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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

• It relates to a compound as an SHP2 inhibitor, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a use for preventing or treating a disease associated with abnormal SHP2 activity.
• the present invention was made by the National New Drug Development Project Support (HN22C0066) of the National New Drug Development Agency funded by the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare.
• Src homology region 2 domain-containing phosphatase-2 is protein tyrosine phosphatase non-receptor type 11 (PTPN11), protein-tyrosine phosphatase 1D (PTP-1D), or It is a protein tyrosine phosphatase (PTP), also called protein-tyrosine phosphatase 2C (PTP-2C).
• PTPN11 protein tyrosine phosphatase non-receptor type 11
• PTP-1D protein-tyrosine phosphatase 1D
• PDP-2C protein-tyrosine phosphatase 2C
• SHP2 is involved in cell growth and differentiation. It is known as a signaling molecule that regulates various cellular functions including cell cycle and oncogenic transformation.
• SHP2 together with SHP1 consists of two tandem SH2 domains at the N-terminus.
• the N-terminal SH2 domain binds to the PTP domain and blocks substrate binding to the active site, thereby inhibiting SHP2.
• the N-terminal SH domain is released from the PTP domain and the enzyme is activated.
• Mutations in SHP2 are known to cause Noonan syndrome and Leopard syndrome, and are known to cause cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colorectal cancer, head cancer, It is known to be associated with squamous-cell carcinoma of the head and neck, gastric carcinoma, anaplastic large cell lymphoma, glioblastoma, pancreatic cancer, biliary tract cancer, uterine cancer, endometrial cancer, liver cancer, and neurofibroma type 1.
• a novel compound capable of inhibiting the activity of SHP2, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is provided.
• compositions for preventing or treating diseases associated with abnormal SHP2 activity using a novel compound capable of inhibiting SHP2 activity, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
• a method for preventing or treating diseases associated with abnormal SHP2 activity using a novel compound capable of inhibiting SHP2 activity, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is provided.
• One aspect provides a compound represented by Formula 1A, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof:
• the compound represented by Chemical Formula 1A may have a structure in which a pyrazine ring, a fused ring of ring A and a benzene ring are connected by a sulfide group (-S-), and the pyrazine ring is connected to a piperidine ring.
• R 1 is H, halogen, hydroxy, cyano or C 1 -C 6 haloalkyl.
• R 1 can be H, halogen or C 1 -C 6 haloalkyl.
• R 1 can be halogen or C 1 -C 3 haloalkyl.
• R 1 can be halogen.
• R 1 can be F or Cl.
• R 2 is H, halogen, hydroxy, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy-(C 1 -C 6 alkyl) -, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl)-, H 2 N-(C 1 -C 6 alkyl)-, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , nitro, cyano, amidino, -C(O)NH 2 , -C(O)(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), and carboxy or a salt thereof.
• R 2 is H, halogen, hydroxy, oxo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, hydroxy-(C 1 -C 3 alkyl) -, (C 1 -C 3 alkoxy)-(C 1 -C 3 alkyl)-, H 2 N-(C 1 -C 3 alkyl)-, -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , nitro, cyano, -C(O)NH 2 , -C(O)(C 1 -C 3 alkyl), -C(O)O(C 1 -C 3 alkyl), and carboxy or a salt thereof.
• R 2 is H, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy-(C 1 -C 6 alkyl)-, -NH 2 , - C(O)NH 2 and -C(O)(C 1 -C 6 alkyl).
• R 2 is H, C 1 -C 3 alkyl, hydroxy-(C 1 -C 3 alkyl)-, -NH 2 , -C(O)NH 2 and -C(O)(C 1 -C 3 alkyl).
• R 2 is H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, amino, methylcarbonyl (acetyl), ethylcarbonyl (propanoyl), carbamoyl etc. may be included.
• R 2 can be H, -CH 3 , -CH 2 OH, -NH 2 , -C(O)NH 2 or -C(O)CH 3 .
• p is an integer from 0 to 2. In some embodiments, when p is 2, two R 2 may be the same or different.
• atoms constituting the pyrazine ring are can have a position number of in this case, represents a bonding position with a sulfur atom, and * represents a bonding position with a nitrogen atom of a piperidine ring.
• R 2 can be bonded to the 3-position and/or 6-position of the pyrazine ring, eg, R 2 is halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 or cyano, and may be bonded to the 3-position of the pyrazine ring.
• R 2 is hydroxy-(C 1 -C 6 alkyl)-, -C(O)NH 2 or -C(O)(C 1 -C 6 alkyl)-, and 6 of the pyrazine ring It can be joined in one position.
• R 2 when p is 2, R 2 may be bonded to the 3-position and 6-position of the pyrazine ring, respectively.
