days. The solution was filtered using a Celite pad and washed with ethyl acetate. After concentration under reduced pressure, ethyl acetate (250 mL) was added for extraction. The solution was washed with water (100 mL x 3), dried with anhydrous magnesium sulfate, and filtered. The target compound (15.4 g, 75%) was obtained by concentration under reduced pressure.

[0919] Step 2: 2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid

[0920] Ethyl 2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (15.3 g, 75 mmol) obtained in Step 1 was added to methanol (75 mL), followed by the addition of 50% NaOH (11 mL, 135 mmol). The mixture was stirred at 70 °C for 15 hours and concentrated under reduced pressure. Water (50 mL) was added, and 1N HCl was added to adjust the pH to ~1. The resulting solid was filtered, washed with water, and dried under reduced pressure to obtain the target compound (9.6 g, 72%).

[0921] Step 3: 3-Bromo-2-methyl-pyrazolo[1,5-a]pyridine

[0922] [1,5-a]pyridine-3-carboxylic acid (9.7 g, 55 mmol) obtained in Step 2 was dissolved in DMF (275 mL), followed by the addition of NaHCO3 (16.2 g, 192.5 mmol). The temperature was lowered to 0 °C, and then NBS (10.8 g, 60.5 mmol) was added all at once. After stirring at 0 °C for 5 hours, the solution was concentrated under reduced pressure. Extraction was performed by adding EtOAc (250 mL), and the organic layer was washed with water (100 mL x 3). Subsequently, the solution was dried with anhydrous magnesium sulfate and filtered. The residue obtained by concentration under reduced pressure was purified by MPLC (100% hex to 60% EtOAc in hex) to obtain the target compound (7.4 g, 63%).

[0923] Step 4: 2-methylpyrazolo[1,5-a]pyridine

[0924] 3-bromo-2-methyl-pyrazolo[1,5-a]pyridine (7.38 g, 35 mmol) obtained in Step 3 was dissolved in THF (150 mL), and the temperature was lowered to -78 °C. Then, 2.5 M n-BuLi (28 mL, 70 mmol) was slowly added, and the mixture was stirred at -78 °C for 3 hours. The reaction was terminated by adding saturated NH4Cl (100 mL), extracted with EtOAc (100 mL x 3), and the organic layer was washed with water (100 mL). The mixture was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (3.4 g, 73%).

[0925] Step 5: 2-methyl-3-nitro-pyrazolo[1,5-a]pyridine

[0926] The 2-methylpyrazolo[1,5-a]pyridine (3.3 g, 25 mmol) obtained in Step 4 was added to conc. sulfuric acid (25 mL), and the temperature was lowered to 0 °C. Subsequently, a solution of ammonium nitrate (2.4 g, 30 mmol) dissolved in conc. sulfuric acid (15 mL) was slowly added. The mixture was stirred at 0 °C for 2 hours, and the reaction was terminated by adding ice (1000 g). The aqueous layer was adjusted to a pH of ~11 by adding NaOH. The resulting solid was filtered and washed with water. The target compound (3.3 g, 74%) was obtained by drying under reduced pressure.

[0927] Step 6: 2-methylpyrazolo[1,5-a]pyridine-3-amine

[0928] The 2-methyl-3-nitro-pyrazolo[1,5-a]pyridine (1.41 g, 8.0 mmol) obtained in Step 5 was dissolved in ethanol (50 mL) and water (5 mL), followed by the addition of zinc (7.85 g, 120 mmol). Acetic acid (3 mL) was then added, and the mixture was stirred at 90 °C for 3 hours. The reaction mixture was filtered using a Celite pad and washed with ethyl acetate. Extraction was performed by adding ethyl acetate (200 mL), after which the organic layer was washed with water (100 mL x 3). The mixture was then dried with anhydrous magnesium sulfate and filtered. The mixture was concentrated under reduced pressure to obtain the target compound (740 mg, 62%).

[0929] Step 7: 6-Bromo-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0930] The target compound (50 mg, 16%) was obtained by applying the method of Step 6 of Preparation Example 6 to 2-methylpyrazolo[1,5-a]pyridine-3-amine (103 mg, 0.7 mmol) obtained in Step 6 and 6-bromo-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride (217 mg, 0.7 mmol) obtained in Step 5 of Preparation Example 6.

[0931]

[0932] Preparation Example 47. 6-Bromo-N-(pyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0933] The target compound (200 mg, 97%) was obtained by applying the method of Step 3 of Preparation Example 2 to pyrazolo[1,5-a]pyridine-3-amine (67 mg, 0.5 mmol) and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (255 mg, 0.5 mmol) obtained in Step 2 of Preparation Example 2.

[0934]

[0935] Preparation Example 48. 6-Bromo-N-(2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0936] Step 1: 2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-amine

[0937] The target compound (88 mg, 97%) was obtained by applying the method of Step 2 of Preparation Example 6 to the 2-methyl-3-nitro-pyrazolo[1,5-a]pyridine (106 mg, 0.6 mmol) obtained in Step 5 of Preparation Example 46.

[0938] Step 2: 6-Bromo-N-(2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0939] The target compound (150 mg, 70%) was obtained by applying the method of Step 3 of Preparation Example 2 to 2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-amine (75 mg, 0.5 mmol) obtained in Step 1 and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (255 mg, 0.5 mmol) obtained in Step 2 of Preparation Example 2.

[0940]

[0941] Preparation Example 49. 6-Bromo-N-(2,5,7-trimethylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0942] Step 1: 2,5,7-trimethylpyrazolo[1,5-a]pyrimidine

[0943] 3-methyl-1H-pyrazole-5-amine (971 mg, 10 mmol) and 2,4-pentanedione (1.2 g, 12 mmol) were added to acetic acid (25 mL), and concentrated sulfuric acid (200 mg, 2.0 mmol) was added. After stirring at 70 °C for 4 hours, the mixture was concentrated under reduced pressure. EtOAc (150 mL) was added, and the organic layer was washed with saturated NaHCO3 (50 mL x 3). Subsequently, after washing with water (50 mL), the mixture was dried with anhydrous magnesium sulfate, filtered, and then subjected to reduced pressure to obtain the target compound (1.6 g, quant).

[0944] Step 2: 2,5,7-trimethyl-3-nitro-pyrazolo[1,5-a]pyrimidine

[0945] The target compound (1.5 g, 90%) was obtained by applying the method of Step 1 of Preparation Example 36 to the 2,5,7-trimethylpyrazolo[1,5-a]pyrimidine (1.29 g, 8.0 mmol) obtained in Step 1.

[0946] Step 3: 2,5,7-trimethylpyrazolo[1,5-a]pyrimidine-3-amine

[0947] The target compound (160 mg, 36%) was obtained by applying the method of Step 6 of Preparation Example 46 to the 2,5,7-trimethyl-3-nitro-pyrazolo[1,5-a]pyrimidine (516 mg, 2.5 mmol) obtained in Step 2.

[0948] Step 4: 6-Bromo-N-(2,5,7-trimethylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydro-1H-isoquinoline-2-sulfonamide

[0949] The target compound (220 mg, 95%) was obtained by applying the method of Step 3 of Preparation Example 2 to 2,5,7-trimethylpyrazolo[1,5-a]pyrimidine-3-amine (90 mg, 0.51 mmol) obtained in Step 3 and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (258 mg, 0.51 mmol) obtained in Step 2 of Preparation Example 2.

[0950]

[0951] Preparation Example 50. 6-Bromo-N-(6-chloro-2-methylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0952] Step 1: 6-chloro-2-methyl-pyrazolo[1,5-a]pyrimidine

[0953] 3-methyl-1H-pyrazole-5-amine (971 mg, 10 mmol) was dissolved in EtOH (20 mL), and 2-chloropropanedial (1.17 g, 11 mmol) and TsOH·H2O (95 mg, 0.5 mmol) were added. After stirring at 90 °C for 3 hours, the mixture was concentrated under reduced pressure, and ethanol (10 mL) was added. The resulting solid was filtered and washed with ethanol. The mixture was dried under reduced pressure to obtain the target compound (950 mg, 56%).

[0954] Step 2: 6-chloro-2-methyl-3-nitro-pyrazolo[1,5-a]pyrimidine

[0955] 6-chloro-2-methyl-pyrazolo[1,5-a]pyrimidine (1.17 g, 7.0 mmol) obtained in Step 1 was dissolved in TFA (7 mL), and HNO3 (2.8 mL, 42 mmol) was slowly added over 5 minutes. After stirring at room temperature for 12 hours, ice (200 g) was added to terminate the reaction. The mixture was extracted with EtOAc (100 mL x 2), washed with water (100 mL), dried with anhydrous magnesium sulfate, and filtered. After concentration under reduced pressure, ethyl acetate was added; the resulting solid was filtered and dried under reduced pressure to obtain the target compound (300 mg, 20%).

[0956] Step 3: 6-chloro-2-methyl-pyrazolo[1,5-a]pyrimidine-3-amine

[0957] 6-chloro-2-methyl-3-nitro-pyrazolo[1,5-a]pyrimidine (213 mg, 1.0 mmol) obtained in Step 2 was added to methanol (9 mL) and water (1 mL), followed by the addition of zinc (262 mg, 4.0 mmol) and NH4Cl (214 mg, 4.0 mmol). After stirring at 80 °C for 2 hours, the mixture was filtered using a Celite pad and washed with ethyl acetate. The residue obtained by concentration under reduced pressure was purified using MPLC (100% DCM to 20% MeOH in DCM) to obtain the target compound (110 mg, 60%).

[0958] Step 4: 6-Bromo-N-(6-chloro-2-methyl-pyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydro-1H-isoquinoline-2-sulfonamide

[0959] The target compound (188 mg, 81%) was obtained by applying the method of Step 3 of Preparation Example 2 to 6-chloro-2-methyl-pyrazolo[1,5-a]pyrimidine-3-amine (92 mg, 0.5 mmol) obtained in Step 3 and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (255 mg, 0.5 mmol) obtained in Step 2 of Preparation Example 2.

[0960]

[0961] Preparation Example 51. 6-Bromo-N-(2-methylpyrazolo[1,5-b]pyridazine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0962] Step 1: Ethyl 2-methylpyrazolo[1,5-b]pyridazine-3-carboxylate

[0963] Amino hydrogen sulfate (8.1 g, 71 mmol) was dissolved in water (13 mL), and then a saturated NaHCO3 solution was slowly added to adjust the pH to 6. Pyridazine (3.4 mL, 47 mmol) was added, and the temperature was raised to 70 °C and stirred for 2 hours. Then, a saturated NaHCO3 solution was added to adjust the pH to 7, and ethyl bu-2-in-oate (1.35 g, 12 mmol) was dissolved in DCM (50 mL) and added. Then, KOH (1.34 g, 24 mmol) was added and stirred at room temperature for 16 hours. The mixture was filtered using a Celite pad and extracted with DCM (100 mL). The organic layer was dried with anhydrous magnesium sulfate, and the residue obtained by filtering and vacuum concentration was purified by MPLC (100% hex to 40% EtOAc in Hex) to obtain the target compound (1.1 g, 44%).

[0964] Step 2: 6-Bromo-N-(2-methylpyrazolo[1,5-b]pyridazine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0965] The ethyl 2-methylpyrazolo[1,5-b]pyridazine-3-carboxylate (1.03 g, 5.0 mmol) obtained in Step 1 was sequentially subjected to the method of Step 2 of Preparation Example 46, Steps 1 and 2 of Preparation Example 33, and Step 3 of Preparation Example 2 to obtain the target compound (27%, Step 4 yield).

[0966]

[0967] Preparation Example 52. 6-Bromo-N-(2-methylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0968] Step 1: 2-methylpyrazolo[1,5-a]pyrimidine

[0969] 3-methyl-1H-pyrazol-5-amine (971 mg, 10 mmol) and 1,1,3,3-tetramethoxypropane (1.97 g, 12 mmol) were dissolved in AcOH (25 mL) and stirred at 70 °C for 24 hours. The mixture was concentrated under reduced pressure and extracted with EtOAc (150 mL). The organic layer was washed with saturated NaHCO3 (50 mL x 3) and water (50 mL). The organic layer was dried with anhydrous magnesium sulfate, and the residue obtained by filtering and reducing pressure concentration was purified by MPLC (100% hex to 100% EtOAc) to obtain the target compound 2-methylpyrazolo[1,5-a]pyrimidine (360 mg, 27%) and 3-methyl-1H-pyrazolo[5,4-b]pyridine (250 mg) as a byproduct.

[0970] Step 2: 6-Bromo-N-(2-methylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0971] The target compound (36%, 3-step yield) was obtained by sequentially applying the method of Step 1 of Preparation Example 36, Step 3 of Preparation Example 50, and Step 3 of Preparation Example 2 to the 2-methylpyrazolo[1,5-a]pyrimidine (1.065 g, 8 mmol) obtained in Step 1.

[0972]

[0973] Preparation Example 53. 6-Bromo-N-(2,7-dimethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0974] Step 1: 2,4-dinitrophenolate; 2-methylpyridine-1-um-1-amine

[0975] 1-(aminooxy)-2,4-dinitrobenzene (9.956 g, 50 mmol) was dissolved in acetonitrile (100 mL), and 2-methylpyridine (4.65 g, 50 mmol) was added. The mixture was stirred at 40 °C for 24 hours and concentrated under reduced pressure. The resulting solid was washed with dichloromethane (100 mL x 2) to obtain the target compound (12.6 g, 86%).

[0976] Step 2: 6-Bromo-N-(2,7-dimethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0977] The target compound (7%, 5-step yield) was obtained by sequentially applying the method of Step 1 and Step 2 of Preparation Example 46, Step 1 and Step 2 of Preparation Example 33, and Step 3 of Preparation Example 2 to the 2,4-dinitrophenolate; 2-methylpyridine-1-um-1-amine (5.85 g, 20 mmol) obtained in Step 1.

[0978]

[0979] Preparation Example 54. 6-Bromo-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0980] Step 1: Methyl 2-ethylpyrazolo[1,5-a]pyridine-3-carboxylate

[0981] Pyridine-1-ium-1-amine iodide (4.00 g, 18.0 mmol) and potassium carbonate (2.99 g, 21.6 mmol) were dissolved in DMF (20 mL), and the temperature was lowered to 0 °C. Subsequently, methyl pent-2-innoate (2.5 mL, 21.6 mmol) was slowly added, and the mixture was stirred at room temperature for 3 days. The mixture was filtered through a Celite pad and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the residue obtained by vacuum concentration after filtration was purified by MPLC to obtain the target compound (2.3 g, 63%).

[0982] Step: 2-ethylpyrazolo[1,5-a]pyridine-3-carboxylic acid

[0983] Methyl 2-ethylpyrazolo[1,5-a]pyridine-3-carboxylate (2.3 g, 11.3 mmol) obtained in Step 1 was dissolved in methanol (14 mL) and THF (14 mL). Then, sodium hydroxide (2.25 g, 56.3 mmol) dissolved in water (7 mL) was added. The temperature was raised to 70 °C and stirred for 12 hours. Extraction with ethyl acetate and concentration under reduced pressure yielded the target compound (1.02 g, 48%). The compound proceeded to the next reaction without further purification.

[0984] Step 3: tert-butyl N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate

[0985] [1,5-a]pyridine-3-carboxylic acid (1.00 g, 5.26 mmol) and triethylamine (2.2 mL, 15.8 mmol) obtained from Step 2 were dissolved in anhydrous tert-butanol (38 mL), and then diphenyl azidophosphate (2.6 mL, 12.1 mmol) was added. The mixture was stirred at room temperature for 16 hours, followed by stirring at 75 °C for 16 hours. The residue obtained by extraction with ethyl acetate and vacuum concentration was purified by MPLC to obtain the target compound (0.32 g, 24%).

[0986] Step 4: 2-ethylpyrazolo[1,5-a]pyridine-3-amine hydrochloride

[0987] The tert-butyl N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (0.32 g, 1.22 mmol) obtained in Step 3 was dissolved in DCM (2 mL), followed by the addition of HCl (1.5 mL, 6.12 mmol 4.0 M in 1,4-dioxane). After stirring at room temperature for 1 hour, the solution was concentrated under reduced pressure to obtain the target compound (0.24 g, 99%). The compound was used in the following reaction without further purification.

[0988] Step 5: 6-Bromo-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0989] The target compound (0.22 g, 42%) was obtained using the method of Step 3 of Preparation Example 2 with 2-ethylpyrazolo[1,5-a]pyridine-3-amine hydrochloride (0.24 g, 1.21 mmol) and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (0.61 g, 1.21 mmol) obtained in Step 4.

[0990]

[0991] Preparation Example 55. 6-Bromo-N-(2,4-dimethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0992] Step 1: 2,4-dinitrophenolate; 3-methylpyridine-1-um-1-amine

[0993] The target compound (12.7 g, 86%) was obtained by applying the method of Step 1 of Preparation Example 53 to 3-methylpyridine (4.65 g, 50 mmol).

[0994] Step 2: Ethyl 2,4-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate

[0995] 2,4-dinitrophenolate obtained in Step 1; 3-methylpyridine-1-um-1-amine (5.85 g, 20 mmol) was subjected to the method of Step 1 of Preparation Example 46 to obtain a mixture of the target compound and ethyl 2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate (2.0 g, 45%).

[0996] Step 3: 2,4-dimethylpyrazolo[1,5-a]pyridine

[0997] The mixture (545 mg, 2.5 mmol) obtained in Step 2 was dissolved in 40% sulfuric acid (25 mL) and stirred at 100 °C for 24 hours. After basicization with NaOH, it was extracted with EtOAc (50 mL X 2). The organic layer was washed with water (50 mL), dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a mixture (330 mg, 90%) of the target compound and 2,6-dimethylpyrazolo[1,5-a]pyridine.

[0998] Step 4: 2,4-dimethyl-3-nitro-pyrazolo[1,5-a]pyridine

[0999] The mixture obtained in Step 3 (337 mg, 2.3 mmol) was subjected to the method of Step 1 of Preparation Example 36 to obtain the target compound (50 mg, 11%) and 2,6-dimethyl-3-nitro-pyrazolo[1,5-a]pyridine (60 mg, 13%) as a byproduct.

[1000] Step 5: 6-Bromo-N-(2,4-dimethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1001] Step 4: 110 mg of 2,4-dimethyl-3-nitro-pyrazolo[1,5-a]pyridine (0.57 mmol) was sequentially applied to the method of Step 6 of Preparation Example 46 and Step 3 of Preparation Example 2 to obtain the target compound (65%, 2-step yield).

[1002]

[1003] Preparation Example 56. 5-Bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindolin-2-sulfonamide

[1004] 5-bromoisoindoline (0.33 g, 1.66 mmol) was prepared by applying the same method as in Preparation Example 2 to obtain the target compound (58%, 3-step yield).

[1005]

[1006] Preparation Example 57. tert-butyl 4-(4-bromopyridine-2-yl)piperazine-1-carboxylate

[1007] 4-bromo-2-fluoro-pyridine (5.28 g, 30 mmol), 1-Boc-piperazine (8.38 g, 45 mmol), and potassium carbonate (12.4 g, 90 mmol) were dissolved in DMSO (60 mL) and stirred at 120 °C for 15 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (Hx:EtOAc=100:0 to 0:100) to obtain the target compound (8.0 g, 78%).

[1008]

[1009] Preparation Example 58. tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)piperazine-1-carboxylate

[1010] The target compound (3.6 g, 92%) was obtained by applying the method of Preparation Example 3 to the tert-butyl 4-(4-bromopyridine-2-yl)piperazine-1-carboxylate (3.42 g, 10 mmol) obtained in Preparation Example 57.

[1011]

[1012] Preparation Example 59. tert-butyl (S)-4-(4-iodopyridine-2-yl)-3-methylpiperazine-1-carboxylate

[1013] The target compound (150 mg, 41%) was obtained by applying the method of Preparation Example 57 to 2-fluoro-4-iodo-pyridine (200 mg, 0.90 mmol) and (S)-4-BOC-2-methylpiperazine (216 mg, 1.08 mmol).

[1014]

[1015] Preparation Example 60. tert-butyl (R)-4-(4-bromopyridine-2-yl)-3-ethylpiperazine-1-carboxylate

[1016] The target compound (73 mg, 12%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (300 mg, 1.70 mmol) and tert-butyl(R)-3-ethylpiperazine-1-carboxylate (548 mg, 2.56 mmol).