• R 3 and R 4 are each independently selected from H, C 1 -C 6 alkyl, an amine group (eg, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 - C 6 alkyl) 2 ) or C 1 -C 6 alkyl substituted with an amine group (eg H 2 N-(C 1 -C 6 alkyl)-), or R 3 and R 4 are linked together to form ring B can do.
• a spiro-polycycle ring including the ring B and a piperidine ring may be formed.
• the ring B is an optionally substituted 3- to 8-membered cyclic ring group containing 1 oxygen atom.
• Ring B may optionally be condensed with a cycloalkyl, aryl or heteroaryl ring. Each of the cycloalkyl, aryl or heteroaryl rings condensed with ring B may be optionally substituted.
• R 3 and R 4 are, independently of each other, H, C 1 -C 3 alkyl, -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , or H 2 N-(C 1 -C 3 alkyl)-.
• either R 3 or R 4 is C 1 -C 3 alkyl and the other can be -NH 2 or H 2 N-(C 1 -C 3 alkyl)-.
• R 3 is methyl or ethyl
• R 4 can be amino, aminomethyl or aminoethyl.
• R 3 can be methyl and R 4 can be amino or aminomethyl.
• ring B can be a C 3 -C 8 cycloalkyl or 3-8 membered heterocycloalkyl ring, optionally containing 1 oxygen atom. Ring B may be optionally substituted with one or more R B . In some embodiments, ring B can be a C 4 -C 6 cycloalkyl or 4-6 membered heterocycloalkyl ring optionally containing 1 oxygen atom and optionally substituted with one or more R B . For example, ring B can be a cyclopentane ring or a tetrahydrofuran ring.
• R B is deuterium, (C 1 -C 6 alkyl), an amine group (eg, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 ) and an amine group. substituted C 1 -C 6 alkyl (eg, H 2 N-(C 1 -C 6 alkyl)-).
• R B is deuterium, (C 1 -C 3 alkyl), -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , and H 2 N It may be selected from the group consisting of -(C 1 -C 3 alkyl)-.
• ring B may be optionally substituted with one or more R B selected from deuterium, C 1 -C 3 alkyl and —NH 2 .
• R B may be one or more selected from deuterium, methyl, and -NH 2 .
• ring B is a 5- to 10-membered heteroaryl ring containing 1 or 2 heteroatoms selected from C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and N, O and S. It may optionally be condensed with a ring BB selected from In this case, ring BB may optionally be substituted with one or more R BB .
• ring BB is a 5- to 7-membered heteroaryl ring containing 1 or 2 heteroatoms selected from C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, and N, O and S. can be selected from.
• the ring BB may be a C 3 -C 6 cycloalkyl ring, a benzene ring, a pyridine ring or a thiazole ring.
• ring B is a cyclopentane ring and may be condensed with ring BB selected from a cyclopropane ring, a benzene ring, a pyridine ring, and a thiazole ring.
• ring B is a tetrahydrofuran ring and may be condensed with ring BB selected from a benzene ring and a pyridine ring.
• R BB is halogen, hydroxy, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy-(C 1 -C 6 alkyl)-, (C 1 - C 6 alkoxy)-(C 1 -C 6 alkyl)-, H 2 N-(C 1 -C 6 alkyl)-, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 - C 6 alkyl) 2 , nitro, cyano and amidino.
• R BB is halogen, hydroxy, oxo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, hydroxy-(C 1 -C 3 alkyl)-, (C 1 -C 3 alkoxy)-(C 1 -C 3 alkyl)-, H 2 N-(C 1 -C 3 alkyl)-, -NH 2 , -NH(C 1 -C 3 alkyl), -N (C 1 -C 3 alkyl) 2 , nitro and cyano.
• R BB may be one or more selected from the group consisting of halogen, cyano, hydroxy, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
• R BB may be one or more selected from the group consisting of halogen, cyano, hydroxy, methyl, and methoxy.
• Formula 1A can be selected from the following structures:
• R 41 is C 1 -C 3 alkyl, and q may be an integer from 0 to 3.
• R 41 is methyl and q can be 0 or 1.
• Ring B in the above structure may be optionally substituted with one or more R B selected from deuterium, methyl and -NH 2 .
• ring BB may be optionally substituted with one or more R BB selected from the group consisting of halogen, cyano, hydroxy, methyl and methoxy.
• Formula 1A can be selected from the following structures:
• ring B may be optionally substituted with one or more R B selected from methyl and -NH 2
• ring BB may be optionally substituted with one or more R BB selected from the group consisting of halogen, cyano, hydroxy, methyl and methoxy. can be substituted.
• Formula 1A can be selected from the following structures:
• Formula 1A can be selected from the following structures:
• Formula 1A WO 2019/183367, 2020/063760, 2020/201991, 2020/081848, 2020/073949, 2021/197452, 2021/147879, Corresponding structures disclosed in 2020/049079, 2021/218752, 2021/218755, 2022/017444, 2021/115286, 2021/088944, etc., or easily derived therefrom by a person skilled in the art. structure may be included.