[1017]

[1018] Preparation Example 61. tert-butyl (S)-4-(4-bromopyridine-2-yl)-2-ethylpiperazine-1-carboxylate

[1019] The target compound (371 mg, 59%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (300 mg, 1.70 mmol) and tert-butyl(S)-2-ethylpiperazine-1-carboxylate (402 mg, 1.88 mmol).

[1020]

[1021] Preparation Example 62. tert-butyl (R)-4-(4-bromopyridine-2-yl)-2-ethylpiperazine-1-carboxylate

[1022] The target compound (370 mg, 59%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (300 mg, 1.70 mmol) and tert-butyl(R)-2-ethylpiperazine-1-carboxylate (402 mg, 1.88 mmol).

[1023]

[1024] Preparation Example 63. tert-butyl 4-(4-chloropyrimidine-2-yl)piperazine-1-carboxylate

[1025] 2,4-dichloropyrimidine (1.0 g, 6.71 mmol), 1-Boc-piperazine (1.38 g, 7.38 mmol), and DIPEA (1.75 mL, 10.07 mmol) were dissolved in DMF (13 mL) and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered, and the residue obtained by reducing pressure concentration was purified by silica gel chromatography (Hx:EtOAc=100:0 to 0:100) to obtain the target compound (450 mg, 22%).

[1026]

[1027] Preparation Example 64. tert-butyl 4-(4-chloro-5-cyanopyrimidine-2-yl)piperazine-1-carboxylate

[1028] 2,4-dichloro-5-cyanopyrimidine (500 mg, 2.87 mmol) and 1-Boc-piperazine (562 mg, 3.02 mmol) were dissolved in ethanol (14 mL) and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate and a saturated NaHCO3 solution. The organic layer was dried with MgSO4, filtered, and then concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (Hx:EtOAc=100:0 to 0:100) to obtain the target compound as a white solid (332 mg, 36%).

[1029]

[1030] Preparation Example 65. tert-butyl 4-(4-chloro-5-cyanopyrimidine-2-yl)piperazine-1-carboxylate

[1031] In the process of obtaining Preparation Example 64, a white solid target compound (210 mg, 23%) was obtained as a byproduct.

[1032]

[1033] Preparation Example 66. tert-butyl 4-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)piperazine-1-carboxylate

[1034] 2,4-dichloro-5-(trifluoromethyl)pyrimidine (500 mg, 2.30 mmol), 1-Boc-piperazine (472 mg, 2.53 mmol), and DIPEA (1.2 mL, 6.91 mmol) were dissolved in DMSO (12 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered, and the residue obtained by reducing pressure concentration was purified by silica gel chromatography (Hx:EtOAc=100:0 to 0:100) to obtain the target compound as a white solid (537 mg, 64%).

[1035]

[1036] Preparation Example 67. tert-butyl 4-(4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)piperazine-1-carboxylate

[1037] In the process of obtaining Preparation Example 66, the target compound (271 mg, 32%) was obtained as a byproduct.

[1038]

[1039] Preparation Example 68. 6-(4,4,5,5-tetramethyl-1,3,2-dioxabololin-2-yl)-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1040] The target compound (0.52 g, 71%) was obtained by applying the method of Preparation Example 3 to the 6-bromo-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.66 g, 1.61 mmol) obtained in Preparation Example 38.

[1041]

[1042] Preparation Example 69. tert-butyl (R)-4-(2-chloropyrimidine-4-yl)-2-ethylpiperazine-1-carboxylate

[1043] 2,4-dichloropyrimidine (300 mg, 2.01 mmol), tert-butyl(R)-2-ethylpiperazine-1-carboxylate (475 mg, 2.21 mmol), and DIPEA (1.05 mL, 6.04 mmol) were dissolved in DMSO (8 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered, and the residue obtained by reduced pressure concentration was purified by silica gel chromatography (Hx:EtOAc=100:0 to 0:100) to obtain a colorless liquid target compound (537 mg, 81%).

[1044]

[1045] Preparation Example 70. tert-butyl (S)-4-(2-chloropyrimidine-4-yl)-2-ethylpiperazine-1-carboxylate

[1046] A colorless liquid target compound (533 mg, 81%) was obtained by applying the method of Preparation Example 69 using 2,4-dichloropyrimidine (300 mg, 2.01 mmol), tert-butyl(S)-2-ethylpiperazine-1-carboxylate (475 mg, 2.21 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (8 mL).

[1047]

[1048] Preparation Example 71. tert-butyl (S)-4-(2-chloropyrimidine-4-yl)-3-ethylpiperazine-1-carboxylate

[1049] The brown liquid target compound (312 mg, 47%) was obtained by applying the method of Preparation Example 69 using 2,4-dichloropyrimidine (300 mg, 2.01 mmol), tert-butyl(S)-3-ethylpiperazine-1-carboxylate (475 mg, 2.21 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (8 mL).

[1050]

[1051] Preparation Example 72. tert-butyl (R)-4-(2-chloropyrimidine-4-yl)-3-ethylpiperazine-1-carboxylate

[1052] The brown liquid target compound (436 mg, 66%) was obtained by applying the method of Preparation Example 69 at 50°C using 2,4-dichloropyrimidine (300 mg, 2.01 mmol), tert-butyl(R)-3-ethylpiperazine-1-carboxylate (475 mg, 2.21 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (8 mL).

[1053]

[1054] Preparation Example 73. tert-butyl 4-(6-chloropyridine-2-yl)piperazine-1-carboxylate

[1055] The target compound (1.52 g, 76%) was obtained by applying the method of Preparation Example 69 using 2,6-dichloropyridine (1.0 g, 6.76 mmol) and 1-Boc-piperazine (1.5 g, 8.11 mmol).

[1056]

[1057] Preparation Example 74. tert-butyl (S)-4-(6-chloropyridine-2-yl)-3-methylpiperazine-1-carboxylate

[1058] The target compound (0.14 g, 33%) was obtained by applying the method of Preparation Example 69 using 2,6-dichloropyridine (0.20 g, 1.35 mmol) and (S)-4-BOC-2-methylpiperazine (0.32 g, 1.62 mmol).

[1059]

[1060] Preparation Example 75. tert-butyl (R)-4-(6-chloropyridine-2-yl)-2-ethylpiperazine-1-carboxylate

[1061] The brown liquid target compound (506 mg, 77%) was obtained by applying the method of Preparation Example 69 at 120 °C using 2,6-dichloropyridine (300 mg, 2.03 mmol), tert-butyl(R)-2-ethylpiperazine-1-carboxylate (478 mg, 2.23 mmol), DIPEA (1.06 mL, 6.04 mmol), and DMSO (8 mL).

[1062]

[1063] Preparation Example 76. tert-butyl (S)-4-(6-chloropyridine-2-yl)-2-ethylpiperazine-1-carboxylate

[1064] A brown liquid target compound (560 mg, 85%) was obtained by applying the method of Preparation Example 69 at 120 °C using 2,6-dichloropyridine (300 mg, 2.03 mmol), tert-butyl(S)-2-ethylpiperazine-1-carboxylate (478 mg, 2.23 mmol), DIPEA (1.06 mL, 6.04 mmol), and DMSO (8 mL).

[1065]

[1066] Preparation Example 77. tert-butyl 4-(6-chloropyridazine-4-yl)piperazine-1-carboxylate

[1067] The target compound (200 mg, 66%) was obtained by applying the method of Preparation Example 69 using 3,5-dichloropyridazine (150 mg, 1.00 mmol) and 1-Boc-piperazine (188 mg, 1.00 mmol).

[1068]

[1069] Preparation Example 78. tert-butyl 4-(5-chloropyridazine-3-yl)piperazine-1-carboxylate

[1070] In the process of synthesizing Preparation Example 77, the target compound (15 mg, 5%) was obtained as a byproduct.

[1071]

[1072] Preparation Example 79. tert-butyl (S)-4-(5-chloropyridazine-3-yl)-3-methylpiperazine-1-carboxylate

[1073] The target compound (120 mg, 7%) was obtained by applying the method of Preparation Example 69 using 3,5-dichloropyridazine (0.42 g, 2.82 mmol) and (S)-4-BOC-2-methylpiperazine (1.24 g, 6.20 mmol).

[1074]

[1075] Preparation Example 80. tert-butyl 4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate

[1076] A white solid target compound (1.43 g, 71%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (1 g, 6.71 mmol), 1-Boc-piperazine (1.37 g, 7.38 mmol), DIPEA (2.6 g, 20.1 mmol), and ethanol (34 mL).

[1077]

[1078] Preparation Example 81. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-3-methylpiperazine-1-carboxylate

[1079] A white solid target compound (230 mg, 55%) was obtained by applying the method of Preparation Example 69 at 140 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(S)-3-methylpiperazine-1-carboxylate (296 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1080]

[1081] Preparation Example 82. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-3-methylpiperazine-1-carboxylate

[1082] The brown liquid target compound (222 mg, 53%) was obtained by applying the method of Preparation Example 69 at 140 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-3-methylpiperazine-1-carboxylate (296 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1083]

[1084] Preparation Example 83. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-methylpiperazine-1-carboxylate

[1085] A colorless liquid target compound (1.26 g, 60%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (1 g, 6.71 mmol), tert-butyl(S)-2-methylpiperazine-1-carboxylate (1.5 g, 7.38 mmol), DIPEA (3.5 mL, 20.1 mmol), and MeCN (34 mL).

[1086]

[1087] Preparation Example 84. tert-butyl 4-(6-chloropyrazine-2-yl)-1,4-diazephane-1-carboxylate

[1088] The brown liquid target compound (356 mg, 85%) was obtained by applying the method of Preparation Example 69 at 140 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl 1,4-diazephane-1-carboxylate (295 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1089]

[1090] Preparation Example 85. tert-butyl (1-(6-chloropyrazine-2-yl)piperidin-4-yl)carbamate

[1091] The brown liquid target compound (561 mg, 89%) was obtained by applying the method of Preparation Example 69 at 50 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl N-(4-piperidyl)carbamate (444 mg, 2.21 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1092]

[1093] Preparation Example 86. tert-butyl 3-(6-chloropyrazine-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[1094] The brown liquid target compound (964 mg, 92%) was obtained by applying the method of Preparation Example 69 at 50 °C using 2,6-dichloropyrazine (500 mg, 3.36 mmol), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (791 mg, 3.69 mmol), DIPEA (1.75 mL, 10 mmol), and DMSO (17 mL).

[1095]

[1096] Preparation Example 87. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-methylpiperazine-1-carboxylate

[1097] A brown liquid target compound (1.3 g, 98%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (630 mg, 4.23 mmol), tert-butyl(R)-2-methylpiperazine-1-carboxylate (931 mg, 4.65 mmol), DIPEA (2.21 mL, 12.7 mmol), and MeCN (21 mL).

[1098]

[1099] Preparation Example 88. tert-butyl ((1-(6-chloropyrazine-2-yl)piperidine-4-yl)methyl)carbamate

[1100] The brown liquid target compound (259 mg, 59%) was obtained by applying the method of Preparation Example 69 at 140 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl N-(4-piperidylmethyl)carbamate (316 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1101]

[1102] Preparation Example 89. 2-chloro-6-((3R,5S)-3,5-dimethylpiperazine-1-yl)pyrazine

[1103] The brown liquid target compound (1.39 g, 91%) was obtained by applying the method of Preparation Example 69 at 50 °C using 2,6-dichloropyrazine (1 g, 6.71 mmol), (2S,6R)-2,6-dimethylpiperazine (843 mg, 7.38 mmol), DIPEA (3.51 mL, 20.1 mmol), and MeCN (34 mL).

[1104]

[1105] Preparation Example 90. tert-butyl 3-(4-(6-chloropyrazine-2-yl)piperazine-1-yl)azetidine-1-carboxylate

[1106] The brown liquid target compound (443 mg, 93%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl 3-(piperazine-1-yl)azetidine-1-carboxylate (356 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1107]

[1108] Preparation Example 91. tert-butyl 4-(6-chloropyrazine-2-yl)-2,3-dimethylpiperazine-1-carboxylate

[1109] The brown liquid target compound (224 mg, 49%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), 2,3-dimethylpiperazine (253 mg, 2.21 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1110]

[1111] Preparation Example 92. tert-butyl 4-(6-chloropyrazine-2-yl)-2-(trifluoromethyl)piperazine-1-carboxylate

[1112] A brown liquid target compound (406 mg, 100%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), 2-(trifluoromethyl)piperazine (228 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1113]

[1114] Preparation Example 93. tert-butyl 4-(6-chloropyrazine-2-yl)-2,2-dimethylpiperazine-1-carboxylate

[1115] The brown liquid target compound (577 mg, 88%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl 2,2-dimethylpiperazine-1-carboxylate (475 mg, 2.21 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1116]

[1117] Preparation Example 94. tert-butyl 4-(6-chloropyrazine-2-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate

[1118] The brown liquid target compound (149 mg, 23%) was obtained by applying the method of Preparation Example 69 at 150 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate (470 mg, 2.22 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1119]

[1120] Preparation Example 95. tert-butyl 4-(5-chlorothiazole-2-yl)piperazine-1-carboxylate

[1121] 5-bromo-2-chlorothiazole (100 mg, 0.50 mmol), 1-Boc-piperazine (103 mg, 0.55 mmol), and K2CO3 (209 mg, 1.51 mmol) were mixed with DMSO (3 mL) at 80°C using the method of Preparation Example 69 to obtain the white liquid target compound (120 mg, 68%).

[1122]

[1123] Preparation Example 96. tert-butyl 6-(6-chloropyrazine-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[1124] The brown liquid target compound (350 mg, 84%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (293 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1125]

[1126] Preparation Example 97. tert-butyl (1S,4S)-5-(6-chloropyrazine-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[1127] A colorless liquid target compound (1.56 g, 75%) was obtained by applying the method of Preparation Example 69 at 50 °C using 2,6-dichloropyrazine (1 g, 6.71 mmol), tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.5 g, 7.38 mmol), DIPEA (3.51 mL, 20.1 mmol), and DMSO (34 mL).

[1128]

[1129] Preparation Example 98. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

[1130] The brown liquid target compound (163 mg, 37%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (319 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1131]

[1132] Preparation Example 99. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-(methoxymethyl)piperazine-1-carboxylate

[1133] A colorless liquid target compound (351 mg, 76%) was obtained by applying the method of Preparation Example 69 at 50 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl (2R)-2-(methoxymethyl)piperazine-1-carboxylate (340 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1134]

[1135] Preparation Example 100. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-3-methyl-1,4-diazephane-1-carboxylate

[1136] The brown liquid target compound (296 mg, 67%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl (3S)-3-methyl-1,4-diazephane-1-carboxylate (316 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1137]

[1138] Preparation Example 101. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-3-ethylpiperazine-1-carboxylate

[1139] A yellow solid target compound (883 mg, 40%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (1 g, 6.71 mmol), tert-butyl (3R)-3-ethylpiperazine-1-carboxylate (1.58 mg, 7.38 mmol), DIPEA (3.51 mL, 20.1 mmol), and DMSO (34 mL).

[1140]

[1141] Preparation Example 102. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-3-isopropylpiperazine-1-carboxylate

[1142] A yellow solid target compound (288 mg, 13%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (1 g, 6.71 mmol), tert-butyl (3R)-3-isopropylpiperazine-1-carboxylate (1.68 mg, 7.38 mmol), DIPEA (3.51 mL, 20.1 mmol), and DMSO (34 mL).

[1143]

[1144] Preparation Example 103. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate

[1145] A white solid target compound (651 mg, 72%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (410 mg, 2.75 mmol), tert-butyl(R)-2-(hydroxymethyl)piperazine-1-carboxylate (654 mg, 3.03 mmol), DIPEA (1.44 mL, 8.26 mmol), and DMSO (13.8 mL).

[1146]

[1147] Preparation Example 104. 1-(tert-butyl)3-methyl(R)-4-(6-chloropyrazine-2-yl)piperazine-1,3-dicarboxylate

[1148] A brown liquid target compound (434 mg, 14%) was obtained by applying the method of Preparation Example 69 at 150 °C using 2,6-dichloropyrazine (1 g, 6.71 mmol), 1-(tert-butyl)3-methyl(R)-piperazine-1,3-dicarboxylate (1.8 g, 7.38 mmol), DIPEA (3.51 mL, 20.1 mmol), and DMSO (34 mL).

[1149]

[1150] Preparation Example 105. 1-(tert-butyl)3-methyl(S)-4-(6-chloropyrazine-2-yl)piperazine-1,3-dicarboxylate

[1151] A brown liquid target compound (484 mg, 15%) was obtained by applying the method of Preparation Example 69 at 150 °C using 2,6-dichloropyrazine (1 g, 6.71 mmol), 1-(tert-butyl)3-methyl(S)-piperazine-1,3-dicarboxylate (1.8 g, 7.38 mmol), DIPEA (3.51 mL, 20.1 mmol), and DMSO (34 mL).

[1152]

[1153] Preparation Example 106. 1-(tert-butyl) 2-methyl (R)-4-(6-chloropyrazine-2-yl)piperazine-1,2-dicarboxylate

[1154] A yellow liquid target compound (3.11 g, 43%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (3 g, 20.1 mmol), 1-(tert-butyl) 2-methyl(R)-piperazine-1,2-dicarboxylate (5.4 g, 22.2 mmol), DIPEA (10.5 mL, 60.4 mmol), and DMSO (100 mL).

[1155]

[1156] Preparation Example 107. 1-(tert-butyl) 2-methyl (S)-4-(6-chloropyrazine-2-yl)piperazine-1,2-dicarboxylate

[1157] A brown liquid target compound (1.09 g, 91%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (500 mg, 3.36 mmol), 1-(tert-butyl)2-methyl(S)-piperazine-1,2-dicarboxylate (902 mg, 3.69 mmol), DIPEA (1.75 mL, 10.1 mmol), and DMSO (17 mL).

[1158]

[1159] Preparation Example 108. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-(dimethylcarbamoyl)piperazine-1-carboxylate

[1160] Step 1: (S)-1-(tert-butoxycarbonyl)-4-(6-chloropyrazine-2-yl)piperazine-2-carboxylic acid

[1161] 1-(tert-butyl) 2-methyl(S)-4-(6-chloropyrazine-2-yl)piperazine-1,2-dicarboxylate (500 mg, 1.40 mmol) obtained in Preparation Example 107 and NaOH (7 mL) were dissolved in methanol (7 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and then acidified by adding 1N HCl dropwise. The mixture was extracted with dichloromethane to obtain the target compound as a brown solid (413 mg, 86%).

[1162] Step 2: tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-(dimethylcarbamoyl)piperazine-1-carboxylate

[1163] (S)-1-(tert-butoxycarbonyl)-4-(6-chloropyrazine-2-yl)piperazine-2-carboxylic acid (407 mg, 1.19 mmol), HATU (542 mg, 1.42 mmol), and DIPEA (0.6 mL, 3.56 mmol) were dissolved in DMF (6 mL) and stirred at room temperature for 20 minutes. Dimethylamine hydrochloride (116 mg, 1.42 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and then extracted with dichloromethane. The organic layer was dried with MgSO4, filtered, and the residue obtained by reduced pressure concentration was purified by silica gel chromatography (EA:MeOH = 100:0 to 95:5) to obtain a colorless liquid target compound (393 mg, 89%).

[1164]

[1165] Preparation Example 109. tert-butyl ((3R,4R)-1-(6-chloropyrazine-2-yl)-3-hydroxypiperidin-4-yl)carbamate

[1166] A white solid target compound (235 mg, 53%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl N-[(3R,4R)-3-hydroxy-4-piperidyl]carbamate (319 mg, 1.48 mmol), DIPEA (0.70 mL, 4.0 mmol), and MeCN (7 mL).

[1167]

[1168] Preparation Example 110. tert-butyl ((3R,4S)-1-(6-chloropyrazine-2-yl)-3-hydroxypiperidin-4-yl)carbamate

[1169] A white solid target compound (295 mg, 67%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl N-[(3R,4S)-3-hydroxy-4-piperidyl]carbamate (319 mg, 1.48 mmol), DIPEA (0.70 mL, 4.0 mmol), and MeCN (7 mL).

[1170]

[1171] Preparation Example 111. tert-butyl ((3S,4R)-1-(6-chloropyrazine-2-yl)-3-hydroxypiperidin-4-yl)carbamate

[1172] The target compound as a white solid (302 mg, 68%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl N-[(3S,4R)-3-hydroxy-4-piperidyl]carbamate (319 mg, 1.48 mmol), DIPEA (0.70 mL, 4.0 mmol), and MeCN (7 mL).