• ring element's valency permits (e.g., a nitrogen atom permits three bonds, a carbon atom permits four bonds).
• X is N
• Y is N
• Z is C(O)
• CR 6 and Y is a double bond
• W is C
• U is N
• V is NR 6
• between V and W is a single bond
• W and U is a double bond
• the 5- and 6-membered rings share is a double bond
• W and U are N and V is CH
• between the carbon atoms shared with each of V and U and the six-membered ring is a double bond
• W and V and W and U becomes a single bond
• the 5- and 6-membered rings share becomes a single bond.
• X may be N or C
• Y may be N, CH or CH 2
• Z may be C(O), S(O) 2 , or N.
• Z is N
• X is C
• Y is CH
• Z is S(O) 2 then both X and Y are N.
• X in the fused ring structure may be N or C
• Y may be N, CH or CH 2
• Z may be C(O) or S(O) 2 .
• Z is S(O) 2
• both X and Y may be N.
• U may be N, NR 6 or CHR 6
• V may be CH, C(O), S, O, N or NR 6
• W may be N or C.
• W when W is C, one of U and V is N and the other is S, O or NR 6 .
• W is N
• U is CHR 6 and V is C(O)
• U is N and V is CH.
• One or two of U, V and W are N.
• U in the fused ring structure may be N or NR 6
• V may be CH, N, or NR 6
• W may be N or C.
• W when W is C, one of U and V is N, and the other is NR 6 .
• W when W is N, then U is N and V is CH.
• formula 1A in formula 1A can be selected from the following structures:
• R 5 is each independently H, a halogen atom, a hydroxyl group, a ketone group, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 2 -C 20 alkoxyalkyl, an amine group, C 1 - substituted with an amine group C 20 Alkyl, imine group, nitro, cyano, amidino, carboxyl group or its salt, C 1 -C 20 Heteroalkyl, C 3 -C 20 Heterocycloalkyl, C 6 -C 20 Aryl, C 6 -C 20 Arylalkyl , C 1 -C 20 heteroaryl, C 1 -C 20 heteroarylalkyl, C 1 -C 20 heteroaryloxy, C 1 -C 20 heteroaryloxyalkyl, and C 3 -C 20 heterocycloalkyl, and between poly click C 5 -C 12 heteroarylalkyl.
• R 5 is H, a C 1 -C 6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted thiazolylalkyl group, a substituted or unsubstituted imidazolylalkyl group, a substituted or unsubstituted imidazolylalkyl group, An unsubstituted pyrrolidinylalkyl group, a substituted or unsubstituted pyridinylalkyl group, a substituted or unsubstituted pyrimidinylalkyl group, a substituted or unsubstituted pyrazinylalkyl group, a substituted or unsubstituted benzimidazolylalkyl group, or a substituted or It may be an unsubstituted pyrrolopyridinylalkyl group.
• the phenyl group, benzyl group, thiazolylalkyl group, imidazolylalkyl group, pyrrolidinylalkyl group, pyridinylalkyl group, pyrimidinylalkyl group, pyrazinylalkyl group, benzimidazolylalkyl group, or pyrrolopyridinylalkyl group is unsubstituted, Alternatively, it may be substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkyl substituted with a halogen atom, -CN, -NH 2 , -NO 2 , -OR a , and -SO 2 R a .
• C 1 -C 6 Alkyl substituted with a halogen atom may be -CF 3 .
• the R a may be H, a halogen atom, or C 1 -C 6 alkyl substituted with a halogen atom.
• the -OR a may be -OCH 3 .
• the -SO 2 R a may be -SO 2 F.
• R 5 are each independently selected from (i) to (vi):
• halogen hydroxy, C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkoxy, amine groups (eg -NR'R'') , Carbonyl group (eg R'C(O)-), sulfonyl group (eg R'S(O) 2 -), alkylsulfonylamine group (eg R'S(O) 2 NR''-), aminocarbonyl group or a C 1 -C 20 alkyl optionally substituted with one or more substituents selected from the group consisting of an alkylaminocarbonyl group (eg, R''R'NC(O)-), and R'C(O)NR''- or C 1 -C 20 alkoxy;
• heteroaryl Heteroaryl-(C 1 -C 8 Alkyl)-, Heteroaryloxy, Heteroaryloxy-(C 1 -C 8 Alkyl)-, Heteroarylcarbonyl, Heteroarylcarbonyl-(C 1 -C 8 alkyl)-, -CONH-heteroaryl, -CONH-(C 1 -C 8 alkyl)-heteroaryl, -NHCO-heteroaryl, or -NHCO-(C 1 -C 8 alkyl)-heteroaryl(
• the heteroaryl ring may be a 4- to 10-membered heteroaryl containing at least one heteroatom selected from N, O and S, or the heteroaryl ring may be a C 1 to C 20 heteroaryl ring);
• heterocycloalkyl heterocycloalkyl-(C 1 -C 8 alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C 1 -C 8 alkyl)-, heterocycloalkylcarbonyl, heterocycloalkyl Carbonyl-(C 1 -C 8 alkyl)-, -CONH-heterocycloalkyl, -CONH-(C 1 -C 8 alkyl)-heterocycloalkyl, -NHCO-heterocycloalkyl, or -NHCO-(C 1 -C 8 alkyl)-heterocycloalkyl (the heterocycloalkyl ring is a 3- to 10-membered fully saturated or partially unsaturated heterocycloalkyl containing at least one heteroatom selected from N, O and S, or the heterocycloalkyl ring may be C 3 to C 20 heterocycloalkyl); and
• R′ and R′′ are each independently H or C 1 -C 10 alkyl.
• R′ and R′′ can each independently be H or C 1 -C 6 alkyl.
• R′ and R′′ may each independently be H or C 1 -C 3 alkyl.
• R' and R'' may each independently be H, methyl or ethyl.
• aryl ring, heteroaryl ring, heterocycloalkyl ring and cycloalkyl ring described in (iii) to (vi) above may be optionally substituted.
• aryl ring, heteroaryl ring, heterocycloalkyl ring and cycloalkyl ring are used to collectively refer to the corresponding ring part in a substituent bonded with another chemical structure. do.
• aryl ring includes aryl as well as arylalkyl, aryloxy, aryloxyalkyl, arylcarbonyl, arylcarbonylalkyl, -CONH-aryl, -CONH-alkyl-aryl, -NHCO-aryl and -NHCO- Alkyl-aryl is used to collectively refer to an aryl ring.
• the R 5 can be independently selected from:
• H, halogen, hydroxy, -NH 2 , NH, -C(O)NH 2 , nitro, cyano, amidino or carboxy or a salt thereof (eg H, halogen, hydroxy, -NH 2 , -C(O)NH 2 , nitro, cyano, or carboxy or a salt thereof);
• heteroaryl Heteroaryl-(C 1 -C 5 Alkyl)-, Heteroaryloxy, Heteroaryloxy-(C 1 -C 5 Alkyl)-, Heteroarylcarbonyl, Heteroarylcarbonyl-(C 1 -C 5 alkyl)-, -CONH-heteroaryl, -CONH-(C 1 -C 5 alkyl)-heteroaryl, -NHCO-heteroaryl, or -NHCO-(C 1 -C 5 alkyl)-heteroaryl(
• heterocycloalkyl heterocycloalkyl-(C 1 -C 5 alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C 1 -C 5 alkyl)-, heterocycloalkylcarbonyl, heterocycloalkyl Carbonyl-(C 1 -C 5 alkyl)-, -CONH-heterocycloalkyl, -CONH-(C 1 -C 5 alkyl)-heterocycloalkyl, -NHCO-heterocycloalkyl, or -NHCO-(C 1 -C 5 alkyl)-heterocycloalkyl (eg, heterocycloalkyl, heterocycloalkyl-(C 1 -C 3 alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C 1 -C 3 alkyl)-, heterocycloalkylcarbonyl, or heterocycloalkylcarbonyl-(C
• C 3 -C 8 cycloalkyl (C 3 -C 8 cycloalkyl)-(C 1 -C 5 alkyl)-, C 3 -C 8 cycloalkyloxy, (C 3 -C 8 cycloalkyloxy) -(C 1 -C 5 alkyl)-, C 3 -C 8 cycloalkylcarbonyl, (C 3 -C 8 cycloalkylcarbonyl)-(C 1 -C 5 alkyl)-, -CONH-(C 3 - C 8 cycloalkyl), -CONH-(C 1 -C 5 alkyl)-(C 3 -C 8 cycloalkyl), -NHCO-(C 3 -C 8 cycloalkyl), or -NHCO-(C 1 -C 5 alkyl)-(C 3 -C 8 cycloalkyl) (eg C 4 -C 8 cycloalkyl, (C 4 -C
• R′ and R′′ are each independently H or C 1 -C 10 alkyl.
• R′ and R′′ can each independently be H or C 1 -C 6 alkyl.
• R′ and R′′ may each independently be H or C 1 -C 3 alkyl.
• R' and R'' may each independently be H, methyl or ethyl.
• R 5a is halogen, hydroxy, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy-(C 1 -C 6 alkyl)-, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl)-, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , nitro, cyano , halogen-SO 2 -, (C 1 -C 6 alkyl)-SO 2 - and -SO 2 NH 2 .