[1173]

[1174] Preparation Example 112. tert-butyl 4-(6-chloropyrazine-2-yl)-3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate

[1175] A white solid target compound (20 mg, 4%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl 3-(hydroxymethyl)-3-methyl-piperazine-1-carboxylate (308 mg, 1.34 mmol), DIPEA (0.70 mL, 4.0 mmol), and DMSO (7 mL).

[1176]

[1177] Preparation Example 113. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate

[1178] The brown liquid target compound (612 mg, 92%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl(S)-2-(hydroxymethyl)piperazine-1-carboxylate (479 mg, 2.22 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1179]

[1180] Preparation Example 114. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-(methoxymethyl)piperazine-1-carboxylate

[1181] The target compound (665 mg, 96%) as a brown liquid was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl(S)-2-(methoxymethyl)piperazine-1-carboxylate (510 mg, 2.22 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1182]

[1183] Preparation Example 115. tert-butyl (1-(6-chloropyrazine-2-yl)piperidin-4-yl)(methyl)carbamate

[1184] The brown liquid target compound (633 mg, 96%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl N-methyl-N-(4-piperidyl)carbamate (475 mg, 2.22 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1185]

[1186] Preparation Example 116. tert-butyl (1-(6-chloropyrazine-2-yl)-3,3-difluoropiperidin-4-yl)carbamate

[1187] A brown liquid target compound (356 mg, 51%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl 2,2-difluoropiperazine-1-carboxylate (523 mg, 2.22 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1188]

[1189] Preparation Example 117. tert-butyl ((3R,4S)-1-(6-chloropyrazine-2-yl)-3-fluoropiperidin-4-yl)carbamate

[1190] The target compound as a white solid (558 mg, 84%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl ((3R)-3-fluoropiperidin-4-yl)carbamate (484 mg, 2.22 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1191]

[1192] Preparation Example 118. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-3-ethylpiperazine-1-carboxylate

[1193] The brown liquid target compound (457 mg, 66%) was obtained by applying the method of Preparation Example 69 at 120 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl (3S)-3-ethylpiperazine-1-carboxylate (475 mg, 2.22 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (8 mL).

[1194]

[1195] Preparation Example 119. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-ethylpiperazine-1-carboxylate

[1196] The brown liquid target compound (685 mg, 104%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl (2R)-2-ethylpiperazine-1-carboxylate (475 mg, 2.22 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (8 mL).

[1197]

[1198] Preparation Example 120. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-ethylpiperazine-1-carboxylate

[1199] The brown liquid target compound (642 mg, 98%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl (2S)-2-ethylpiperazine-1-carboxylate (475 mg, 2.22 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (8 mL).

[1200]

[1201] Preparation Example 121. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

[1202] A brown solid target compound (85 mg, 18%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-3-(hydroxymethyl)piperazine-1-carboxylate (340 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1203]

[1204] Preparation Example 122. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-isopropylpiperazine-1-carboxylate

[1205] A colorless liquid target compound (405 mg, 86%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(S)-2-isopropylpiperazine-1-carboxylate (337 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (5 mL).

[1206]

[1207] Preparation Example 123. tert-butyl 5-(6-chloropyrazine-2-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate

[1208] The target compound as a yellow solid (503 mg, 80%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (439 mg, 2.22 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1209]

[1210] Preparation Example 124. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-3-isobutylpiperazine-1-carboxylate

[1211] The brown liquid target compound (199 mg, 42%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(S)-3-isobutylpiperazine-1-carboxylate (358 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1212]

[1213] Preparation Example 125. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-isobutylpiperazine-1-carboxylate

[1214] The brown liquid target compound (395 mg, 83%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-2-isobutylpiperazine-1-carboxylate (358 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1215]

[1216] Preparation Example 126. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate

[1217] The brown liquid target compound (191 mg, 42%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-3-(2-hydroxyethyl)piperazine-1-carboxylate (340 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1218]

[1219] Preparation Example 127. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-3-propylpiperazine-1-carboxylate

[1220] A brown liquid target compound (185 mg, 40%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-3-propylpiperazine-1-carboxylate (337 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1221]

[1222] Preparation Example 128. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-3-phenylpiperazine-1-carboxylate

[1223] A brown liquid target compound (67 mg, 13%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-3-phenylpiperazine-1-carboxylate (387 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1224]

[1225] Preparation Example 129. tert-butyl (R)-3-benzyl-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate

[1226] A brown liquid target compound (184 mg, 35%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-3-benzylpiperazine-1-carboxylate (408 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1227]

[1228] Preparation Example 130. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-(2-hydroxyethyl)piperazine-1-carboxylate

[1229] A colorless liquid target compound (380 mg, 83%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl (R)-2-(2-hydroxyethyl)piperazine-1-carboxylate hydrochloride (394 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1230]

[1231] Preparation Example 131. tert-butyl (R)-2-benzyl-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate

[1232] A colorless liquid target compound (485 mg, 93%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-2-benzylpiperazine-1-carboxylate (408 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1233]

[1234] Preparation Example 132. tert-butyl (2R,5S)-4-(6-chloropyrazine-2-yl)-2,5-diethylpiperazine-1-carboxylate

[1235] A colorless liquid target compound (255 mg, 53%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl (2R,5S)-2,5-diethylpiperazine-1-carboxylate (358 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1236]

[1237] Preparation Example 133. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate

[1238] A colorless liquid target compound (191 mg, 42%) was obtained by applying the method of Preparation Example 69 at 120 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(S)-3-(2-hydroxyethyl)piperazine-1-carboxylate (340 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1239]

[1240] Preparation Example 134. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[1241] A colorless liquid target compound (343 mg, 76%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-2-(cyanomethyl)piperazine-1-carboxylate (332 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1242]

[1243] Preparation Example 135. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-3-(cyanomethyl)piperazine-1-carboxylate

[1244] A brown liquid target compound (31 mg, 7%) was obtained by applying the method of Preparation Example 69 at 120 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-3-(cyanomethyl)piperazine-1-carboxylate (333 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1245]

[1246] Preparation Example 136. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-3-(cyanomethyl)piperazine-1-carboxylate

[1247] A brown liquid target compound (39 mg, 9%) was obtained by applying the method of Preparation Example 69 at 120 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(S)-3-(cyanomethyl)piperazine-1-carboxylate (333 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1248]

[1249] Preparation Example 137. tert-butyl (1-(6-chloropyrazine-2-yl)pyrrolidin-3-yl)carbamate

[1250] The brown liquid target compound (370 mg, 92%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-pyrrolidin-3-ylcarbamate (276 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1251]

[1252] Preparation Example 138. tert-butyl 3-(6-chloropyrazine-2-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate

[1253] A colorless liquid target compound (187 mg, 89%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (100 mg, 0.67 mmol), tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (146 mg, 0.74 mmol), DIPEA (0.35 mL, 2.01 mmol), and DMSO (3 mL).

[1254]

[1255] Preparation Example 139. tert-butyl (3aR,6aS)-5-(6-chloropyrazine-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[1256] 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (470 mg, 2.22 mmol) and DIPEA (1.05 mL, 6.04 mmol) were mixed with DMSO (10 mL) at 80 °C using the method of Preparation Example 69 to obtain a colorless liquid target compound (534 mg, 82%).

[1257]

[1258] Preparation Example 140. tert-butyl (S)-(1-(6-chloropyrazine-2-yl)pyrrolidin-3-yl)carbamate

[1259] 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl(S)-pyrrolidine-3-ylcarbamate (275 mg, 1.48 mmol), and DIPEA (0.70 mL, 4.03 mmol) were mixed in DMSO (7 mL) at 80 °C to obtain the target compound (376 mg, 93%) as a white solid.

[1260]

[1261] Preparation Example 141. tert-butyl (R)-(1-(6-chloropyrazine-2-yl)pyrrolidin-3-yl)carbamate

[1262] 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-pyrrolidine-3-ylcarbamate (275 mg, 1.48 mmol), and DIPEA (0.70 mL, 4.03 mmol) were mixed in DMSO (7 mL) at 80 °C to obtain the target compound (370 mg, 92%) as a white solid.

[1263]

[1264] Preparation Example 142. tert-butyl (S)-(1-(6-chloropyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate

[1265] 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(S)-methyl(pyrrolidin-3-yl)carbamate (296 mg, 1.48 mmol), and DIPEA (0.70 mL, 4.03 mmol) were mixed with DMSO (7 mL) at 80 °C using the method of Preparation Example 69 to obtain a colorless liquid target compound (416 mg, 99%).

[1266]

[1267] Preparation Example 143. tert-butyl (R)-(1-(6-chloropyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate

[1268] 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-methyl(pyrrolidin-3-yl)carbamate (296 mg, 1.48 mmol) and DIPEA (0.70 mL, 4.03 mmol) were mixed with DMSO (7 mL) at 80 °C using the method of Preparation Example 69 to obtain a colorless liquid target compound (460 mg, 100%).

[1269]

[1270] Preparation Example 144. (3R,4R)-4-azido-1-(6-chloropyrazine-2-yl)pyrrolidin-3-ol

[1271] Step 1: (3R,4R)-4-azidopyrrolidine-3-ol hydrochloride

[1272] tert-butyl (3R,4R)-3-azido-4-hydroxy-pyrrolidine-1-carboxylate (0.50 g 2.19 mmol) was dissolved in 11 mL of DCM, and HCl (4 M in 1,4-dioxane) (2.74 mL, 10.95 mmol) was slowly added. After stirring at room temperature for 3 hours, the solution was concentrated under reduced pressure to obtain the target compound (3R,4R)-4-azidopyrrolidine-3-ol hydrochloride. The compound was used in the following reaction without further purification.

[1273] Step 2: (3R,4R)-4-azido-1-(6-chloropyrazine-2-yl)pyrrolidin-3-ol. The (3R,4R)-4-azidopyrrolidin-3-ol hydrochloride obtained in Step 1 and 2,6-dichloropyrazine (0.30 mg, 2.01 mmol) were dissolved in 10 mL of DMSO, and diisopropylethylamine (1.05 mL, 6.04 mmol) was added. The temperature was raised to 80 °C and stirred for 8 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate and washed with soapy water. The organic layer was dried with sodium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the target compound (3R,4R)-4-azido-1-(6-chloropyrazine-2-yl)pyrrolidin-3-ol (0.33 g, 68%).

[1274]

[1275] Preparation Example 145. tert-butyl 3-((6-chloropyrazine-2-yl)amino)pyrrolidine-1-carboxylate

[1276] 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (296 mg, 1.48 mmol) and DIPEA (0.70 mL, 4.03 mmol) were mixed in DMSO (7 mL) at 80 °C using the method of Preparation Example 69 to obtain a colorless liquid target compound (253 mg, 63%).

[1277]

[1278] Preparation Example 146. tert-butyl (S)-3-((6-chloropyrazine-2-yl)amino)pyrrolidine-1-carboxylate

[1279] 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (295 mg, 1.48 mmol), and DIPEA (0.70 mL, 4.03 mmol) were mixed in DMSO (7 mL) at 80 °C using the method of Preparation Example 69 to obtain a colorless liquid target compound (256 mg, 64%).

[1280]

[1281] Preparation Example 147. tert-butyl 4-(6-chloropyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1282] 2,6-dichloropyrazine (0.25 g, 1.70 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.50 g, 1.62 mmol), 2N sodium carbonate (2.45 mL, 4.85 mmol), tetrakis(triphenylphosphine)palladium (93 mg, 0.081 mmol), and 1,2-dimethoxyethane (8.1 mL) were added. The reaction mixture was degassed using nitrogen for 5 minutes and stirred at 100 °C for 3 hours. After extraction with ethyl acetate (150 mL), the organic layer was washed with water (50 mL x 2). Then, it was dried with anhydrous magnesium sulfate and filtered. The residue obtained by concentration under reduced pressure was purified by MPLC (100% Hex to 100% EtOAc) to obtain the target compound (0.17 g, 36%).

[1283]

[1284] Preparation Example 148. tert-butyl 4-(3-bromophenyl)piperazine-1-carboxylate

[1285] 1-Bromo-3-iodo-benzene (3.0 g, 10.7 mmol), tert-butylpiperazine-1-carboxylate (2.0 g, 10.7 mmol), sodium tert-butoxide (1.55 g, 16.1 mmol), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (42 mg, 0.11 mmol) were added to toluene (11 mL). The reaction mixture was degassed using nitrogen for 5 minutes and stirred at 90 °C for 12 hours. After extraction with ethyl acetate (150 mL), the organic layer was washed with water (50 mL x 2). Subsequently, it was dried with anhydrous magnesium sulfate and filtered. The residue obtained by concentration under reduced pressure was purified by MPLC (100% Hex to 100% EtOAc) to obtain the target compound (1.5 g, 41%).

[1286]

[1287] Preparation Example 149. tert-butyl (R)-4-(3-bromophenyl)-3-ethylpiperazine-1-carboxylate

[1288] 1-Bromo-3-iodo-benzene (500 mg, 1.77 mmol), tert-butyl(R)-3-ethylpiperazine-1-carboxylate (379 mg, 1.77 mmol), potassium tert-butoxide (594 mg, 5.30 mmol), BINAP (110 mg, 0.18 mmol), and Tris(dibenzylideneacetone)dipalladium (81 mg, 0.09 mmol) were dissolved in toluene (9 mL), degassed for 10 minutes, and stirred at 100 °C for 18 hours. The reaction mixture was concentrated under reduced pressure and filtered using a Celite filter. The mixture was extracted with ethyl acetate, and the resulting residue was purified by MPLC to obtain the target compound (129 mg, 20%).

[1289]

[1290] Preparation Example 150. (S)-2-chloro-6-(2,4-dimethylpiperazine-1-yl)pyrazine

[1291] 2,6-dichloropyrazine (200 mg, 1.34 mmol) was dissolved in DMSO (6.7 mL), followed by the addition of (S)-1,3-dimethylpiperazine (166 mg, 1.47 mmol) and DIPEA (0.70 mL, 4.02 mmol), and the mixture was stirred at 140 °C for 18 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (Hx:EtOAc=100:0 to 0:100) to obtain the target compound (151 mg, 50%) as a brown liquid.

[1292]

[1293] Preparation Example 151. 1-(6-chloropyrazine-2-yl)-N,N-dimethylazetidine-3-amine

[1294] The target compound (180 mg, 63%) was obtained by applying the method of Preparation Example 69 to 2,6-dichloropyrazine (200 mg, 1.34 mmol) and N,N-dimethylazetidin-3-amine dihydrochloride (256 mg, 1.48 mmol).

[1295]

[1296] Preparation Example 152. 1-(6-chloropyrazine-2-yl)-4-methyl-1,4-diazephane

[1297] 2,6-dichloropyrazine (200 mg, 1.34 mmol), 1-methyl-1,4-diazephane (169 mg, 1.48 mmol), and DIPEA (0.70 mL, 4.03 mmol) were mixed in DMSO (7 mL) at 120 °C using the method of Preparation Example 69 to obtain the target compound (158 mg, 52%) as a brown liquid.

[1298]

[1299] Preparation Example 153. 1-(6-chloropyrazine-2-yl)-N,N-dimethylpiperidine-4-amine

[1300] 2,6-dichloropyrazine (200 mg, 1.34 mmol), N,N-dimethylpiperidine-4-amine (189 mg, 1.48 mmol), and DIPEA (0.70 mL, 4.03 mmol) were mixed with DMSO (7 mL) at 120 °C using the method of Preparation Example 69 to obtain the brown liquid target compound (205 mg, 63%).

[1301]

[1302] Preparation Example 154. tert-butyl 4-(4-chlorothiazole-2-yl)piperazine-1-carboxylate

[1303] 2,4-dichlorothiazole (300 mg, 1.95 mmol), 1-Boc-piperazine (363 mg, 1.95 mmol), and cesium carbonate (635 mg, 1.95 mmol) were mixed with DMSO (10 mL) at 150°C using the method of Preparation Example 69 to obtain the target compound (249 mg, 42%) as a brown liquid.

[1304]

[1305] Preparation Example 155. N-(1,3-dimethylisoquinoline-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1306] The target compound (0.45 g, 93%) was obtained by applying the method of Preparation Example 3 to the 6-bromo-N-(1,3-dimethylisoquinoline-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.44 g, 0.99 mmol) obtained in Preparation Example 42.

[1307]

[1308] Preparation Example 156. 6-Bromo-N-(1,3-dimethylisoquinoline-4-yl)-8-fluoro-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1309] The target compound (60 mg, 27%) was obtained by applying the method of Step 3 of Preparation Example 2 to 6-bromo-8-fluoro-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (0.25 g, 0.48 mmol) and 1,3-dimethylisoquinoline-4-amine (82 mg, 0.48 mmol) obtained in the synthesis process of Preparation Example 13.

[1310]

[1311] Preparation Example 157. N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1312] The target compound (2.06 g, 79%) was obtained by applying the method of Preparation Example 3 to the 6-bromo-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (3.34 g, 5.55 mmol) obtained in Preparation Example 46.

[1313]

[1314] Preparation Example 158. 8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1315] Step 1: 6-Bromo-8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydro-1H-isoquinoline-2-sulfonamide

[1316] The target compound (0.20 g, 96%) was obtained by applying the method of Step 3 of Preparation Example 2 to 6-bromo-8-fluoro-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (0.25 g, 0.48 mmol) and 2-methylpyrazolo[1,5-a]pyridine-3-amine (70 mg, 0.48 mmol) obtained during the synthesis of Preparation Example 13.

[1317] Step 2: 8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1318] The target compound (0.22 g, 99%) was obtained by applying the method of Preparation Example 3 to 6-bromo-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (3.34 g, 5.55 mmol).

[1319] The target compound (0.22 g, 99%) was obtained by applying the method of Preparation Example 3 to the 6-bromo-8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydro-1H-isoquinoline-2-sulfonamide (0.20 g, 0.46 mmol) obtained in Step 1.

[1320]

[1321] Preparation Example 159. 6-Bromo-N-(2-methylpyrazolo[1,5-a]pyrazine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1322] Step 1: Amino 2,4,6-trimethylbenzenesulfonate

[1323] Ethyl (1Z)-N-(2,4,6-trimethylphenyl)sulfonyloxyethaneimidate (15 g, 52.5 mmol) was dissolved in THF (15 mL) and the temperature was lowered to 0 °C. Then, 70% perchloric acid (13.7 mL, 157 mmol) was slowly added over 1 hour, and the temperature was raised to room temperature and stirred for 30 minutes. The reaction was terminated with ice (300 g) and extracted with DCM (100 mL). The target compound was obtained by drying with anhydrous magnesium sulfate, filtering, and vacuum distillation. The compound was used in the following reaction without purification.

[1324] Step 2: Pyrazine-1-um-1-amine; 2,4,6-trimethylbenzenesulfonate

[1325] Pyrazine (3.2 g, 40 mmol) was dissolved in DCM (40 mL), and the temperature was lowered to 0 °C. The amino 2,4,6-trimethylbenzenesulfonate (10 g, 46 mmol) obtained in Step 1 was dissolved in DCM (100 mL) and slowly added. The temperature was raised to room temperature and stirred for 16 hours. The mixture was concentrated under reduced pressure, and diethyl ether (100 mL) was added. The resulting solid was filtered and dried under reduced pressure to obtain the target compound (12.5 g, quant).

[1326] Step 3: 6-Bromo-N-(2-methylpyrazolo[1,5-a]pyrazine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1327] The target compound (2%, 5-step yield) was obtained by sequentially applying the method of Step 1 of Preparation Example 46, Step 2 of Preparation Example 46, and Steps 1, 2, and 3 of Preparation Example 33 to the pyrazine-1-um-1-amine; 2,4,6-trimethylbenzenesulfonate (3.0 g, 10 mmol) obtained in Step 2.

[1328]

[1329] Preparation Example 160. N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1330] The target compound (0.18 g, 96%) was obtained by applying the method of Preparation Example 3 to the 6-bromo-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.17 g, 0.39 mmol) obtained in Preparation Example 54.

[1331]

[1332] Preparation Example 161. 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-i)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindolin-2-sulfonamide

[1333] The target compound (693 mg, 62%) was obtained by applying the method of Preparation Example 3 to the 5-bromo-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindolin-2-sulfonamide (1.0 g, 2.60 mmol) obtained in Preparation Example 56.

[1334]

[1335] Preparation Example 162. 5-Bromo-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)isoindolin-2-sulfonamide

[1336] The target compound (55 mg, 99%) was obtained by applying the method of Step 3 of Preparation Example 2 to 5-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-isoindoline trifluoromethanesulfonate (67 mg, 0.14 mmol) and 2-methylpyrazolo[1,5-a]pyridine-3-amine (20 mg, 0.14 mmol) obtained during the synthesis of Preparation Example 56.

[1337]

[1338] Preparation Example 163. N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-sulfonamide

[1339] The target compound (1.16 g, 100%) was obtained by applying the method of Preparation Example 3 to the 5-bromo-N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-2-sulfonamide (1.4 g, 2.41 mmol) obtained in Preparation Example 162.

[1340]

[1341] Preparation Example 164. tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate

[1342] The target compound (0.22 g, 77%) was obtained by applying the method of Preparation Example 3 to the tert-butyl 4-(3-bromophenyl)piperazine-1-carboxylate (0.25 g, 0.73 mmol) obtained in Preparation Example 148.

[1343]

[1344] Preparation Example 165. 6-Bromo-N-(3-ethyl-1,5-dimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1345] Step 1: 1,5-dimethyl-3-vinyl-pyrazol

[1346] Methyl(triphetyl)phosphonium bromide (4.5 g, 12.5 mmol) was dissolved in THF (40 mL), and the temperature was lowered to -20°C. Then, 1.6 M N-butyllithium (7.8 mL, 12.5 mmol) was slowly added. After stirring for 1 hour at the same temperature, 1,5-dimethylpyrazole-3-carbaldehyde (1.25 g, 10 mmol) was dissolved in THF (30 mL) and slowly added. The temperature was slowly raised to room temperature and stirred for 15 hours. A saturated aqueous NH4Cl solution (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the target compound (673 mg, 55%).

[1347] Step 2: 3-ethyl-1,5-dimethyl-pyrazole

[1348] The 1,5-dimethyl-3-vinyl-pyrazole (672 mg, 5.5 mmol) obtained in Step 1 was used to obtain the target compound (570 mg, 83%) using the method of Step 2 of Preparation Example 6.

[1349] Step 3: 3-ethyl-1,5-dimethyl-4-nitro-pyrazol

[1350] At 0 ℃, 3 mL of conc. H2SO4 was slowly added to the 3-ethyl-1,5-dimethyl-pyrazole (560 mg, 4.5 mmol) obtained in Step 2, followed by 2 mL of conc. HNO3. The reaction mixture was stirred at 100 ℃ for 15 hours. Ice (50 g) was added to terminate the reaction, and the mixture was stirred for 10 minutes. The resulting white solid was filtered and washed with water. It was dried under reduced pressure to obtain the target compound (600 mg, 78%).

[1351] Step 4: 3-ethyl-1,5-dimethyl-pyrazol-4-amine

[1352] The 3-ethyl-1,5-dimethyl-4-nitro-pyrazole (610 mg, 3.6 mmol) obtained in Step 3 was used to obtain the target compound (500 mg, quant) using the method of Step 2 of Preparation Example 6.

[1353] Step 5: 6-Bromo-N-(3-ethyl-1,5-dimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1354] The target compound (1.165 g, 78%) was obtained by applying the method of Step 3 of Preparation Example 2 to 3-ethyl-1,5-dimethyl-pyrazole-4-amine (501 mg, 3.6 mmol) obtained in Step 4 and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (1.83 g, 3.6 mmol) obtained in Step 2 of Preparation Example 2.

[1355]

[1356] Preparation Example 166. 6-Bromo-N-(2-ethylpyrazolo[1,5-b]pyridazine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1357] The target compound (20%, 5-step yield) was obtained by applying the method of Preparation Example 51 to amino hydrogen sulfate (32.57 g, 288 mmol), pyridazine (14 mL, 192 mmol), and ethylbu-2-inoate (6.0 g, 48 mmol).

[1358]

[1359] Preparation Example 167. 6-Bromo-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1360] Amino 3-ethyl-1H-pyrazole-5-amine (1.11 g, 10 mmol) and 1,1,3,3-tetramethoxypropane (1.97 g, 12 mmol) were used to obtain the target compound (15%, 4-step yield) by applying the method of Preparation Example 52.

[1361]

[1362] Preparation Example 168. 6-Bromo-N-(2-ethyl-5,6-dimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1363] Step 1: 2-Bromo-5,6-dimethyl-pyridine-3-amine

[1364] 5,6-dimethylpyridine-3-amine (1.16 g, 9.5 mmol) was dissolved in MeCN (95 mL), and the temperature was lowered to 0 °C. Then, NBS (1.86 g, 10.45 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Ethyl acetate and water were added, and extraction was performed. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the target compound (1.117 g, 58%).

[1365] Step 2: 5,6-dimethyl-2-vinyl-pyridine-3-amine

[1366] 2-bromo-5,6-dimethyl-pyridine-3-amine (202 mg, 1.0 mmol), potassium trifluoro(vinyl)boronate (167 mg, 1.25 mmol), PdCl2(dppf).DCM (42 mg, 0.05 mmol), and Na2CO3 (318 mg, 3.0 mmol) obtained in Step 1 were dissolved in dioxane (9 mL) and water (1 mL), and degassed with nitrogen for 5 minutes. The temperature was raised to 95 °C and stirred for 6 hours. Ethyl acetate and water were added, and extraction was performed. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the target compound (52 mg, 35%).

[1367] Step 3: 2-ethyl-5,6-dimethyl-pyridine-3-amine

[1368] The 5,6-dimethyl-2-vinyl-pyridine-3-amine (52 mg, 0.35 mmol) obtained in Step 2 was subjected to the method of Step 2 of Preparation Example 6 to obtain the target compound (50 mg, 94%).

[1369] Step 4: 6-Bromo-N-(2-ethyl-5,6-dimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1370] The target compound (100 mg, 33%) was obtained by applying the method of Step 3 of Preparation Example 2 to 2-ethyl-5,6-dimethyl-pyridine-3-amine (105 mg, 0.7 mmol) obtained in Step 3 and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (355 mg, 0.7 mmol) obtained in Step 2 of Preparation Example 2.

[1371]

[1372] Preparation Example 169. 6-Bromo-N-(2-methoxy-5,6-dimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1373] Step 1: 2-Methoxy-5,6-Dimethyl-pyridine-3-amine

[1374] 2-bromo-5,6-dimethyl-pyridine-3-amine (302 mg, 1.5 mmol) obtained in Step 1 of Preparation Example 168 was dissolved in dioxane (10 mL), and 5 M NaOMe (2.4 mL, 12 mmol) was added. The temperature was raised to 120 °C and stirred for 15 hours. The solvent was removed under reduced pressure and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the target compound (154 mg, 67%).

[1375] Step 2: 6-Bromo-N-(2-methoxy-5,6-dimethyl-3-pyridyl)-3,4-dihydro-1H-isoquinoline-2-sulfonamide

[1376] The target compound (421 mg, 98%) was obtained by applying the method of Step 3 of Preparation Example 2 to 2-methoxy-5,6-dimethyl-pyridine-3-amine (153 mg, 1.0 mmol) obtained in Step 1 and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (507 mg, 1.0 mmol) obtained in Step 2 of Preparation Example 2.

[1377]

[1378] Preparation Example 170. 6-Bromo-N-(5,6-dimethyl-2-(methylthio)pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1379] Step 1: 5,6-dimethyl-2-methylsulfanyl-pyridine-3-amine

[1380] 2-bromo-5,6-dimethyl-pyridine-3-amine (302 mg, 1.5 mmol) obtained in Step 1 of Preparation Example 168 was dissolved in DMSO (5 mL), and 2 M NaSMe aqueous solution (7.5 mL, 15 mmol) was added. The temperature was raised to 140 °C and stirred for 15 hours. The mixture was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the target compound (111 mg, 44%).

[1381] Step 2: 6-Bromo-N-(5,6-dimethyl-2-(methylthio)pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1382] The target compound (207 mg, 71%) was obtained by applying the method of Step 3 of Preparation Example 2 to 5,6-dimethyl-2-methylsulfanyl-pyridine-3-amine (110 mg, 0.65 mmol) obtained in Step 1 and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (331 mg, 0.65 mmol) obtained in Step 2 of Preparation Example 2.

[1383]

[1384] Preparation Example 171. 6-Bromo-N-(2-methylindazole-3-yl)-3,4-dihydro-1H-isoquinoline-2-sulfonamide

[1385] The target compound (60 mg, 14%) was obtained by applying the method of Step 3 of Preparation Example 2 to 2-methylindazole-3-amine (150 mg, 1.02 mmol) and 6-bromo-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (516 mg, 1.02 mmol) obtained in Step 2 of Preparation Example 2.

[1386]

[1387] Preparation Example 172. N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-sulfonamide

[1388] Step 1: 6-Bromo-8-fluoro-2-(3-methylimidazole-1-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate

[1389] The target compound (3.38 g, 47%, Step 2) was obtained by sequentially applying the method of Step 1 and Step 2 of Preparation Example 2 to 6-bromo-8-fluoro-1,2,3,4-tetrahydroisoquinoline (3.81 g, 16.6 mmol) and 1-imidazole-1-ilsulfonyl-3-methyl-imidazole-1-um trifluoromethanesulfonate (5.0 g, 13.8 mmol).

[1390] Step 2: N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-sulfonamide

[1391] The target compound (1.45 g, 93%, Step 2) was obtained by sequentially applying Step 3 of Preparation Example 2 and the method of Preparation Example 2 to the 6-bromo-8-fluoro-2-(3-methylimidazole-1-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethanesulfonate (1.63 g, 3.10 mmol) and 2-ethylpyrazolo[1,5-a]pyridine-3-amine (0.50 g, 3.10 mmol) obtained in Step 1.

[1392]

[1393] Preparation Example 173. 6-Bromo-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-8-fluoro-3,4-dihydro-1H-isoquinoline-2-sulfonamide

[1394] The target compound (0.57 g, 92%, step 2) was obtained by sequentially applying Step 3 of Preparation Example 2 and the method of Preparation Example 2 to 2-ethylpyrazolo[1,5-a]pyrimidine-3-amine (0.20 g, 1.23 mmol) and 6-bromo-8-fluoro-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethane sulfonate (0.65 g, 1.23 mmol).

[1395]

[1396] Preparation Example 174. 6-Bromo-N-(3-ethyl-1,5-dimethyl-pyrazole-4-yl)-8-fluoro-3,4-dihydro-1H-isoquinoline-2-sulfonamide

[1397] The target compound (0.56 g, 81%, Step 2) was obtained by sequentially applying Step 3 of Preparation Example 2 and the method of Preparation Example 2 to 3-ethyl-1,5-dimethyl-pyrazole-4-amine (0.20 g, 1.44 mmol) and 6-bromo-8-fluoro-2-(3-methylimidazole-3-yum-1-yl)sulfonyl-3,4-dihydro-1H-isoquinoline trifluoromethane sulfonate (0.75 g, 1.44 mmol).

[1398]

[1399] Preparation Example 175. 6-Bromo-N-(3-isopropyl-1,5-dimethyl-pyrazole-4-yl)-3,4-dihydro-1H-isoquinoline-2-sulfonamide

[1400] 3-bromo-1,5-dimethyl-pyrazole (350 mg, 2.0 mmol), 2-isoprofenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (505 mg, 3.0 mmol), Pd(OAc)2 (45 mg, 0.2 mmol), lufos (187 mg, 0.4 mmol), and K3PO4 (1.28 g, 6.0 mmol) were dissolved in toluene (18 mL) and water (2 mL) and degassed with nitrogen for 10 minutes. The temperature was raised to 100 °C and stirred for 15 hours. The mixture was extracted with ethyl acetate, the organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain 3-isoprofenyl-1,5-dimethyl-pyrazole (160 mg, 58%). Next, steps 2 and 3 of Preparation Example 6, step 2 of Preparation Example 6, and step 3 of Preparation Example 2 were applied sequentially to obtain the target compound (23%, 4-step yield).

[1401]

[1402] Preparation Example 176. 6-Bromo-N-(1,5-dimethyl-3-propyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1403] At 0 ℃, 10 mL of H2SO4 was added to 3-bromo-1,5-dimethyl-pyrazole (525 mg, 3.00 mmol), and KNO3 (1.51 g, 15 mmol) was added over 10 minutes. The temperature was raised to 45 ℃ and stirred for 15 hours. Ice (200 g) was added to terminate the reaction, and the mixture was stirred for 10 minutes. The resulting solid was filtered and washed with water. It was dried under reduced pressure to obtain 3-bromo-1,5-dimethyl-4-nitro-pyrazole (270 mg, 41%). Subsequently, Step 1 of Preparation Example 175, Step 2 of Preparation Example 6, and Step 3 of Preparation Example 2 were applied sequentially to obtain the target compound (76%, 3-step yield).

[1404]

[1405] Preparation Example 177. 6-Bromo-N-(2-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1406] Step 1: 2-prop-2-inoxytetrahydropyran

[1407] Propargyl alcohol (5.3 g, 95 mmol) and p-TsOH (0.10 g, 0.95 mmol) were dissolved in DCM (90 mL), and the temperature was lowered to 0°C. DHP (8.8 g, 105 mmol) was slowly added, and the mixture was stirred for 5 minutes. The temperature was raised to room temperature and stirred for 12 hours. The reaction was terminated by adding a saturated aqueous NaHCO3 solution (30 mL), and the mixture was extracted with DCM. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (11 g, 82%).

[1408] Step 2: Ethyl 4-tetrahydropyran-2-yloxybu-2-inoate

[1409] 2-prop-2-inoxytetrahydropyran (5.00 g, 35.70 mmol) obtained in Step 1 was dissolved in THF (100 mL), and the temperature was lowered to -78 °C. Then, n-BuLi (24.50 mL, 1.6 M hexane solution, 39.27 mmol) was slowly added and stirred for 1 hour. Ethyl chloroformate (7.75 g, 71.40 mmol) was slowly added, the temperature was raised to room temperature, and the mixture was stirred for 12 hours. Saturated aqueous NH4Cl solution (50 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (8.3 g, crude).

[1410] Step 3: 6-Bromo-N-(2-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1411] Pyridine-1-um-1-amine iodide (6.66 g, 30 mmol) was dissolved in DMF (40 mL), and K2CO3 (6.2 g, 45 mmol) was added. Then, ethyl 4-tetrahydropyran-2-yloxybu-2-inoate (7.64 g, 36 mmol) was added in step 2, and the mixture was stirred at room temperature for 24 hours. It was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain ethyl 2-(tetrahydropyran-2-yloxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (5.0 g, 54%). Next, steps 2, 3, and 4 of Preparation Example 54 and step 3 of Preparation Example 2 were applied sequentially to obtain the target compound (11%, 4-step yield).

[1412]

[1413] Preparation Example 178. 6-Bromo-N-(2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1414] Ethyl 2-(tetrahydropyran-2-iloxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (1.217 g, 4.0 mmol) obtained from the process of obtaining step 3 of Preparation Example 177 was dissolved in MeOH, and p-TsOH·H2O (0.190 g, 1.0 mmol) was added. The mixture was then stirred at room temperature for 15 hours, and the reaction was terminated by adding a saturated aqueous solution of NaHCO3. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered, and the residue obtained by reducing pressure concentration was purified by MPLC to obtain ethyl 2-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (820 mg, 93%). Next, steps 2, 3, and 4 of Preparation Example 54 and step 3 of Preparation Example 2 were applied sequentially to obtain the target compound (23%, 4-step yield).

[1415]

[1416] Preparation Example 179. 2-chloro-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-7,8-dihydro-1,6-naphthiridine-6(5H)-sulfonamide

[1417] Step 1: 2-chloro-6-imidazole-1-ylsulfonyl-7,8-dihydro-5H-1,6-naphthiridine

[1418] 2-chloro-5,6,7,8-tetrahydro-1,6-naphthiridine hydrochloride (1.23 g, 6.0 mmol) was dissolved in MeCN (25 mL), followed by the addition of DIPEA (1.05 mL, 6.0 mmol). After stirring at room temperature for 5 minutes, 1-imidazole-1-ylsulfonyl-3-methyl-imidazole-3-ium trifluoromethanesulfonate (2.7 g, 7.2 mmol) was added. The mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure, and then extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the target compound (1.23 g, 68%).

[1419] Step 2: 2-chloro-6-(3-methylimidazole-3-yum-1-yl)sulfonyl-7,8-dihydro-5H-1,6-naphthiridine trifluoromethanesulfonate

[1420] 2-chloro-6-imidazole-1-ylsulfonyl-7,8-dihydro-5H-1,6-naphthiridine (1.236 g, 4.13 mmol) obtained in Step 1 was dissolved in DCM (15 mL), the temperature was lowered to 0°C, and methyl trifluoromethanesulfonate (0.47 mL, 4.137 mmol) was slowly added over 15 minutes. After stirring for 3 hours, the resulting solid was dried under reduced pressure to obtain the target compound (1.9 g, crude).

[1421] Step 3: 2-chloro-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-7,8-dihydro-1,6-naphthiridine-6(5H)-sulfonamide

[1422] The target compound (125 mg, 32%) was obtained by applying the method of Step 3 of Preparation Example 2 to the 2-chloro-6-(3-methylimidazole-3-yum-1-yl)sulfonyl-7,8-dihydro-5H-1,6-naphthiridine trifluoromethanesulfonate (463 mg, 1.0 mmol) obtained in Step 2 and the 2-ethylpyrazolo[1,5-a]pyridine-3-amine (162 mg, 1.0 mmol) obtained in Step 4 of Preparation Example 54.

[1423]

[1424] Preparation Example 180. 2-chloro-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-sulfonamide

[1425] Tert-butyl 2-chloro-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (1.888 g, 7.0 mmol) was dissolved in DCM (35 mL), and then TFA (5.5 mL, 70 mmol) was added. The mixture was stirred at room temperature for 7 hours and concentrated under reduced pressure. The resulting solid was washed with a DCM:MTBE (2:1) mixture and dried under reduced pressure to obtain 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine 2,2,2-trifluoroacetic acid (1.93 g, 97%). Subsequently, steps 1 and 2 of Preparation Example 179 and step 3 of Preparation Example 2 were applied sequentially to obtain the target compound (16%, 3-step yield).

[1426]

[1427] Preparation Example 181. 6-chloro-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydro-2,7-naphthiridine-2(1H)-sulfonamide

[1428] Step 1: Diethyl 2-(2-chloro-5-ethoxycarbonyl-4-pyridyl)propanedioate

[1429] Ethyl 4,6-dichloropyridine-3-carboxylate (20 g, 91 mmol) was dissolved in DMF (365 mL), followed by the addition of K2CO3 (37.7 g, 273 mmol). Diethyl malonate (16.5 mL, 109.2 mmol) was slowly added, and the mixture was stirred at 100 °C for 24 hours. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the target compound (32 g, crude).

[1430] Step 2: 4-(carboxymethyl)-6-chloro-pyridine-3-carboxylic acid

[1431] The diethyl 2-(2-chloro-5-ethoxycarbonyl-4-pyridyl)propanedioate (31.5 g, 91 mmol) obtained in Step 1 was dissolved in MeOH (150 mL), and then LiOH·H2O (19 g, 455 mmol) dissolved in water (150 mL) was added. The temperature was raised to 70 °C and stirred for 3 hours, then concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the target compound (14 g, 71%).

[1432] Step 3: 2-[2-chloro-5-(hydroxymethyl)-4-pyridyl]ethanol

[1433] 4-(carboxymethyl)-6-chloro-pyridine-3-carboxylic acid (2.0 g, 9.3 mmol) obtained in Step 2 was dissolved in THF (30 mL), and the temperature was lowered to 10 °C. Then, NaBH4 (1.06 g, 27.9 mmol) was added and stirred for 30 minutes. The temperature was lowered to 0 °C, and boron trifluorodiethyl isherate (3.5 mL, 27.9 mmol) was slowly added. The temperature was slowly raised to room temperature and stirred for 15 hours. After adding a saturated aqueous NaCl solution (100 mL), the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the target compound (1.4 g, 80%).

[1434] Step 4: 6-chloro-2-[(2,4-dimethoxyphenyl)methyl]-3,4-dihydro-1H-2,7-naphthiridine

[1435] 4-(carboxymethyl)-6-chloro-pyridine-3-carboxylic acid (1.4 g, 7.46 mmol) obtained in Step 3 was dissolved in THF (40 mL), and the temperature was lowered to 0 °C. Then, NET3 (2.6 mL, 18.65 mmol) and methanesulfonyl chloride (1.3 mL, 16.4 mmol) were added sequentially. After stirring at 0 °C for 30 minutes, K3CO3 (2.6 g, 18.65 mmol) and KI (250 mg, 1.49 mmol) were added, followed by (2,4-dimethoxyphenyl)methaneamine (1 mL, 6.71 mmol). The mixture was stirred at room temperature for 15 hours and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the target compound (1.4 g, 58%).