• R 5 can be independently selected from (i) to (vi):
• phenyl phenyl-(C 1 -C 3 alkyl)-, phenyloxy, phenyloxy-(C 1 -C 3 alkyl)-, phenylcarbonyl, or phenylcarbonyl-(C 1 -C 3 alkyl) - (the phenyl ring may be optionally substituted with one or more R 5a );
• heteroaryl heteroaryl, heteroaryl-(C 1 -C 3 alkyl)-, heteroaryloxy, heteroaryloxy-(C 1 -C 3 alkyl)-, heteroarylcarbonyl, or heteroarylcarbonyl-(C 1 -C 3 alkyl)-(the heteroaryl ring is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl , pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzooxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl and 1H-P is selected from the group consisting of rollo[2,3
• heterocycloalkyl heterocycloalkyl-(C 1 -C 3 alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C 1 -C 3 alkyl)-, heterocycloalkylcarbonyl, or heterocyclo Alkylcarbonyl-(C 1 -C 3 alkyl)-
• the heterocycloalkyl ring is aziridinyl, oxiranyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, Piperidinyl, tetrahydropyranyl, 4H-pyranyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 1,2-dihydropyranyl, 1,4 -dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,
• R 5a is halogen, hydroxy, oxo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, hydroxy-(C 1 -C 3 alkyl)-, - NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , nitro, cyano, -SO 2 F and -SO 2 Cl.
• the heteroaryl ring of (iii) is pyridinyl, pyrazolyl, isoxazolyl, furanyl, pyrimidinyl, thiazolyl, pyrazinyl, benzimidazolyl, benzooxazolyl and 1H-pyrrolo It may be selected from the group consisting of [2,3-b]pyridinyl.
• heterocycloalkyl ring of (iv) is pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 3,6-dihydro-2H-pyranyl, morpholinyl, oxetanyl, piperidinyl and 2-oxo-oxazolidinyl.
• R 5 is phenyl, benzyl, 1-phenylethyl, phenoxy, pyridinylmethyl, pyridinyloxy, pyridinylcarbonylmethyl, pyrazolylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, isoxazole Ilmethyl, tetrahydrofuranylmethyl, tetrahydrofuranyloxy, tetrahydropyranylmethyl, 3,6-dihydro-2H-pyranylmethyl, morpholinylmethyl, oxetanylmethyl, piperidinylcarbonylmethyl , 2-oxo-oxazolidinylethyl, 2-oxo-oxazolidinylmethyl, furanylmethyl, pyrimidinylmethyl, thiazolylmethyl, pyrazinylmethyl, benzimidazolylmethyl, benzooxazolylmethyl, 1H-p selected from the group consisting of rollo[
• R 5 can be selected from the following structures:
• R 6 is H or C 1 -C 6 alkyl. In some embodiments, R 6 can be H or C 1 -C 3 alkyl. In some embodiments, R 6 can be H or methyl.
• the compound represented by Formula 1A may be a compound represented by Formula 1A-1:
• the compound represented by Formula 1A can be selected from:
• the compound represented by Formula 1A may be a compound represented by any one of Formulas 1A-2 to 1A-9 below:
• the compound may be a compound of Formulas 1A-4, 1A-5, 1A-8 or 1A-9 above.
• a compound of Formula 1A-4, 1A-5, 1A-8 or 1A-9 is represented by Formula 1A this , and U, V and W are defined as:
• W is N, U is N, V is CH, or U is CHR 6 and V is C(O); or
• W is C, U is N and V, one of which is N, and the other is NR 6 .
• R 5 of Formulas 1A-4, 1A-5, 1A-8 or 1A-9 can be selected from (i) to (vi):
• C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 ; C 1 -C 6 alkoxy; or (C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy)-(eg C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy)-, and can also be methyl, ethyl, methoxy, ethoxy, methoxyethoxy, ethoxyethoxy, etc.);
• heteroaryl heteroaryl-(C 1 -C 3 alkyl)- or heteroaryloxy
• the heteroaryl ring may be a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 N atoms). and, for example, the heteroaryl ring may be pyrimidinyl or pyridinyl;
• heterocycloalkyl is a 4-membered to 4-membered heteroatom containing 1 or 2 heteroatoms selected from N and O; can be a 7-membered fully saturated or partially unsaturated heterocycloalkyl, eg the heterocycloalkyl ring can be tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl or morpholinyl); and
• Each of the aryl ring, heteroaryl ring, heterocycloalkyl ring and cycloalkyl ring described in (iii) to (vi) above may be optionally substituted.
• these rings may be optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, -NH 2 , cyano, nitro, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
• R 5 of Formulas 1A-4, 1A-5, 1A-8, or 1A-9 is C 1 -C 6 alkyl (eg, methyl, ethyl), benzyl, phenyl, phenoxy, tetrahydrofuranyl , tetrahydrofuranyloxy, methoxy, ethoxy, methoxyethoxy, ethoxyethoxy, pyridinyl, pyridinyloxy, pyridinylmethyl, pyrimidinyl, pyrimidinylmethyl, pyrimidinyloxy, methoxy phenyl, or methoxybenzyl.