[1436] Step 5: 6-chloro-1,2,3,4-tetrahydro-2,7-naphthiridine

[1437] 6-chloro-2-[(2,4-dimethoxyphenyl)methyl]-3,4-dihydro-1H-2,7-naphthiridine (1.4 g, 4.4 mmol) obtained in Step 4 was dissolved in TFA (9 mL), and then triethylsilane (0.85 mL, 5.28 mmol) was added. After stirring at 85 °C for 4 hours, the solution was concentrated under reduced pressure. The pH was adjusted to 14 with a 50% aqueous NaOH solution, and the solution was extracted with DCM. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (700 mg, 94%).

[1438] Step 6: 6-chloro-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydro-2,7-naphthiridine-2(1H)-sulfonamide

[1439] 6-chloro-1,2,3,4-tetrahydro-2,7-naphthiridine (700 mg, 4.15 mmol) obtained in Step 5 was dissolved in MeCN (20 mL), and 1-imidazole-1-ylsulfonyl-3-methyl-imidazole-3-ium trifluorosulfonate (1.8 g, 4.98 mmol) was added. The mixture was stirred at room temperature for 24 hours, and the residue obtained by vacuum concentration was purified by MPLC to obtain 6-chloro-2-imidazole-1-ylsulfonyl-3,4-dihydro-1H-2,7-naphthiridine. Subsequently, Step 2 of Preparation Example 179 and Step 3 of Preparation Example 2 were applied sequentially to obtain the target compound (15%, 3-step yield).

[1440]

[1441] Preparation Example 182. tert-butyl (2R)-4-(6-chloropyrazine-2-yl)-2-(1-hydroxyethyl)piperazine-1-carboxylate

[1442] The tert-butyl (R)-2-acetyl-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate (300 mg, 0.88 mmol) obtained in Preparation Example 191 was dissolved in methanol (1.4 mL), and then LiBH4 (4.4 mL, 8.8 mmol) was added at 0°C and stirred for 1 minute at room temperature. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered, and the residue obtained by reducing pressure concentration was purified by silica gel chromatography (EA:MeOH=100:0 to 95:5) to obtain the target compound (123 mg, 41%) as a brown liquid.

[1443]

[1444] Preparation Example 183. tert-butyl (2R,5R)-4-(6-chloropyrazine-2-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate

[1445] A white solid target compound (295 mg, 64%) was obtained by applying the method of Preparation Example 69 at 120 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (340 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1446]

[1447] Preparation Example 184. tert-butyl (R)-2-butyl-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate

[1448] A white solid target compound (450 mg, 94%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-2-butylpiperazine-1-carboxylate (358 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1449]

[1450] Preparation Example 185. tert-butyl (S)-2-butyl-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate

[1451] A white solid target compound (407 mg, 85%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(S)-2-butylpiperazine-1-carboxylate (358 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1452]

[1453] Preparation Example 186. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-(ethoxymethyl)piperazine-1-carboxylate

[1454] The tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (164 mg, 0.49 mmol) obtained in Preparation Example 113 was dissolved in DMSO (2.4 mL), KOH (56 mg, 1.0 mmol) was added, and the mixture was stirred at 0 °C for 10 minutes. Then, iodoethane (0.04 mL, 0.6 mol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (EA:MeOH = 100:0 to 95:5) to obtain the target compound (112 mg, 63%) as a brown liquid.

[1455]

[1456] Preparation Example 187. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-propylpiperazine-1-carboxylate

[1457] A white solid target compound (425 mg, 93%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(R)-2-propylpiperazine-1-carboxylate (337 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1458]

[1459] Preparation Example 188. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-propylpiperazine-1-carboxylate

[1460] A white solid target compound (422 mg, 92%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(S)-2-propylpiperazine-1-carboxylate (337 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1461]

[1462] Preparation Example 189. tert-butyl (2S)-4-(6-chloropyrazine-2-yl)-2-(1-hydroxyethyl)piperazine-1-carboxylate

[1463] The brown liquid target compound (LP) (674 mg, 28%) and target compound (MP) (675 mg, 28%) were obtained by applying the method of Preparation Example 182 to the tert-butyl (S)-2-acetyl-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate (2.4 g, 7.0 mmol), NaBH4 (318 mg, 8.4 mmol), and methanol (17 mL) obtained in Preparation Example 190.

[1464]

[1465] Preparation Example 190. tert-butyl (S)-2-acetyl-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate

[1466] Step 1: (S)-1-(tert-butoxycarbonyl)-4-(6-chloropyrazine-2-yl)piperazine-2-carboxylic acid

[1467] A white solid target compound (4.8 g, 100%) was obtained by applying Step 1 of Preparation Example 108 at room temperature using 1-(tert-butyl) 2-methyl (S)-4-(6-chloropyrazine-2-yl)piperazine-1,2-dicarboxylate (5 g, 14.01 mmol) obtained in Preparation Example 107, NaOH (70 mL), and methanol (70 mL).

[1468] Step 2: tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-(methoxy(methyl)carbamoyl)piperazine-1-carboxylate

[1469] The target compound as a white solid (4.3 g, 80%) was obtained by applying Step 2 of Preparation Example 108 at room temperature using (S)-1-(tert-butoxycarbonyl)-4-(6-chloropyrazine-2-yl)piperazine-2-carboxylic acid (4.8 g, 14.00 mmol) obtained in Step 1, HATU (6.4 g, 16.8 mmol), dimethylamine hydrochloride (1.64 g, 16.8 mmol), DIPEA (7.3 mL, 42.0 mmol), and DMF (70 mL).

[1470] Step 3: tert-butyl (S)-2-acetyl-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate

[1471] tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-(methoxy(methyl)carbamoyl)piperazine-1-carboxylate (1.3 g, 8.4 mmol) obtained in Step 2 and 3M methyl magnesium bromide (2.8 mL, 8.4 mmol) were dissolved in THF (11 mL) and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure to obtain the target compound (800 mg, 70%) as a brown liquid.

[1472]

[1473] Preparation Example 191. tert-butyl (R)-2-acetyl-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate

[1474] Step 1: (R)-1-(tert-butoxycarbonyl)-4-(6-chloropyrazine-2-yl)piperazine-2-carboxylic acid

[1475] A white solid target compound (5.3 g, 100%) was obtained by applying Step 1 of Preparation Example 108 at room temperature using 1-(tert-butyl) 2-methyl (R)-4-(6-chloropyrazine-2-yl)piperazine-1,2-dicarboxylate (4.5 g, 12.6 mmol) obtained in Preparation Example 106, NaOH (63 mL), and methanol (63 mL).

[1476] Step 2: tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-(methoxy(methyl)carbamoyl)piperazine-1-carboxylate

[1477] The target compound as a white solid (4.1 g, 68%) was obtained by applying Step 2 of Preparation Example 108 at room temperature using (R)-1-(tert-butoxycarbonyl)-4-(6-chloropyrazine-2-yl)piperazine-2-carboxylic acid (5.3 g, 15.6 mmol) obtained in Step 1, HATU (7.1 g, 18.7 mmol), dimethylamine hydrochloride (1.8 g, 18.7 mmol), DIPEA (8.1 mL, 46.7 mmol), and DMF (72 mL).

[1478] Step 3: tert-butyl (R)-2-acetyl-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate

[1479] The brown liquid target compound (2.4 g, 65%) was obtained by applying Step 3 of Preparation Example 190 to the tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-(methoxy(methyl)carbamoyl)piperazine-1-carboxylate (4.1 g, 10.6 mmol) obtained in Step 2, 3M methyl magnesium bromide (4.3 mL, 12.8 mmol), and THF (50 mL).

[1480]

[1481] Preparation Example 192. tert-butyl (2R)-4-(6-chloropyrazine-2-yl)-2-(1-hydroxyethyl)piperazine-1-carboxylate

[1482] The brown liquid target compound (LP) (290 mg, 12%) and target compound (MP) (650 mg, 27%) were obtained by applying the method of Preparation Example 182 to the tert-butyl (R)-2-acetyl-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate (2.4 g, 7.0 mmol), LiBH4 (3.8 mL, 7.6 mmol), and methanol (34 mL) obtained in Preparation Example 191.

[1483]

[1484] Preparation Example 193. (S)-2-(4-(6-chloropyrazine-2-yl)piperazine-2-yl)propan-2-ol

[1485] A white solid target compound (476 mg, 100%) was obtained by applying the method of Preparation Example 69 at 70 °C using 2,6-dichloropyrazine (170 mg, 1.14 mmol), (S)-2-(2-methoxypropane-2-yl)piperazine dihydrochloride (260 mg, 1.20 mmol), DIPEA (0.60 mL, 3.42 mmol), and DMSO (6 mL).

[1486]

[1487] Preparation Example 194. tert-butyl 2-(2-amino-2-oxoethyl)-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate

[1488] A brown liquid target compound (89 mg, 83%) was obtained by applying Step 2 of Preparation Example 108 at room temperature using 2-(1-(tert-butoxycarbonyl)-4-(6-chloropyrazine-2-yl)piperazine-2-yl)acetic acid (100 mg, 0.28 mmol) obtained in Step 2 of Preparation Example 205, HATU (128 mg, 0.34 mmol), dimethylamine hydrochloride (27 mg, 0.34 mmol), DIPEA (0.14 mL, 0.84 mmol), and DMF (1.4 mL).

[1489]

[1490] Preparation Example 195. tert-butyl 4-(6-chloropyrazine-2-yl)-2-(2-(methylamino)-2-oxoethyl)piperazine-1-carboxylate

[1491] A brown liquid target compound (91 mg, 88%) was obtained by applying Step 2 of Preparation Example 108 at room temperature using 2-(1-(tert-butoxycarbonyl)-4-(6-chloropyrazine-2-yl)piperazine-2-yl)acetic acid (100 mg, 0.28 mmol) obtained in Step 2 of Preparation Example 205, HATU (128 mg, 0.34 mmol), dimethylamine hydrochloride (23 mg, 0.34 mmol), DIPEA (0.14 mL, 0.84 mmol), and DMF (1.4 mL).

[1492]

[1493] Preparation Example 196. tert-butyl 4-(6-chloropyrazine-2-yl)-2-(2-(dimethylamino)-2-oxoethyl)piperazine-1-carboxylate

[1494] A brown liquid target compound (89 mg, 83%) was obtained by applying Step 2 of Preparation Example 108 at room temperature using 2-(1-(tert-butoxycarbonyl)-4-(6-chloropyrazine-2-yl)piperazine-2-yl)acetic acid (100 mg, 0.28 mmol) obtained in Step 2 of Preparation Example 205, HATU (128 mg, 0.34 mmol), dimethylamine hydrochloride (27 mg, 0.34 mmol), DIPEA (0.14 mL, 0.84 mmol), and DMF (1.4 mL).

[1495]

[1496] Preparation Example 197. tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-((dimethylamino)methyl)piperazine-1-carboxylate

[1497] Step 1: tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-formylpiperazine-1-carboxylate

[1498] tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (1.5 g, 4.56 mmol) and DIPEA (2.4 mL, 13.7 mmol) obtained in Preparation Example 113 were dissolved in DCM (22 mL) and then purged with nitrogen. Subsequently, SO3-py complex (2.2 g, 14 mmol) and DMSO (6.5 mL) were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with dichloromethane, and the organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (EA:MeOH = 100:0 to 95:5) to obtain the target compound (1.6 g, 100%) as a brown liquid.

[1499] Step 2: tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-((dimethylamino)methyl)piperazine-1-carboxylate

[1500] The tert-butyl (R)-4-(6-chloropyrazine-2-yl)-2-formylpiperazine-1-carboxylate (98 mg, 0.3 mmol) obtained in Step 1, dimethylamine (0.3 mL, 0.6 mmol), and AcOH (0.009 mL, 0.15 mmol) were dissolved in THF (1.5 mL) and stirred at room temperature for 1 hour. Then, NaHB(OAc)3 (140 mg, 0.66 mmol) was added and stirred at room temperature for 30 minutes. The solvent was concentrated under reduced pressure, the reaction mixture was extracted with ethyl acetate, the organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (EA:MeOH = 100:0 to 95:5) to obtain the target compound (70 mg, 66%) as a brown liquid.

[1501]

[1502] Preparation Example 198. tert-butyl (3R)-4-(6-chloropyrazine-2-yl)-3-cyclopropyl-piperazine-1-carboxylate

[1503] A white solid target compound (370 mg, 54%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl (3R)-3-cyclopropylpiperazine-1-carboxylate (479 mg, 2.11 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1504]

[1505] Preparation Example 199. tert-butyl (3R)-4-(6-chloropyrazine-2-yl)-3-isobutyl-piperazine-1-carboxylate

[1506] A white solid target compound (780 mg, 71%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (300 mg, 2.01 mmol), tert-butyl (3R)-3-isobutylpiperazine-1-carboxylate (513 mg, 2.11 mmol), DIPEA (1.05 mL, 6.04 mmol), and DMSO (10 mL).

[1507]

[1508] Preparation Example 200. tert-butyl 3-[(6-chloropyrazine-2-yl)amino]azetidine-1-carboxylate

[1509] A white solid target compound (850 mg, 81%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (550 mg, 3.69 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (668 mg, 3.88 mmol), DIPEA (1.93 mL, 11.08 mmol), and DMSO (18 mL).

[1510]

[1511] Preparation Example 201. tert-butyl (3R)-3-[(6-chloropyrazine-2-yl)amino]pyrrolidine-1-carboxylate

[1512] A white solid target compound (900 mg, 78%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (550 mg, 3.69 mmol), tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (722 mg, 3.88 mmol), DIPEA (1.93 mL, 11.08 mmol), and DMSO (18 mL).

[1513]

[1514] Preparation Example 202. tert-butyl 4-[(6-chloropyrazine-2-yl)amino]piperidine-1-carboxylate

[1515] A white solid target compound (900 mg, 78%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (550 mg, 3.69 mmol), tert-butyl 4-aminopiperidin-1-carboxylate (776 mg, 3.88 mmol), DIPEA (1.93 mL, 11.08 mmol), and DMSO (18 mL).

[1516]

[1517] Preparation Example 203. tert-butyl (2R)-4-(6-chloropyrazine-2-yl)-2-cyclopropyl-piperazine-1-carboxylate

[1518] Step 1: 2-chloro-6-[(3R)-3-cyclopropylpiperazine-1-yl]pyrazine

[1519] The target compound (530 mg, 94%) was obtained by applying the method of Preparation Example 69 at 100 °C using 2,6-dichloropyrazine (350 mg, 2.35 mmol), (2R)-2-cyclopropylpiperazine (491 mg, 2.47 mmol), DIPEA (2.05 mL, 11.75 mmol), and DMSO (18 mL).

[1520] Step 2: tert-butyl (2R)-4-(6-chloropyrazine-2-yl)-2-cyclopropyl-piperazine-1-carboxylate

[1521] 2-chloro-6-[(3R)-3-cyclopropylpiperazine-1-yl]pyrazine (0.53 g, 2.22 mmol) obtained in Step 1 was dissolved in DCM (11 mL), and the temperature was lowered to 0 °C. Tert-butyl dicarbonate (0.53 g, 2.44 mmol) and triethylamine (0.34 mL, 2.44 mmol) were added sequentially, and the mixture was stirred at room temperature for 20 hours. After adding water to the reaction mixture and extracting with DCM, the organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the target compound (650 mg, 86%).

[1522]

[1523] Preparation Example 204. tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-(2-hydroxyethyl)piperazine-1-carboxylate

[1524] A white solid target compound (463 mg, 100%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (200 mg, 1.34 mmol), tert-butyl(S)-2-(2-hydroxyethyl)piperazine-1-carboxylate (340 mg, 1.48 mmol), DIPEA (0.70 mL, 4.03 mmol), and DMSO (7 mL).

[1525]

[1526] Preparation Example 205. 2-(1-(tert-butoxycarbonyl)-4-(6-chloropyrazine-2-yl)piperazine-2-yl)acetic acid

[1527] Step 1: tert-butyl 4-(6-chloropyrazine-2-yl)-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate

[1528] A brown solid target compound (1.1 g, 78%) was obtained by applying the method of Preparation Example 69 at 80 °C using 2,6-dichloropyrazine (550 mg, 3.70 mmol), tert-butyl 2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (1.0 g, 3.88 mmol), DIPEA (1.93 mL, 11.1 mmol), and DMSO (18 mL).

[1529] Step 2: 2-(1-(tert-butoxycarbonyl)-4-(6-chloropyrazine-2-yl)piperazine-2-yl)acetic acid

[1530] The target compound as a white solid (1.0 g, 100%) was obtained by applying Step 1 of Preparation Example 108 at room temperature using tert-butyl 4-(6-chloropyrazine-2-yl)-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (1.07 g, 2.89 mmol) obtained in Step 1, NaOH (14 mL), and methanol (14 mL).

[1531]

[1532] Preparation Example 206. tert-butyl (R)-2-(aminomethyl)-4-(6-chloropyrazine-2-yl)piperazine-1-carboxylate

[1533] The colorless liquid target compound (386 mg, 73%) was obtained by applying the method of Preparation Example 197 to tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-formylpiperazine-1-carboxylate (500 mg, 1.5 mmol) obtained in Step 2 of Preparation Example 197, ammonia (7.7 mL, 3.1 mmol), AcOH (0.04 mL, 0.77 mmol), NaHB(OAc)3 (713 mg, 3.37 mmol), and THF (6.1 mL).

[1534]

[1535] Preparation Example 207. tert-butyl (3R)-3-[(6-chloropyrazine-2-yl)-ethyl-amino]pyrrolidine-1-carboxylate

[1536] NaH (16 mg, 0.40 mmol) was dissolved in DMF (1.7 mL), the temperature was lowered to 0 °C, and then tert-butyl (3R)-3-[(6-chloropyrazine-2-yl)amino]pyrrolidine-1-carboxylate (100 mg, 0.33 mmol) obtained in Preparation Example 201 was added. After stirring for 15 minutes, iodoethane (40 μL, 0.50 mmol) was slowly added. After stirring at room temperature for 12 hours, water and ethyl acetate were added for extraction. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the target compound (100 mg, 91%).

[1537]

[1538] Preparation Example 208. tert-butyl (3R)-3-[2-[tert-butyl(dimethyl)silyl]oxyethyl-(6-chloropyrazine-2-yl)amino]pyrrolidine-1-carboxylate

[1539] The target compound (98 mg, 64%) was obtained by applying the method of Preparation Example 207 to tert-butyl (3R)-3-[(6-chloropyrazine-2-yl)amino]pyrrolidin-1-carboxylate (100 mg, 0.33 mmol) and 2-bromoethoxy-tert-butyl-dimethyl-silane (120 mg, 0.50 mmol) obtained in Preparation Example 201.

[1540]

[1541] Preparation Example 209. tert-butyl N-[(3R)-1-(6-chloropyrazine-2-yl)pyrrolidin-3-yl]-N-ethyl-carbamate

[1542] The target compound (105 mg, 96%) was obtained by applying the method of Preparation Example 207 to tert-butyl N-[(3R)-1-(6-chloropyrazine-2-yl)pyrrolidin-3-yl]carbamate (0.10 g, 0.34 mmol) and iodoethane (0.040 mL, 0.50 mmol).

[1543]

[1544] Preparation Example 210. (R)-(4-(6-chloropyrazine-2-yl)-1-methylpiperazine-2-yl)methaneamine

[1545] Step 1: (S)-(4-(6-chloropyrazine-2-yl)piperazine-2-yl)methanol

[1546] The yellow solid target compound (825 mg, 100%) was obtained by applying Step 1 of Preparation Example 144 to tert-butyl (S)-4-(6-chloropyrazine-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (908 mg, 2.77 mmol) obtained in Preparation Example 113, HCl (4M in 1,4-dioxane) (3.5 mL, 13.8 mmol), and DCM (14 mL).

[1547] Step 2: (S)-(4-(6-chloropyrazine-2-yl)-1-methylpiperazine-2-yl)methanol

[1548] (S)-(4-(6-chloropyrazine-2-yl)piperazine-2-yl)methanol (366 mg, 1.60 mmol) obtained in Step 1 and 35% formaldehyde (0.25 mL, 3.20 mmol) were dissolved in methanol (8 mL) and stirred at 60 °C for 1 hour. Then, NaHB(OAc)3 (678 mg, 3.20 mmol) was added and stirred at 60 °C for 12 hours. The solvent was concentrated under reduced pressure, the reaction mixture was extracted with ethyl acetate, the organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure to obtain the target compound (314 mg, 81%) as a brown liquid.

[1549] Step 3: (S)-4-(6-chloropyrazine-2-yl)-1-methylpiperazine-2-carbaldehydride

[1550] The (S)-(4-(6-chloropyrazine-2-yl)-1-methylpiperazine-2-yl)methanol (569 mg, 2.34 mmol), DIPEA (1.2 mL, 7.03 mmol), SO3-py complex (746 mg, 4.69 mmol), DMSO (3.3 mL), and DCM (12 mL) obtained in Step 2 were applied to the method of Preparation Example 197 to obtain a colorless liquid target compound (200 mg, 35%).

[1551] Step 4: (R)-(4-(6-chloropyrazine-2-yl)-1-methylpiperazine-2-yl)methaneamine

[1552] (S)-4-(6-chloropyrazine-2-yl)-1-methylpiperazine-2-carbaldehyde (200 mg, 0.831 mmol), ammonia (4.2 mL, 1.66 mmol), AcOH (0.02 mL, 0.5 mmol), NaHB(OAc)3 (387 mg, 1.82 mmol), and THF (4.2 mL) obtained in Step 3 were applied to Preparation Example 197 to obtain the brown liquid target compound (63 mg, 31%).

[1553]

[1554] Preparation Example 211. tert-butyl 4-(2-chlorothieno[3,2-d]pyrimidine-4-yl)piperazine-1-carboxylate

[1555] A white solid target compound (750 mg, 87%) was obtained by applying the method of Preparation Example 69 at room temperature using 2,4-dichlorothieno[3,2-d]pyrimidine (500 mg, 2.44 mmol), 1-Boc-piperazine (500 mg, 2.68 mmol), DIPEA (0.64 mL, 3.66 mmol), and DMF (4.9 mL).

[1556]

[1557] Preparation Example 212. tert-butyl 4-(2,5-dichloropyrimidine-4-yl)piperazine-1-carboxylate

[1558] A white solid target compound (1.38 g, 76%) was obtained by applying the method of Preparation Example 69 at room temperature using 2,4,5-trichloropyrimidine (1.00 g, 5.45 mmol), 1-Boc-piperazine (1.12 g, 6.00 mmol), DIPEA (1.42 mL, 8.18 mmol), and DMF (10.9 mL).

[1559]

[1560] Preparation Example 213. tert-butyl ((3R,4S)-1-(6-chloropyrazine-2-yl)-4-hydroxypiperidin-3-yl)carbamate

[1561] The target compound as a white solid (293 mg, 100%) was obtained by applying the method of Preparation Example 69 at 60 °C using 2,6-dichloropyrazine (100 mg, 0.67 mmol), tert-butyl ((3R,4S)-4-hydroxypiperidin-3-yl)carbamate (152 mg, 0.70 mmol), DIPEA (0.35 mL, 2.01 mmol), and DMSO (3 mL).

[1562]

[1563] Preparation Example 214. tert-butyl ((3S,4R)-1-(6-chloropyrazine-2-yl)-4-hydroxypiperidin-3-yl)carbamate

[1564] A white solid target compound (300 mg, 100%) was obtained by applying the method of Preparation Example 69 at 60 °C using 2,6-dichloropyrazine (100 mg, 0.67 mmol), tert-butyl ((3S,4R)-4-hydroxypiperidin-3-yl)carbamate (152 mg, 0.70 mmol), DIPEA (0.35 mL, 2.01 mmol), and DMSO (3 mL).

[1565]

[1566] Preparation Example 215. tert-butyl ((3R,4R)-1-(6-chloropyrazine-2-yl)-4-hydroxypiperidin-3-yl)carbamate

[1567] The target compound as a white solid (206 mg, 93%) was obtained by applying the method of Preparation Example 69 at 60 °C using 2,6-dichloropyrazine (100 mg, 0.67 mmol), tert-butyl ((3R,4R)-4-hydroxypiperidin-3-yl)carbamate (152 mg, 0.70 mmol), DIPEA (0.35 mL, 2.01 mmol), and DMSO (3 mL).

[1568]

[1569] Preparation Example 216. tert-butyl ((3S,4S)-1-(6-chloropyrazine-2-yl)-4-hydroxypiperidin-3-yl)carbamate

[1570] A white solid target compound (225 mg, 100%) was obtained by applying the method of Preparation Example 69 at 60 °C using 2,6-dichloropyrazine (100 mg, 0.67 mmol), tert-butyl ((3S,4S)-4-hydroxypiperidin-3-yl)carbamate (152 mg, 0.70 mmol), DIPEA (0.35 mL, 2.01 mmol), and DMSO (3 mL).

[1571]

[1572] Preparation Example 217. tert-butyl (R)-4-(4-bromopyridine-2-yl)-3-methylpiperazine-1-carboxylate

[1573] The target compound (143 mg, 35%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (200 mg, 1.13 mmol) and tert-butyl(R)-3-methylpiperazine-1-carboxylate (239 mg, 1.19 mmol).

[1574]

[1575] Preparation Example 218. tert-butyl (S)-4-(4-bromopyridine-2-yl)-3-ethylpiperazine-1-carboxylate

[1576] The target compound (54 mg, 13%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (200 mg, 1.13 mmol) and tert-butyl(S)-3-ethylpiperazine-1-carboxylate (256 mg, 1.19 mmol).

[1577]

[1578] Preparation Example 219. tert-butyl (S)-4-(5-chloropyridine-3-yl)-3-ethylpiperazine-1-carboxylate

[1579] The target compound (550 mg, 84%) was obtained by applying the method of Preparation Example 149 to tert-butyl (3S)-3-ethylpiperazine-1-carboxylate (428 mg, 2.0 mmol) and 3-bromo-5-chloro-pyridine (461 mg, 2.4 mmol).

[1580]

[1581] Preparation Example 220. tert-butyl 4-(5-chloropyridine-3-yl)piperazine-1-carboxylate

[1582] The target compound (500 mg, 83%) was obtained by applying the method of Preparation Example 149 to 1-Boc-piperazine (373 mg, 2.0 mmol) and 3-bromo-5-chloro-pyridine (461 mg, 2.4 mmol).

[1583]

[1584] Preparation Example 221. tert-butyl (R)-4-(4-bromopyridine-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

[1585] The target compound (40 mg, 6%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (300 mg, 1.70 mmol) and tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate (372 mg, 1.72 mmol).

[1586]

[1587] Preparation Example 222. tert-butyl (S)-4-(4-bromopyridine-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

[1588] The target compound (58 mg, 9%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (300 mg, 1.70 mmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (372 mg, 1.72 mmol).

[1589]

[1590] Preparation Example 223. tert-butyl (S)-4-(4-bromopyridine-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate

[1591] The target compound (267 mg, 42%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (300 mg, 1.70 mmol) and tert-butyl(S)-2-(hydroxymethyl)piperazine-1-carboxylate (372 mg, 1.72 mmol).

[1592]

[1593] Preparation Example 224. tert-butyl (R)-4-(4-bromopyridine-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate

[1594] The target compound (305 mg, 48%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (300 mg, 1.70 mmol) and tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate (372 mg, 1.72 mmol).

[1595]

[1596] Preparation Example 225. tert-butyl (R)-4-(4-bromopyridine-2-yl)-2-(2-hydroxyethyl)piperazine-1-carboxylate

[1597] The target compound (367 mg, 56%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (300 mg, 1.70 mmol) and tert-butyl (R)-2-(2-hydroxyethyl)piperazine-1-carboxylate hydrochloride (459 mg, 1.72 mmol).

[1598]

[1599] Preparation Example 226. tert-butyl (S)-4-(4-bromopyridine-2-yl)-2-(2-hydroxyethyl)piperazine-1-carboxylate

[1600] The target compound (297 mg, 45%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (300 mg, 1.70 mmol) and tert-butyl(S)-2-(2-hydroxyethyl)piperazine-1-carboxylate (396 mg, 1.72 mmol).

[1601]

[1602] Preparation Example 227. tert-butyl (S)-4-(4-bromopyridine-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate

[1603] The target compound (42 mg, 6%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (300 mg, 1.70 mmol) and tert-butyl(S)-3-(2-hydroxyethyl)piperazine-1-carboxylate (396 mg, 1.72 mmol).

[1604]

[1605] Preparation Example 228. tert-butyl (R)-4-(4-bromopyridine-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate

[1606] The target compound (11 mg, 3%) was obtained by applying the method of Preparation Example 57 to 4-bromo-2-fluoro-pyridine (190 mg, 1.07 mmol) and tert-butyl (R)-3-(2-hydroxyethyl)piperazine-1-carboxylate (251 mg, 1.09 mmol).

[1607]

[1608] Preparation Example 229. tert-butyl (2R,6S)-4-(6-chloropyrazine-2-yl)-2-ethyl-6-(2-hydroxyethyl)piperazine-1-carboxylate

[1609] Step 1: tert-butyl N-[(1R)-1-(hydroxymethyl)propyl]carbamate

[1610] (2R)-2-aminobutan-1-ol (5.08 g, 57 mmol) was dissolved in DCM (115 mL), and Boc anhy. (13.4 mL, 57 mmol) was slowly added. After stirring at 45 °C for 24 hours, the mixture was extracted with DCM. The organic layer was dried with anhydrous magnesium sulfate, and after filtration, concentrated under reduced pressure to obtain the target compound (10.8 g, quant).

[1611] Step 2: tert-butyl N-[(1R)-1-[(1,3-dioxoisoindolin-2-yl)methyl]propyl]carbamate

[1612] The tert-butyl N-[(1R)-1-(hydroxymethyl)propyl]carbamate (10.8 g, 57 mmol) obtained in Step 1 was dissolved in THF (115 mL), and the temperature was lowered to 0 °C. Then, PPh3 (15.7 g, 59.85 mmol) and phthalimide (9.3 g, 62.7 mmol) were added. Subsequently, diisopropyl azodicarboxylate (DIAD) (11.8 mL, 59.85 mmol) was added, the temperature was raised to room temperature, and the mixture was stirred for 8 hours. The residue obtained by concentration under reduced pressure was purified by MPLC to obtain the target compound (9.5 g, 52%).

[1613] Step 3: tert-butyl N-[(1R)-1-(aminomethyl)propyl]carbamate

[1614] The tert-butyl N-[(1R)-1-[(1,3-dioxoisoindolin-2-yl)methyl]propyl]carbamate (9.5 g, 28.9 mmol) obtained in Step 2 was dissolved in MeOH (300 mL), and then hydrazine hydrate (7.5 mL, 123.7 mmol) was added. The temperature was raised to 80 °C and stirred for 15 hours. The mixture was concentrated under reduced pressure and extracted with DCM. The organic layer was dried with anhydrous magnesium sulfate, and after filtration, concentrated under reduced pressure to obtain the target compound (5.2 g, 92%).

[1615] Step 4: tert-butyl N-[(1R)-1-[[(4-nitrophenyl)sulfonylamino]methyl]propyl]carbamate

[1616] The tert-butyl N-[(1R)-1-(aminomethyl)propyl]carbamate (1.9 g, 10 mmol) obtained in Step 3 was dissolved in DCM (50 mL), and NET3 (4.2 mL, 30 mmol) was added. The temperature was lowered to 0 °C, 4-nitrobenzenesulfonyl chloride (2.2 g, 10 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The organic layer obtained by extraction with DCM was dried and filtered with anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by MPLC to obtain the target compound (2.6 g, 69%).

[1617] Step 5: Ethyl (E)-4-[[(2R)-2-(tert-butoxycarbonylamino)butyl]-(4-nitrophenyl)sulfonyl-amino]but-2-enoate

[1618] The tert-butyl N-[(1R)-1-[[(4-nitrophenyl)sulfonylamino]methyl]propyl]carbamate (2.62 g, 7.0 mmol) obtained in Step 4 was dissolved in DMF (35 mL), and K2CO3 (1.94 g, 14 mmol) and ethyl (E)-4-bromobutyl-2-enoate (1.16 mL, 8.4 mmol) were added. The mixture was stirred at room temperature for 15 hours and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and filtered. The residue obtained by concentration under reduced pressure was purified by MPLC to obtain the target compound (2.9 g, 85%).

[1619] Step 6: Ethyl 2-[(2S,6R)-6-ethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-yl]acetate

[1620] Ethyl (E)-4-[[(2R)-2-(tert-butoxycarbonylamino)butyl]-(4-nitrophenyl)sulfonyl-amino]but-2-enoate (2.915 g, 6.0 mmol) obtained in Step 5 was dissolved in DCM (20 mL), and TFA (5 mL, 64 mmol) was added. The mixture was stirred at room temperature for 2 hours. It was concentrated under reduced pressure and extracted with DCM. It was washed with a saturated aqueous solution of NaHCO3, and the organic layer was dried with anhydrous magnesium sulfate and filtered. The residue obtained by concentration under reduced pressure was purified by MPLC to obtain the target compound (718 mg, 31%).

[1621] Step 7: tert-butyl (2S,6R)-2-(2-ethoxy-2-oxo-ethyl)-6-ethyl-4-(4-nitrophenyl)sulfonyl-piperazine-1-carboxylate

[1622] Ethyl 2-[(2S,6R)-6-ethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-yl]acetate (1.112 g, 2.885 mmol) obtained in Step 6 was dissolved in DCM (3 mL), followed by the addition of (Boc)2O (2.0 mL, 8.65 mmol) and I2 (catalyst amount). After stirring at 50 °C for 18 hours, the mixture was extracted with DCM. The organic layer was dried with anhydrous magnesium sulfate and filtered. The residue obtained by concentration under reduced pressure was purified by MPLC to obtain the target compound (1.4 g, 99%).

[1623] Step 8: tert-butyl (2S,6R)-2-(2-ethoxy-2-oxo-ethyl)-6-ethyl-piperazine-1-carboxylate

[1624] The tert-butyl (2S,6R)-2-(2-ethoxy-2-oxo-ethyl)-6-ethyl-4-(4-nitrophenyl)sulfonyl-piperazine-1-carboxylate (1.4 g, 2.9 mmol) obtained in Step 7 was dissolved in THF (6 mL), followed by the addition of Cs2CO3 (1.9 g, 5.8 mmol) and 1-dodecanethiol (2.1 mL, 8.7 mmol). After stirring at 45 °C for 15 hours, the mixture was concentrated under reduced pressure. The organic layer obtained by extraction with ethyl acetate was dried and filtered with anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by MPLC to obtain the target compound (862 mg, 98%).

[1625] Step 9: tert-butyl (2S,6R)-4-(6-chloropyrazine-2-yl)-2-(2-ethoxy-2-oxo-ethyl)-6-ethyl-piperazine-1-carboxylate

[1626] The tert-butyl (2S,6R)-2-(2-ethoxy-2-oxo-ethyl)-6-ethyl-piperazine-1-carboxylate (862 mg, 2.86 mmol) obtained in Step 8 was dissolved in DMSO (15 mL), and 2,6-dichloropyrazine (430 mg, 2.86 mmol) and DIPEA (1.5 mL, 8.6 mmol) were added. The temperature was raised to 100 °C and stirred for 15 hours. The organic layer obtained by extraction with ethyl acetate was dried and filtered with anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by MPLC to obtain the target compound (1.0 g, 84%).

[1627] Step 10: tert-butyl (2R,6S)-4-(6-chloropyrazine-2-yl)-2-ethyl-6-(2-hydroxyethyl)piperazine-1-carboxylate

[1628] The tert-butyl (2S,6R)-4-(6-chloropyrazine-2-yl)-2-(2-ethoxy-2-oxo-ethyl)-6-ethyl-piperazine-1-carboxylate (413 mg, 1.0 mmol) obtained in Step 9 was dissolved in THF (10 mL), and the temperature was lowered to -15 °C. Then, 2.4 M LiAlH4 (0....