• the compounds represented by Formulas 1A-2 to 1A-9 may be selected from:
• the pyrazine core of the compound represented by Formula 1A may be replaced with another heteroaryl ring, for example, a 5- to 10-membered heteroaryl ring containing a nitrogen atom.
• the 5- to 10-membered heteroaryl ring containing a nitrogen atom may include pyridine, pyridazine, pyrimidine, triazine, imidazopyrimidine, pyrazolopyrazine or pyrazolopyrimidine.
• ring D is selected from the following structures:
• compounds in which ring D has a structure other than a pyrazine core may be selected from compounds represented by the following formula:
• One aspect provides a compound represented by Formula 2, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof:
• T may be C or N.
• R 7 may be H, a halogen atom, or C 1 -C 6 haloalkyl.
• R 8 may be -COOR c , -SO 2 R c , -SO 2 NR c R d , -COR c , -NHCOR c or -CONHR c .
• R c and R d are each independently H, halogen, C 1 -C 6 alkyl, -(CH 2 )m-(C 6 -C 10 aryl), -(CH 2 )m-(5- to 10-membered hetero aryl).
• m may be an integer of 0, 1 or 2.
• the C 6 -C 10 aryl may be phenyl.
• the 5- to 10-membered heteroaryl may contain 1 or 2 heteroatoms selected from N, O and S.
• the 5-membered to 10-membered heteroaryl may be a 5-membered or 6-membered heteroaryl (eg, pyrrolyl, pyridinyl, pyrimidinyl, etc.) containing 1 or 2 N atoms.
• R 8 is -CONH-CH 2 -phenyl, -CONH-CH 2 -pyridinyl, -COOCH 3 , -SO 2 F, -SO 2 -NH 2 , -SO 2 -NH-CH 3 , or -SO 2 -NH-CH 2 -phenyl.
• R 9 is H, halogen, hydroxy, oxo, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 2 -C 20 alkoxyalkyl, amine group, C 1 -C substituted with an amine group It may be selected from the group consisting of an alkyl of 20 , an imine group, a nitro group, a cyano group, an amidino group, and a carboxyl group or a salt thereof.
• R 10 and R 11 are each independently H, C 1 -C 6 alkyl, an amine group, or a C 1 -C 6 alkyl substituted with an amine group, or R 10 and R 11 are linked to each other to form ring C.
• the R 10 may be an amine group or an aminomethyl group.
• the R 11 may be a methyl group.
• the ring C is a 3-, 4-, 5-, 6-, 7-, or 8-membered cyclic ring group optionally containing one oxygen atom, optionally a C 1 -C 6 alkyl, amine group, or It may be substituted with a C 1 -C 6 alkyl group substituted with an amine group.
• the ring C may be substituted or unsubstituted tetrahydrofuran.
• the tetrahydrofuran may be substituted with one or more selected from the group consisting of a C 1 -C 6 alkyl group, an amine group, and a C 1 -C 6 alkyl group substituted with an amine group.
• Ring C may optionally be condensed with an aryl or heteroaryl ring.
• R 10 and R 11 are linked together to form ring C
• ring C is cyclopentane or tetrahydrofuran
• ring C may be optionally substituted with C 1 -C 6 alkyl or -NH 2 .
• the ring C may optionally be condensed with phenyl or pyridine.
• the formula (2) can be selected from:
• q may be an integer of 0, 1 or 2.
• the compound of Formula 2 may be selected from the group consisting of the following formula:
• One aspect provides a compound represented by Formula 3A, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof:
• J may be absent or S.
• G can be C or N.
• o may be an integer of 0, 1, 2, 3, 4, or 5.
• the o may be 0 or 1.
• R 31 may be H, a halogen atom, or C 1 -C 6 alkyl substituted with a halogen atom.
• the R 31 may be H or a halogen atom.
• R 32 is H, a halogen atom, a hydroxyl group, a ketone group, a C 1 -C 20 alkyl, a C 1 -C 20 alkoxy, a C 2 -C 20 alkoxyalkyl, an amine group, or a C 1 -C substituted with an amine group.
• R 32 may be selected from the group consisting of H, a halogen atom, an amine group, -COOH, or -COORe .
• R e may be H, a halogen atom, or a C 1 -C 6 alkyl group optionally substituted with a halogen atom.
• R 31 and R 32 may each be halogen.
• R 33 and R 34 may each independently be H, a C 1 to C 6 alkyl, an amine group, or a C 1 -C 6 alkyl substituted with an amine group.