Claims

Sulfonamide derivative compounds represented by the following chemical formula 1, their hydrates, their solvates, or their pharmaceutically acceptable salts: <Chemical Formula 1> In the above formula, A and B are independently C or N, R 1 Silver is hydrogen, C 1-4 Straight-chain or branched-chain alkyl, -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b , -(CH2) x -OH, -(CH2) y -aryl, or a heteroaryl having one or two rings of 4 to 10 molecules containing one to three heteroatoms selected from N, O, and S, or a heterocyclil having one or two rings of 4 to 10 molecules containing one to three heteroatoms selected from N, O, and S, and R 1 is a singular or plural independent R 1-1 Whether replaced or not, The above R 1-1 C 1-6 Straight-chain or branched-chain alkyl, C 2-8 Alkenyl, C 1-4 Alkoxy, halogen, -(CH2) x -OH, -SR a , Oxo, -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b A heteroaryl comprising 1 to 3 heteroatoms selected from , N, O, and S, or a heterocyclil comprising 4 to 6 heteroatoms selected from N and O, wherein R 1-1 is a singular or plural independent R 1-2 Whether replaced or not, The above R 1-2 is C 1-4 Straight-chain or branched-chain alkyl, C 1-4 Alkoxy, oxo, -(CH2) x -OH, acetyl, C 1-4 It is a alkylsulfonyl, or a quaternary to six-membered heterocyclile comprising one to two heteroatoms selected from N and O, and R 2 is hydrogen, C 1-4 Straight-chain or branched-chain alkyl, C 3-8 Cycloalkyl, -(CH2) y -aryl, a heteroaryl having one or two rings of 5 to 10 molecules containing 1 to 3 Ns, or a partially unsaturated heterocyclil having two rings of 10 molecules containing 1 N, wherein R 2 is a singular or plural independent R 2-1 Whether replaced or not, The above R 2-1 C 1-4 It is a straight-chain or branched-chain alkyl, or nitro, and R 3 is hydrogen, halogen, -(CH2) y -aryl, or a heteroaryl of one or two rings of 5 to 10 molecules containing 1 to 3 Ns, and said R 3 is a singular or plural independent R 3-1 Whether replaced or not, The above R 3-1 C 1-4 Straight-chain or branched-chain alkyl, -(CH2) r -NR a R b , or is a heterocyclile of 4 to 7 groups containing 1 to 3 Ns, and R 4 is absent, or hydrogen, C 1-4 Straight-chain or branched-chain alkyl, hydroxy, C 1-3 It is an alkoxy or aryl, and R 5 is hydrogen, -(CH2) y - It is a heteroaryl or partially unsaturated heterocyclile of one or three rings comprising four to thirteen members, containing one to three heteroatoms selected from N, O, and S, and R 5 is a singular or plural independent R 5-1 Whether replaced or not, The above R 5-1 C 1-4 Straight-chain or branched-chain alkyl, halogen, C 1-4 haloalkyl, -(CH2) x -OH, C 1-4 Alkoxy, cyano, -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b or a saturated or partially unsaturated heterocyclile of one or two rings of 4 to 10 molecules comprising one to three heteroatoms selected from N and O, and said R 5-1 is a singular or plural independent R 5-2 Whether replaced or not, The above R 5-2 is C 1-6 Straight-chain or branched-chain alkyl, halogen, C 1-4 haloalkyl, oxo, -(CH2) x -CN, -(CH2) x -OH, -(CH2) x -OR a , -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b , -(CH2) y - It is an aryl, or a 4- to 6-membered heterocyclile containing 1 to 2 Ns, and R 6 is a heteroaryl of one or two rings of 4 to 10 molecules containing no, hydrogen, halogen, or 1 to 3 N, and R 6 is a singular or plural independent R 6-1 Whether replaced or not, The above R 6-1 -(CH2) r -NR a R b And, The above R a and R b is independently hydrogen, C 1-6 Straight-chain or branched-chain alkyl, -(CH2) x -OH, C 1-4 Alkoxy, -(CH2) y -aryl, a 5- to 10-membered heteroaryl containing 1 to 2 Ns, or a saturated or partially unsaturated heterocyclile of 1 or 2 rings of 4 to 10 members containing 1 to 2 heteroatoms selected from N and O, or R a and R b N and R connected to a and R b A forms a ring and further comprises 0 to 1 heteroatom selected from N and O, forming a heterocyclile of 1 or 2 rings of 4 to 10, and m is an integer from 1 to 3, and n is an integer from 0 to 2, and o is an integer from 0 to 2, and p is an integer from 0 to 7, and q is an integer from 0 to 3, and r is an integer from 0 to 6, and x is an integer from 0 to 6, and y is an integer from 0 to 3. In claim 1, a compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the above chemical formula 1 is the following chemical formula 1a: <Chemical Formula 1a> In the above formula, R 1 Silver is hydrogen, C 1-4 Straight-chain or branched-chain alkyl, -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b , -(CH2) x -OH, -(CH2) y -aryl, or a heteroaryl having one or two rings of 4 to 10 molecules containing one to three heteroatoms selected from N, O, and S, or a heterocyclil having one or two rings of 4 to 10 molecules containing one to three heteroatoms selected from N, O, and S, and R 1 is a singular or plural independent R 1-1 Whether replaced or not, The above R 1-1 C 1-6 Straight-chain or branched-chain alkyl, C 2-8 Alkenyl, C 1-4 Alkoxy, halogen, -(CH2) x -OH, -SR a , Oxo, -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b A heteroaryl comprising 1 to 3 heteroatoms selected from , N, O, and S, or a heterocyclil comprising 4 to 6 heteroatoms selected from N and O, wherein R 1-1 is a singular or plural independent R 1-2 Whether replaced or not, The above R 1-2 is C 1-4 Straight-chain or branched-chain alkyl, C 1-4 Alkoxy, oxo, -(CH2) x -OH, acetyl, C 1-4 It is a alkylsulfonyl, or a quaternary to six-membered heterocyclile comprising one to two heteroatoms selected from N and O, and R 2 is hydrogen, C 1-4 Straight-chain or branched-chain alkyl, C 3-8 Cycloalkyl, -(CH2) y -aryl, a heteroaryl having one or two rings of 5 to 10 molecules containing 1 to 3 Ns, or a partially unsaturated heterocyclil having two rings of 10 molecules containing 1 N, wherein R 2 is a singular or plural independent R 2-1 Whether replaced or not, The above R 2-1 C 1-4 It is a straight-chain or branched-chain alkyl, or nitro, and R 3 is hydrogen, halogen, -(CH2) y -aryl, or a heteroaryl of one or two rings of 5 to 10 molecules containing 1 to 3 Ns, and said R 3 is a singular or plural independent R 3-1 Whether replaced or not, The above R 3-1 C 1-4 Straight-chain or branched-chain alkyl, -(CH2) r -NR a R b , or is a heterocyclile of 4 to 7 groups containing 1 to 3 Ns, and R 4 is hydrogen, C 1-4 Straight-chain or branched-chain alkyl, hydroxy, C 1-3 It is an alkoxy or aryl, and R 5 is hydrogen, -(CH2) y - It is a heteroaryl or partially unsaturated heterocyclile of one or three rings comprising four to thirteen members, containing one to three heteroatoms selected from N, O, and S, and R 5 is a singular or plural independent R 5-1 Whether replaced or not, The above R 5-1 C 1-4 Straight-chain or branched-chain alkyl, halogen, C 1-4 haloalkyl, -(CH2) x -OH, C 1-4 Alkoxy, cyano, -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b or a saturated or partially unsaturated heterocyclile of one or two rings of 4 to 10 molecules comprising one to three heteroatoms selected from N and O, and said R 5-1 is a singular or plural independent R 5-2 Whether replaced or not, The above R 5-2 is C 1-6 Straight-chain or branched-chain alkyl, halogen, C 1-4 haloalkyl, oxo, -(CH2) x -CN, -(CH2) x -OH, -(CH2) x -OR a , -(CH2) o -C(O)R a , -(CH2) p -C(O)OR a , -(CH2) q -C(O)NR a R b , -(CH2) r -NR a R b , -(CH2) y - It is an aryl, or a 4- to 6-membered heterocyclile containing 1 to 2 Ns, and R 6 is a heteroaryl of one or two rings of 4 to 10 molecules containing hydrogen, a halogen, or 1 to 3 Ns, and R 6 is a singular or plural independent R 6-1 Whether replaced or not, The above R 6-1 -(CH2) r -NR a R b And, The above R a and R b is independently hydrogen, C 1-6 Straight-chain or branched-chain alkyl, -(CH2) x -OH, C 1-4 Alkoxy, -(CH2) y -aryl, a 5- to 10-membered heteroaryl containing 1 to 2 Ns, or a saturated or partially unsaturated heterocyclile of 1 or 2 rings of 4 to 10 members containing 1 to 2 heteroatoms selected from N and O, or R a and R b N and R connected to a and R b A forms a ring and further comprises 0 to 1 heteroatom selected from N and O, forming a heterocyclile of 1 or 2 rings of 4 to 10, and m is an integer from 1 to 3, and n is an integer from 0 to 2, and o is an integer from 0 to 2, and p is an integer from 0 to 7, and q is an integer from 0 to 3, and r is an integer from 0 to 6, and x is an integer from 0 to 6, and y is an integer from 0 to 3. In paragraph 1, The above R 1 This hydrogen, methyl, ethyl, propyl, isopropyl, 2-oxoethyl, -(CH2)C(O)OH, -(CH2)C(O)OCH3, -(CH2)3C(O)OH, -(CH2)6C(O)OH, -(CH2)6C(O)OCH3, -(CH2)C(O)NR a R b , -(CH2)2C(O)NH2, -(CH2)2NR a R b , -(CH2)3NR a R b , -(CH2)4NR a R b , -(CH2)5NR a R b , hydroxyethyl, hydroxypropaneyl, benzyl, phenethyl, pyrazolyl, thiazoleyl, isooxazoleyl, pyridineyl, pyrazolopyridineyl, indazoleyl, pyrazolopyrimidineyl, pyrazolopyridazineyl, pyrazolopyrazineyl, quinolineyl, isoquinolineyl, or tetrahydropyrazolopyridineyl, and The above R 1-1 This is methyl, ethyl, propyl, isopropyl, isobutyl, methylpropyl, propenyl, methylpropenyl, methoxy, chloro, bromo, hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxydimethylpropyl, -SH, -SCH3, oxo, acetyl, C(O)C(CH3)3, C(O)OH, C(O)NH2, C(O)NH(CH3), C(O)N(CH3)2, C(O)N(CH3)(OCH3), C(O)NH(C6H5), -NH2, -(CH2)2NH2, oxazolyl, pyridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazineyl or morpholino, The above R 1-2 ga methyl, methoxy, oxo, hydroxy, hydroxymethyl, acetyl, methylsulfonyl, or morpholino, and The above R a and R b is independently hydrogen, methyl, ethyl, dimethylaminoethyl, hydroxyethyl, hydroxypropaneyl, phenyl, benzyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or isoindolinyl, or R a and R b N and R connected to a and R b A compound, its hydrate, its solvate, or its pharmaceutically acceptable salt, which forms a ring to form azetidinyl, pyrrolidinyl, piperidinyl, piperazineyl, morpholino, or octahydro-2H-pyrido[1,2-a]pyrazineyl. In paragraph 1, The above R 2 ga is hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl, phenyl, pyrazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, or dihydroisoquinolineyl, and The above R 2-1 A compound, hydrate thereof, solvate thereof, or pharmaceutically acceptable salt thereof, wherein α is methyl, ethyl, or nitro. In paragraph 1, The above R 3 ga is hydrogen, fluoro, phenyl, pyridinyl, indazoleyl, or imidazopyridinyl, and The above R 3-1 A compound that is methyl, methylaminomethyl, dimethylaminomethyl, or piperazine, its hydrate, its solvate, or its pharmaceutically acceptable salt. In paragraph 1, the above R 4 A compound, its hydrate, its solvate, or its pharmaceutically acceptable salt, which is absent or hydrogen. In paragraph 1, The above R 5 ga hydrogen, phenyl, thiazoleyl, pyrazolyl, pyridineyl, pyrimidineyl, pyrazineyl, pyridazineyl, naphthaleneyl, thienopyrimidineyl, imidazopyridineyl, quinolineyl, dihydrocyclopentapyrimidineyl, hexahydrobisisoquinolineyl, tetrahydroquinazolinyl, or tetrahydrobenzofuro[3,2-c]pyridineyl, and The above R 5-1 This is methyl, ethyl, fluoro, chloro, trifluoromethyl, hydroxymethyl, hydroxypropyl, methoxy, cyano, -(CH2)2C(O)NH2, amino, aminomethyl, aminoethyl, C(O)OH, azetidinyl, pyrrolidinyl, piperidinyl, piperazineyl, diazepanyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[3.2.0]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[4.1.0]heptanyl, tetrahydropyridinyl, hexahydropyrrolo[3,4-c]pyrroloyl, diazapyrolo[2.5]octanyl, or hexahydro-2H,6H-pyrazino[1,2-c][1,3]oxazineyl, and The above R 5-2 a compound, hydrate thereof, solvate thereof, of which is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, fluoro, trifluoromethyl, cyano, cyanomethyl, hydroxy, oxo, amino, methylamino, dimethylamino, ethylamino, aminomethyl, dimethylaminomethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, ethoxymethyl, oxopropyl, C(O)OH, C(O)OCH3, CH3C(O)OH, CH3C(O)OC2H5, C(O)NH2, C(O)NH(CH3), C(O)N(CH3)2, CH3C(O)NH2, CH3C(O)NH(CH3), CH3C(O)N(CH3)2, phenyl, benzyl, azetidinyl, pyrrolidinyl, or piperidinyl; which is a compound, hydrate thereof, solvate thereof, or of thereof Pharmaceutically acceptable salt. In paragraph 1, The above R 6 It is absent or hydrogen, fluoro, or imidazopyridine, and The above R 6-1 A compound that is methylaminomethyl, its hydrate, its solvate, or its pharmaceutically acceptable salt. In paragraph 1, the above R a and R b is independently hydrogen, methyl, ethyl, butyl, dimethylaminoethyl, hydroxy, hydroxyethyl, hydroxypropyl, methoxy, phenyl, benzyl, pyridine-4-yl, azetidine-3-yl, pyrrolidine-3-yl, tetrahydrofuran-3-yl, piperidine-3-yl, piperidine-4-yl, or isoindolin-5-yl, or R a and R b N and R connected to a and R b A compound, its hydrate, its solvate, or its pharmaceutically acceptable salt, which forms a ring to form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazine-1-yl, morpholino, or octahydro-2H-pyrido[1,2-a]pyrazine-2-yl. In claim 1, a compound, its hydrate, its solvate, or its pharmaceutically acceptable salt, wherein the sulfonamide derivative compound represented by Formula 1 is selected from the group consisting of the following compounds: [1] 5-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [2] 5-(3-((dimethylamino)methyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [3] 5-(3-((dimethylamino)methyl)-1-methyl-1H-indazole-5-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [4] 7-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [5] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [6] 8-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [7] N-(3-isobutyl-1,5-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [8] 6-(2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [9] 6-(6-(piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [10] 6-(6-(piperazine-1-yl)pyridine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [11] 6-(6-(piperazine-1-yl)pyridazine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [12] 6-(5-(piperazine-1-yl)pyridazine-3-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [13] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [14] N,N,1,5-tetramethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-3-carboxamide 2HCl, [15] N-(2-methylpyridine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [16] N-(2-isopropylpyridine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [17] 1,5-dimethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-3-carboxamide 2HCl, [18] N,1,5-trimethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-3-carboxamide 2HCl, [19] (S)-6-(6-(2,4-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [20] (S)-6-(6-(2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [21] (R)-6-(6-(2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [22] 6-(6-(4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [23] (S)-6-(6-(3-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [24] 6-(6-(1,4-diazepan-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [25] 6-(6-(4-aminopiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [26] 6-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [27] 6-(6-(3-(dimethylamino)azetidine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [28] (S)-6-(6-(2-methylpiperazine-1-yl)pyridine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [29] (S)-6-(6-(2-methylpiperazine-1-yl)pyridazine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [30] (S)-6-(2-(2-methylpiperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [31] 6-(6-(1,2,3,6-tetrahydropyridine-4-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [32] N-(2-ethylpyridine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [33] N-(2-isobutylpyridine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [34] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [35] 6-(6-(4-methyl-1,4-diazepan-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [36] 6-(6-(4-(dimethylamino)piperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [37] (R)-6-(6-(3-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [38] 6-(6-(4-(aminomethyl)piperidine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [39] N-(1-methyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [40] N-(3,5-dimethylisooxazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [41] 6-(2-(piperazine-1-yl)pyridin-4-yl)-N-(pyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfoamide, [42] N-(2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [43] 6-(6-((3S,5R)-3,5-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [44] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(piperazine-1-yl)pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [45] (R)-6-(6-(3,4-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [46] N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-6-(6-((3S,5R)-3,4,5-trimethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [47] 6-(6-(4-(azetidine-3-yl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [48] ​​6-(2-(piperazine-1-yl)thieno[3,2-d]pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [49] 6-(6-(4-methyl-1,4-diazepan-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [50] 6-(6-(4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [51] (R)-6-(6-(2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [52] (R)-6-(6-(3-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [53] 6-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [54] 6-(6-(4-aminopiperidin-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [55] N-(6-methylquinoline-5-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [56] N-(1-ethyl-3,5-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [57] 6-(6-(2,3-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [58] 6-(6-(3-(trifluoromethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [59] 6-(6-(3,3-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [60] 6-(6-(3-aminopyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [61] N-(3-methylisoquinoline-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [62] N-(1,3-dimethylisoquinoline-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [63] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(2,4,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [64] N-(2,6-dimethylpyridine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [65] 5-fluoro-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [66] 6-(5-fluoro-2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [67] 6-(5-methyl-2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [68] 6-(6-((3R,5S)-3,5-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [69] 6-(6-(2,3-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [70] 6-(2-(piperazine-1-yl)thiazole-5-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [71] 6-(2-(piperazine-1-yl)thiazole-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [72] 6-(6-(3,3-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [73] 6-(6-(1,4-diazepan-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [74] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(2,5,7-trimethylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [75] N-(2-methylquinoline-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [76] N-(6-chloro-2-methylpyrazolo[1,5-a]pyrimidine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [77] N-(2-methylpyrazolo[1,5-b]pyridazine-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [78] N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1',2',3,3',4,4'-hexahydro-[6,7'-bis-isoquinoline]-2(1H)-sulfonamide, [79] 6-(3-((methylamino)methyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [80] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3R,5S)-3,4,5-trimethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [81] 5-fluoro-6-(6-(piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [82] 6-(2-(piperazine-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [83] 6-(2-(piperazine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [84] 6-(6-(3,6-diazabicyclo[3.2.0]heptane-3-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [85] 6-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [86] 8-fluoro-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [87] N-(2,4-dimethylthiazole-5-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [88] N-(2-methylpyrazolo[1,5-a]pyrimidine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [89] 5-(3-((methylamino)methyl)imidazo[1,2-a]pyridine-8-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [90] 8-fluoro-6-(1-(piperidin-4-yl)-1H-pyrazole-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [91] 6-(6-(1,4-diazepan-1-yl)pyrazine-2-yl)-8-fluoro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [92] 6-(6-(4,7-diazaspyro[2.5]octane-4-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [93] 6-(4-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [94] 6-(2-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [95] N-(2-methylpyrazolo[1,5-a]pyrazine-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [96] 6-(5-cyano-2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [97] 6-(5-cyano-4-(piperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [98] 6-(3-((methylamino)methyl)imidazo[1,2-a]pyridine-8-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [99] 6-(3-((dimethylamino)methyl)imidazo[1,2-a]pyridine-6-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [100] 6-(5-chloro-2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [101] 6-(5-methoxy-2-(piperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [102] (S)-6-(6-(3-aminopyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [103] (R)-6-(6-(3-aminopyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [104] (S)-6-(6-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [105] (R)-6-(6-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [106] 6-(3-cyano-6-(piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [107] 6-(3-(piperazine-1-yl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [108] 6-(6-(3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [109] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [110] 6-(6-(2-cyanopiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [111] 6-(6-(3-cyanopiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [112] 6-(3-((methylamino)methyl)quinoline-6-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [113] (S)-6-(6-(2-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [114] (R)-6-(6-(3-(methoxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [115] (S)-6-(6-(2-methyl-1,4-diazepan-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [116] 6-(6-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [117] 6-(3-(2-oxopiperazine-1-yl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [118] N-(2,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [119] N-(5-isobutyl-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [120] N-(5-isopropyl-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [121] N-(5-bromo-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [122] 6-(6-(pyrrolidin-3-ylamino)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [123] (S)-6-(6-(pyrrolidin-3-ylamino)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [124] 5-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindoline-2-sulfonamide, [125] (R)-6-(6-(3-isopropylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [126] 6-(3-cyano-2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [127] N-(3-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [128] 6-(3-((methylamino)methyl)imidazo[1,2-a]pyridine-6-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [129] (R)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [130] (R)-6-(6-(2-isopropylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [131] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [132] 6-(6-((methylamino)methyl)naphthalene-1-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [133] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [134] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-5-(2-(piperazine-1-yl)pyridin-4-yl)isoindoline-2-sulfonamide, [135] 8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [136] 5-fluoro-N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [137] N-(2,4-dimethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [138] N-(1,3-dimethyl-5-(2-methylprop-1-en-1-yl)-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [139] N-(1,3-dimethyl-5-(prop-1-en-2-yl)-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [140] 5-(6-((3R,5S)-3,5-dimethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindoline-2-sulfonamide, [141] (R)-5-(6-(2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindoline-2-sulfonamide, [142] 5-(6-(1,4-diazepan-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindoline-2-sulfonamide, [143] (R)-5-(6-(3-aminopyrrolidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindoline-2-sulfonamide, [144] 5-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindoline-2-sulfonamide, [145] 5-(6-(4-aminopiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindole-2-sulfonamide, [146] (R)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [147] Methyl (R)-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylate, [148] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(3-(piperazine-1-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [149] 8-fluoro-6-(3-(piperazine-1-yl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [150] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyrazine-2-yl)-8-fluoro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [151] 8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(3-(piperazine-1-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [152] (R)-8-fluoro-6-(6-(3-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [153] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyrazine-2-yl)-8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [154] (R)-8-fluoro-6-(6-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [155] 8-fluoro-N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)thieno[3,2-d]pyrimidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [156] N-(1,3-dimethylisoquinoline-4-yl)-8-fluoro-6-(3-(piperazine-1-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [157] (R)-5-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)isoindoline-2-sulfonamide, [158] (R)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [159] (R)-6-(3-(2-ethylpiperazine-1-yl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [160] (R)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [161] 6-(6-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [162] 6-(6-((3R,4S)-4-amino-3-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [163] 6-(6-((3S,4R)-4-amino-3-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [164] (S)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [165] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [166] 6-(6-(2-(hydroxymethyl)-2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [167] (R)-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylic acid, [168] Methyl (S)-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylate, [169] (R)-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxamide, [170] (R)-N-methyl-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxamide, [171] (R)-N,N-dimethyl-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxamide, [172] (S)-4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylic acid, [173] N-(1,3-dimethyl-5-phenyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [174] N-(1,3-dimethyl-5-(pyridin-3-yl)-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [175] N-(3-acetyl-1,5-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [176] N-(3-(1-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [177] (R)-5-(6-(2-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)isoindoline-2-sulfonamide, [178] (R)-5-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)isoindoline-2-sulfonamide, [179] 5-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)isoindolin-2-sulfonamide, [180] (R)-5-(6-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)isoindolin-2-sulfonamide, [181] Methyl 2-((dimethylamino)methyl)-4-(2-(N-(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)benzoate, [182] 6-(3-((dimethylamino)methyl)-4-(hydroxymethyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [183] ​​(S)-6-(3-(1-amino-3-hydroxypropyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 2HCl, [184] (R)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [185] (S)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [186] (S)-6-(6-(3-(methoxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [187] 6-(6-(4-(methylamino)piperidine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [188] 6-(6-(4-amino-3,3-difluoropiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [189] 6-(6-((3R,4S)-4-amino-3-fluoropiperidin-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [190] 2-((dimethylamino)methyl)-4-(2-(N-(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)benzoic acid, [191] (S)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [192] (S)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [193] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [194] (R)-6-(6-(2-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [195] (R)-6-(3-(1-amino-3-hydroxypropyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [196] 6-(3-(aminomethyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [197] 6-(3-(2-(methylamino)ethyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [198] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [199] (R)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [200] (R)-N-(1,3-dimethylisoquinoline-4-yl)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [201] (R)-N-(1,3-dimethylisoquinoline-4-yl)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [202] 8-(3-((methylamino)methyl)imidazo[1,2-a]pyridine-6-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [203] N,N,2,6-tetramethyl-5-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)nicotinamide, [204] N-(1,3-dimethyl-5-(pyridin-4-yl)-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [205] N-(1,3-dimethyl-5-(5-methylpyridine-3-yl)-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [206] Methyl (R)-1-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylate, [207] Methyl (S)-1-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxylate, [208] (S)-N,N-dimethyl-4-(6-(2-(N-(1,3,5--dimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-carboxamide, [209] N-methoxy-N,1,3-trimethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-5-carboxamide, [210] (R)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [211] (R)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2,5,6-trimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [212] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [213] (S)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [214] (S)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [215] (R)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [216] (S)-N-(1,3-dimethylisoquinoline-4-yl)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [217] (R)-N-(1,3-dimethylisoquinoline-4-yl)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [218] (S)-6-(6-(3-isopropylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [219] (R)-6-(6-(3-ethylpiperazine-1-yl)pyridine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [220] 6-(6-(2,5-diazabicyclo[4.1.0]heptane-2-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [221] (S)-6-(6-(2-isobutylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [222] (R)-6-(6-(3-isobutylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [223] (R)-6-(6-(2-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [224] (R)-6-(6-(2-propylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [225] (R)-6-(6-(2-phenylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [226] (R)-6-(6-(2-benzylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [227] (R)-6-(2-(3-ethylpiperazine-1-yl)thieno[3,2-d]pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [228] (S)-6-(2-(3-ethylpiperazine-1-yl)thieno[3,2-d]pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [229] N-(1,3-dimethyl-5-pivaloyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [230] N-(5-acetyl-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [231] N-(5-(1-hydroxy-2,2-dimethylpropyl)-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [232] N-(5-(1-hydroxyethyl)-1,3-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [233] N,N,1,3-tetramethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-5-carboxamide 2HCl, [234] 1,3-dimethyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-5-carboxamide 2HCl, [235] 1,3-dimethyl-N-phenyl-4-((6-(2-(piperazine-1-yl)pyridine-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-1H-pyrazol-5-carboxamide 2HCl, [236] (R)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [237] (R)-6-(6-(3-benzylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [238] 6-(6-((2S,5R)-2,5-diethylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [239] (S)-6-(6-(2-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [240] (R)-6-(6-(3-(cyanomethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [241] (R)-6-(6-(2-(cyanomethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [242] (S)-6-(6-(2-(cyanomethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [243] 6-(3-(1-(methylamino)ethyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [244] 6-(3-(1-(methylamino)-2-phenylethyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [245] (S)-6-(3-(3-hydroxy-1-(methylamino)propyl)phenyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [246] (R)-N-(1,3-dimethylisoquinoline-4-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [247] (S)-N-(1,3-dimethylisoquinoline-4-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [248] (R)-6-(4-(3-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [249] (S)-6-(6-(3-ethylpiperazine-1-yl)pyridine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [250] (S)-6-(4-(3-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [251] (S)-6-(4-(2-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [252] (R)-6-(4-(2-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [253] (R)-6-(2-(3-ethylpiperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [254] (S)-6-(2-(3-ethylpiperazine-1-yl)pyrimidine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [255] (R)-6-(6-(3-ethylpiperazine-1-yl)pyridine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [256] (S)-6-(6-(3-ethylpiperazine-1-yl)pyridine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [257] (R)-6-(4-(3-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [258] (S)-6-(4-(3-ethylpiperazine-1-yl)pyrimidine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [259] N-methyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [260] N-(3-ethyl-1,5-dimethyl-1H-pyrazole-4-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [261] (S)-3-amino-3-(3-(2-(N-(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)propanamide, [262] (S)-3-amino-N-methyl-3-(3-(2-(N-(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)propanamide, [263] N-ethyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [264] 6-(6-((3R)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [265] 6-(6-((2R,5R)-2-(hydroxymethyl)-5-methylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [266] (R)-6-(6-(3-butylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [267] (S)-6-(6-(3-butylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [268] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-methyl-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [269] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [270] N-ethyl-N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [271] N-methyl-N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [272] (S)-6-(6-(3-(ethoxymethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [273] (R)-6-(6-(3-propylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [274] (S)-6-(6-(3-propylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [275] N-benzyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [276] N-(2-hydroxyethyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [277] N-cyclopentyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [278] N-isopropyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [279] N-(4-nitrophenyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [280] (R)-N-ethyl-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [281] (R)-N-(3-ethyl-1,5-dimethyl-1H-pyrazol-4-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [282] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-b]pyridazine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [283] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [284] (R)-N-(2-ethyl-5,6-dimethylpyridine-3-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [285] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-methoxy-5,6-dimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [286] (R)-N-(5,6-dimethyl-2-(methylthio)pyridine-3-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [287] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-mercapto-5,6-dimethylpyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [288] 2-((6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [289] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-propyl-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [290] N-phenethyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [291] 6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [292] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [293] 6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [294] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [295] (S)-6-(6-(3-acetylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [296] (R)-6-(6-(3-acetylpiperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [297] 6-(6-((3R)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [298] 6-(6-((3R)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [299] N-cyclopropyl-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [300] N-(2-(piperazine-1-yl)ethyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [301] (S)-6-(6-(3-(2-hydroxypropane-2-yl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [302] 2-(4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazole-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetamide, [303] N-methyl-2-(4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetamide, [304] N,N-dimethyl-2-(4-(6-(2-(N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetamide, [305] 6-(6-(3-(2-oxopropyl)piperazine-1-yl)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [306] N-(2-(3-aminoazetidine-1-yl)-2-oxoethyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [307] 6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(pyrrolidin-3-ylmethyl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [308] N-methyl-2-((6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [309] 6-(6-(3-(2-hydroxypropyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [310] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxylophil)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [311] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [312] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [313] N-(5-aminopentyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [314] N-(4-aminobutyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [315] N-(2-aminoethyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [316] N-(3-hydroxybenzyl)-2-((6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [317] (R)-6-(6-(2-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [318] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(2-propylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [319] (R)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [320] N-(3-aminopropyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [321] (R)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [322] 6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [323] 6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [324] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3R)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [325] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3R)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [326] N-(2-hydroxypropyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [327] N-(oxazole-5-ylmethyl)-2-((6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [328] (R)-6-(6-(3-((dimethylamino)methyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [329] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [330] (R)-6-(6-(2-cyclopropylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [331] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(2-isobutylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [332] 6-(6-(azetidine-3-ylamino)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [333] (R)-6-(6-(pyrrolidin-3-ylamino)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [334] 6-(6-(piperidin-4-ylamino)pyrazine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [335] (R)-6-(6-(3-cyclopropylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [336] N-(2-methyl-2H-indazole-3-yl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [337] (R)-N-(2-(3-(dimethylamino)azetidine-1-yl)-2-oxoethyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [338] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-methoxyethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [339] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [340] (R)-N-(azetidine-3-yl)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [341] N-(2-(dimethylamino)ethyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [342] N-(3-(dimethylamino)propyl)-6-(2-(piperazine-1-yl)pyridine-4-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [343] (R)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [344] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(1-methylazetidine-3-yl)acetamide, [345] (R)-N-(azetidine-3-ylmethyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [346] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [347] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-8-fluoro-6-(6-((3S)-3-(1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [348] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-8-fluoro-6-(6-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [349] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(methylamino)pyrrolidin-1-yl)pyrazin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [350] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-isopropylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [351] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [352] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [353] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-8-fluoro-6-(6-(3-isopropylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [354] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3S)-3-(1-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [355] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [356] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [357] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [358] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(hydroxymethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [359] (R)-N-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycine, [360] N-(2-aminoethyl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(piperidin-1-yl)pyrazin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [361] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [362] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(hexahydro-2H,6H-pyrazino[1,2-c][1,3]oxazine-2-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [363] 2-(4-(6-(2-(N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetic acid, [364] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-8-fluoro-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [365] (R)-N-(3-ethyl-1,5-dimethyl-1H-pyrazol-4-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [366] (R)-6-(6-(3-(aminomethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [367] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(3-isopropyl-1,5-dimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [368] (R)-N-(1,5-dimethyl-3-propyl-1H-pyrazol-4-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [369] 6-(6-((3R,4S)-4-amino-3-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [370] (R)-6-(6-(ethyl(pyrrolidin-3-yl)amino)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [371] (R)-6-(6-(3-(ethylamino)pyrrolidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [372] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2-hydroxyethyl)(pyrrolidin-3-yl)amino)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [373] (R)-6-(6-(3-(aminomethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [374] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-morpholino-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [375] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(pyridine-4-yl)acetamide, [376] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [377] N-(2-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-2-oxoethyl)-6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [378] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [379] Methyl (R)-N-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycinate, [380] (R)-N-(2-(dimethylamino)ethyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [381] (R)-N-(3-(dimethylamino)propyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [382] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(4-(piperazine-1-yl)pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [383] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(4-(piperazine-1-yl)pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [384] 6-(4-(piperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [385] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(4-(piperazine-1-yl)thieno[3,2-d]pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [386] N-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(4-(piperazine-1-yl)thieno[3,2-d]pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [387] 6-(4-(piperazine-1-yl)thieno[3,2-d]pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [388] 6-(5-chloro-4-(piperazine-1-yl)pyrimidine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [389] 6-(5-chloro-4-(piperazine-1-yl)pyrimidine-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [390] 6-(5-chloro-4-(piperazine-1-yl)pyrimidine-2-yl)-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [391] 6-(6-((3R,4S)-3-amino-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [392] 6-(6-((3S,4R)-3-amino-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [393] 6-(6-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [394] 6-(6-((3S,4S)-3-amino-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [395] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(2-methylpiperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [396] (S)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [397] (S)-6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [398] (S)-6-(2-(3-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [399] (R)-N-(1,3-dihydroxypropane-2-yl)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [400] N-(1-chloro-3-hydroxypropane-2-yl)-2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [401] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(3-hydroxypropyl)acetamide, [402] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [403] (S)-6-(5-(2-ethylpiperazine-1-yl)pyridine-3-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [404] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(5-(piperazine-1-yl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [405] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(2-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [406] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(2-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [407] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [408] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [409] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(2-hydroxyethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [410] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(2-hydroxyethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [411] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(2-hydroxyethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [412] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(2-hydroxyethyl)piperazine-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [413] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [414] 6-(6-((3R,4R)-3-(dimethylamino)-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [415] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(2-hydroxyethyl)acetamide, [416] N-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-L-proline, [417] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [418] Methyl (R)-5-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-2,2-dimethylpentanoate, [419] N-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-D-proline, [420] N-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-L-serine, [421] (R)-5-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-2,2-dimethylpentanoic acid, [422] (R)-6-(5-(3-ethylpiperazine-1-yl)pyridine-3-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [423] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [424] (R)-2-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-7,8-dihydro-1,6-naphthiridine-6(5H)-sulfonamide, [425] N-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-D-serine, [426] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3R,4R)-4-hydroxy-3-(methylamino)piperidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [427] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-methylpiperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [428] N-(2,3-dihydroxypropyl)-2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [429] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-yl)pyrazine-2-yl)3,4-dihydroisoquinoline-2(1H)-sulfonamide, [430] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(1-methylpiperidine-4-yl)acetamide, [431] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-(2-hydroxyethyl)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [432] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2S,4R)-2-(hydroxymethyl)-4-(methylamino)pyrrolidin-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [433] (R)-6-(6-(3-ethylpiperazine-1-yl)pyridazine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [434] (R)-6-(5-(3-ethylpiperazine-1-yl)pyridazine-3-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [435] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [436] (R)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [437] Ethyl 2-((2S,6R)-6-ethyl-4-(6-(2-(N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetate, [438] 2-((2S,6R)-6-ethyl-4-(6-(2-(N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetic acid, [439] (R)-2-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-sulfonamide, [440] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydro-2,7-naphthiridine-2(1H)-sulfonamide, [441] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-(2-hydroxyethyl)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [442] (S)-N-(3-(dimethylamino)propyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [443] (S)-N-(3-(dimethylamino)propyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [444] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(piperidin-4-yl)pyrazin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [445] N-(2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-6-(6-(piperidin-4-yl)pyrazin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [446] (R)-2-(2-((6-(6-(R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamido)-3-hydroxypropanamide, [447] (R)-N-(2-(dimethylamino)ethyl)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [448] (R)-N-(2-([1,4'-bipiperidin]-1'-yl)-2-oxoethyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [449] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(2-(piperidine-1-yl)ethyl)acetamide, [450] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2S,5S)-5-(hydroxymethyl)-2-methylpiperazine-1-yl)pyrazine-2-yl)3,4-dihydroisoquinoline-2(1H)-sulfonamide, [451] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2R,5S)-5-(hydroxymethyl)-2-methylpiperazine-1-i)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [452] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-(2-hydroxyethyl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [453] N-(3-(dimethylamino)propyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [454] 6-(6-((3R,5R)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [455] (S)-2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(hydroxymethyl)piperazine-1-yl)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [456] 2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-i)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [457] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(methylamino)piperidin-1-yl)pyrazin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [458] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(methylamino)piperidin-1-yl)pyrazin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [459] 6-(6-((R)-3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-((S)-3-(methylamino)pyrrolidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [460] 6-(6-((R)-3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-((R)-3-(methylamino)pyrrolidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [461] N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-2-oxoethyl)-6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [462] 2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-((R)-1-methylpyrrolidine-3-yl)acetamide, [463] 2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-((S)-1-methylpyrrolidine-3-yl)acetamide, [464] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((2S,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-yl)pyrazine-2-yl)3,4-dihydroisoquinoline-2(1H)-sulfonamide, [465] (S)-2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [466] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [467] (R)-N-(2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [468] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3R,5S)-3-methyl-5-(methylamino)piperidin-1-yl)pyrazin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [469] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3S,5R)-3-methyl-5-(methylamino)piperidin-1-yl)pyrazin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [470] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3S,5S)-3-methyl-5-(methylamino)piperidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [471] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((3R,5R)-3-methyl-5-(methylamino)piperidine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [472] 2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(2-oxopyrrolidine-3-yl)acetamide, [473] 2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(2-oxotetrahydrofuran-3-yl)acetamide, [474] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-morpholinopiperidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [475] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(octahydro-2H-pyrido[1,2-a]pyrazine-2-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [476] (R)-N-(2-(4-(dimethylamino)piperidin-1-yl)-2-oxoethyl)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [477] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-8-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [478] (R)-3-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)propanamide, [479] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(3-morphopropyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [480] (R)-4-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)butanoic acid, [481] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [482] 6-(6-((3S,4S)-3-(dimethylamino)-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [483] (R)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-oxo-2-(3-(piperazine-1-yl)azetidine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [484] (R)-2-((6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(isoindoline-5-yl)acetamide, [485] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(4-(4-methylpiperazine-1-yl)phenyl)acetamide, [486] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(4-(4-morpholinopiperidin-1-yl)phenyl)acetamide, [487] (R)-2-((6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(3-(4-methylpiperazine-1-yl)benzyl)acetamide, [488] (R)-N-(2-(4-(azetidine-3-yl)piperazine-1-yl)-2-oxoethyl)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [489] 2-((2S,6R)-6-ethyl-4-(6-(2-(N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)piperazine-2-yl)acetamide, [490] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(((R)-1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [491] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(((S)-1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [492] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(2-oxomidazolidine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [493] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-methyl-2-oxomidazolidine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [494] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [495] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(4-methylpiperazine-1-yl)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [496] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-(1-methylazetidin-3-yl)piperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [497] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-((3R,4S)-3-(hydroxymethyl)-4-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [498] N-(2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-6-(2-((3R,4S)-3-(hydroxymethyl)-4-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [499] (3S,4R)-1-(6-(2-(N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)-N,N-dimethyl-4-(methylamino)pyrrolidine-3-carboxamide, [500] N-(3-(dimethylamino)propyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [501] 6-(6-((3S,5R)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [502] 6-(6-((3S,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [503] N-(2-(3-(dimethylamino)azetidine-1-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [504] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(hydroxymethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [505] (S)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [506] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [507] N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [508] (R)-6-(6-(3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(4-hydroxypiperidine-1-yl)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [509] 2-((6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(1-(2-hydroxyethyl)piperidine-3-yl)acetamide, [510] 6-(6-((R)-3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(((R)-pyrrolidin-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [511] 6-(6-((R)-3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(((S)-pyrrolidin-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [512] (R)-N-(azetidine-3-ylmethyl)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [513] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-methylpiperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [514] N-(2-([1,4'-bipiperidin]-1'-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [515] N-(2-(dimethylamino)ethyl)-2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [516] N-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycine, [517] (S)-2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(hydroxymethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [518] (S)-2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-(3-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [519] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [520] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((S)-3-(hydroxymethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-((S)-3-(methylamino)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [521] N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(6-((S)-3-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-((S)-3-(methylamino)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [522] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-((S)-3-(methylamino)pyrrolidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [523] 6-(6-((R)-3-ethylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-((S)-3-(hydroxymethyl)-4-methylpiperazine-1-yl)piperidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [524] N-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-D-serine, [525] N-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)glycyl-L-serine, [526] (R)-6-(6-(3-ethyl-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-oxo-2-(4-(piperidin-4-yl)piperazine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [527] N-(2,3-dihydroxypropyl)-2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [528] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-(1-methylazetidin-3-yl)piperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [529] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-(1-methylpiperidin-4-yl)piperazine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [530] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(4-methylpiperazine-1-yl)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [531] N-(1,3-dihydroxypropane-2-yl)-2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [532] 6-(6-((3R,4R)-3-(dimethylamino)-4-hydroxypiperidin-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [533] (R)-2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [534] 2-((6-(2-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [535] (R)-2-((N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [536] (R)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-6-(2-(3-(hydroxymethyl)piperazine-1-yl)pyridin-4-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [537] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-8-fluoro-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [538] N-(1,3-dihydroxy-2-(hydroxymethyl)propane-2-yl)-2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [539] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [540] (R)-2-((6-(2-(2-ethylpiperazine-1-yl)pyridine-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [541] N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [542] 2-((6-(2-((3R,4R)-3-(dimethylamino)-4-hydroxypiperidin-1-yl)pyridin-4-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [543] 2-((N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, [544] N-(2-(3-(dimethylamino)azetidine-1-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [545] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-N-(2-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [546] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)-4-methylpiperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-N-(2-(3-(methylamino)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [547] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-morpholinozetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [548] N-(2-(3-(4-acetylpiperazine-1-yl)azetidine-1-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [549] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-oxo-2-(3-(3-oxopiperazine-1-yl)azetidine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [550] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(3-(4-(methylsulfonyl)piperazine-1-yl)azetidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [551] N-(2-(4-(4-acetylpiperazine-1-yl)piperidin-1-yl)-2-oxoethyl)-6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [552] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-(4-morpholinopiperidine-1-yl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [553] 6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(2-oxo-2-(4-(3-oxopiperazine-1-yl)piperidine-1-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide, [554] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)-N-(2-morpholinoethyl)acetamide, [555] 2-((6-(6-((3R,5S)-3-ethyl-5-(2-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-N-(2-ethylpyrazolo[1,5-a]pyrimidine-3-yl)-8-fluoro-1,2,3,4-tetrahydroisoquinoline)-2-sulfonamido)acetamide, and [556] N-(2-(3-(dimethylamino)azetidine-1-yl)-2-oxoethyl)-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-6-(6-((S)-3-((R)-1-hydroxyethyl)piperazine-1-yl)pyrazine-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide. A pharmaceutical composition for the prevention or treatment of NMT inhibition-related diseases, comprising as an active ingredient a sulfonamide derivative compound of any one of claims 1 to 10, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition according to claim 11, wherein the NMT inhibition-related disease is any one selected from the group consisting of myeloma, leukemia, lymphoma, blastoma, solid tumor, protozoal infection, and viral infection. In claim 11, the above NMT inhibition-related disease is a myeloma in which the disease is multiple myeloma; one or more leukemias selected from the group consisting of chronic lymphocytic leukemia, myeloid leukemia, and acute lymphoblastic leukemia; one or more lymphomas selected from the group consisting of follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and Burkitt lymphoma; one or more blastomas selected from the group consisting of neuroblastoma, retinoblastoma, and glioblastoma; one or more solid tumors selected from the group consisting of brain cancer, lung cancer, breast cancer, prostate cancer, ovarian cancer, colon cancer, rectal cancer, gallbladder cancer, kidney cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, and liver cancer; one or more protozoal infections selected from the group consisting of malaria, candidiasis, and leishmaniasis; A pharmaceutical composition comprising one or more viruses selected from the group consisting of rhinovirus and HIV. A pharmaceutical composition comprising a sulfonamide derivative compound of any one of claims 1 to 10, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

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