• R 33 and R 34 may each independently be H, a methyl group, an amine group, or a C 1 to C 6 alkyl group substituted with an amine group.
• R 35 may represent two or more substituents. Two or more R 35 may be the same as or different from each other.
• R 35 is H, halogen, hydroxy, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 2 -C 20 alkoxyalkyl, an amine group, a C 1 -C 20 alkyl substituted with an amine group, an imine group, Nitro group, cyano group, amidino group, carboxyl group or its salt, C 1 -C 20 heteroalkyl, substituted or unsubstituted C 6 -C 20 aryl, substituted or unsubstituted C 6 -C 20 arylalkyl, substituted or Unsubstituted C 6 -C 20 heteroaryl, substituted or unsubstituted C 6 -C 20 heteroarylalkyl, substituted or unsubstituted C 6 -C 20 heteroaryloxy, substituted or unsubstituted C 6 -C 20 hetero It may be at least one selected from the group consisting of aryloxyalkyl, and a substituted or unsubsti
• R 35 - is H, halogen atom, C 1 -C 20 alkyl, amine group, C 1 -C 20 alkyl substituted with an amine group, substituted or unsubstituted C 6 -C 20 aryl, substituted or unsubstituted C 6 It may be one or more selected from the group consisting of -C 20 arylalkyl, substituted or unsubstituted C 6 -C 20 heteroaryl, and substituted or unsubstituted C 6 -C 20 heteroarylalkyl.
• R 35 can be C 1 -C 6 alkyl or NH 2 .
• One aspect provides a compound represented by Formula 3B, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof:
• J may be absent or S.
• o may be an integer of 0, 1, 2, 3, 4, or 5.
• the o may be 0 or 1.
• R 31 may be H, a halogen atom, or C 1 -C 6 alkyl substituted with a halogen atom.
• the R 31 may be H or a halogen atom.
• R 33 and R 34 may each independently be H, C 1 -C 6 alkyl, an amine group, or a C 1 -C 6 alkyl substituted with an amine group.
• R 33 and R 34 may each independently be H, a methyl group, an amine group, or a C 1 -C 6 alkyl substituted with an amine group.
• R 35 may represent two or more substituents. Two or more R 35 may be the same as or different from each other.
• R 35 is H, a halogen atom, a hydroxy group, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 2 -C 20 alkoxyalkyl, an amine group, a C 1 -C 20 alkyl substituted with an amine group, an imine group, or a nitro group, cyano group, amidino group, carboxyl group or its salt, C 1 -C 20 heteroalkyl, substituted or unsubstituted C 6 -C 20 aryl, substituted or unsubstituted C 6 -C 20 arylalkyl, substituted or unsubstituted cyclic C 6 -C 20 heteroaryl, substituted or unsubstituted C 6 -C 20 heteroarylalkyl, substituted or unsubstituted C 6 -C 20 heteroaryloxy, substituted or unsubstituted C 6 -C 20 heteroaryl It may be one or more selected from the group consisting of
• R 35 is H, halogen atom, C 1 -C 20 alkyl, amine group, C 1 -C 20 alkyl substituted with an amine group, substituted or unsubstituted C 6 -C 20 aryl, substituted or unsubstituted C 6 - It may be at least one selected from the group consisting of C 20 arylalkyl, substituted or unsubstituted C 6 -C 20 heteroaryl, and substituted or unsubstituted C 6 -C 20 heteroarylalkyl.
• R 35 can be C 1 -C 6 alkyl or NH 2 .
• R 21 and R 22 are each independently substituted with H, a halogen atom, a hydroxyl group, a ketone group, a C 1 -C 20 alkyl, a C 1 -C 20 alkoxy, a C 2 -C 20 alkoxyalkyl, an amine group, or an amine group.
• R 21 and R 22 are each independently selected from H, C 1 -C 20 alkyl, amine group, C 1 -C 20 alkyl substituted with an amine group, C 6 -C 20 aryl, C 6 -C 20 arylalkyl, C 6 -C 20 heteroaryl, and C 6 -C 20 heteroarylalkyl.
• R 21 and R 22 may independently represent H or a phenyl group.
• One aspect provides a compound represented by Formula 3C, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof:
• J may be absent or S.
• G can be C or N.
• L can be C, N, or O.
• R 35 may be substituted on a carbon atom or nitrogen atom of L.
• o can be an integer of 0, 1, 2, 3, 4, or 5.
• the o may be 0 or 1.
• R 31 may be H, a halogen atom, or C 1 -C 6 alkyl substituted with a halogen atom.
• the R 1 may be H or a halogen atom.
• R 32 is H, a halogen atom, a hydroxyl group, a ketone group, a C 1 -C 20 alkyl, a C 1 -C 20 alkoxy, a C 2 -C 20 alkoxyalkyl, an amine group, or an amine group-substituted C 1 - C 20 alkyl, imine group, nitro group, cyano group, amidino group, carboxyl group or its salt, C 1 -C 20 heteroalkyl, C 6 -C 20 aryl, C 6 -C 20 arylalkyl, C 6 -C 20 hetero aryl, C 6 -C 20 heteroarylalkyl, C 6 -C 20 heteroaryloxy, C 6 -C 20 heteroaryloxyalkyl, and C 6 -C 20 heterocycloalkyl.
• R 32 may be selected from the group consisting of H, a halogen atom, an amine group, -COOH, or -COOR f .
• the R f may be H, a halogen atom, or C 1 -C 6 alkyl optionally substituted with a halogen atom.
• R 31 and R 32 may each be halogen.
• R 33 and R 34 may each independently be H, C 1 -C 6 alkyl, an amine group, or a C 1 -C 6 alkyl substituted with an amine group.
• R 33 and R 34 may each independently be H, a methyl group, an amine group, or a C 1 -C 6 alkyl substituted with an amine group.
• R 33 and R 34 are independently of each other H, C 1 -C 6 alkyl, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or H 2 N-(C 1 -C 6 alkyl)-.
• R 33 and R 34 can independently of each other be C 1 -C 3 alkyl or -NH 2 .
• R 33 is -NH 2 and R 34 can be methyl.
• R 35 may represent two or more substituents. Two or more R 35 may be the same as or different from each other.
• R 35 is H, a halogen atom, hydroxy, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 2 -C 20 alkoxyalkyl, an amine group, a C 1 -C 20 alkyl substituted with an amine group, an imine group, Nitro group, cyano group, amidino group, carboxyl group or its salt, C 1 -C 20 heteroalkyl, substituted or unsubstituted C 6 -C 20 aryl, substituted or unsubstituted C 6 -C 20 arylalkyl, substituted or Unsubstituted C 6 -C 20 heteroaryl, substituted or unsubstituted C 6 -C 20 heteroarylalkyl, substituted or unsubstituted C 6 -C 20 heteroaryloxy, substituted or unsubstituted C 6 -C 20 hetero It may be one or more selected from the group consisting of aryloxyalkyl, and substituted or un
• R 35 is H, halogen atom, C 1 -C 20 alkyl, amine group, C 1 -C 20 alkyl substituted with an amine group, substituted or unsubstituted C 6 -C 20 aryl, substituted or unsubstituted C 6 - It may be at least one selected from the group consisting of C 20 arylalkyl, substituted or unsubstituted C 6 -C 20 heteroaryl, and substituted or unsubstituted C 6 -C 20 heteroarylalkyl.
• the R 35 may represent two or more substituents.
• R 35 is C 1 -C substituted with one or more substituents selected from the group consisting of —NH 2 , 5- to 10-membered heteroaryl (eg, pyridinyl), and C 6 -C 10 aryl (eg, phenyl). 6 alkyl.
• (C 6 -C 12 aryl)-(C 1 -C 8 alkyl)-, heteroaryl-(C 1 -C 8 alkyl)- and heteroaryloxy-(C 1 -C 8 alkyl)- (C 1 -C 8 alkyl)- may be optionally substituted with halogen, hydroxy, -NH 2 , nitro or cyano.
• the compound represented by Formula 3A, 3B or 3C may be selected from compounds represented by Formula:
• halogen or “halogen atom” refers to an atom belonging to group 17 of the periodic table. Halogen atoms include F, Cl, Br, I and the like.
• alkyl refers to a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon.
• the alkyl may be substituted or unsubstituted alkyl.
• the C 1 -C 20 alkyl may be, for example, C 1 -C 15 , C 1 -C 10 , or C 1 -C 6 alkyl.
• the C 1 -C 6 alkyl may be C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , or C 1 -C 2 alkyl.
• the alkyl can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, or n-hexyl.
• haloalkyl refers to an alkyl substituted with one or more halogens.
• hydroxy refers to the -OH functional group (hydroxyl group).
• alkoxy refers to an alkyl bonded to an oxygen atom.
• the C 1 -C 20 alkoxy may be, for example, C 1 -C 15 , C 1 -C 10 , or C 1 -C 6 alkoxy.
• the C 1 -C 6 alkoxy may be C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , or C 1 -C 2 alkoxy.
• the alkoxy may be methoxy, ethoxy, propoxy, butoxy, and the like.
• alkoxyalkyl refers to an alkoxy bonded to an alkyl.
• the C 2 -C 20 alkoxyalkyl may be, for example, C 2 -C 15 , C 2 -C 10 , or C 2 -C 6 alkoxyalkyl.
• C 2 -C 20 alkoxyalkyl may be (C 1 -C 10 alkoxy)-(C 1 -C 10 alkyl), (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl), etc.
• alkoxy The carbon number of the group and the alkyl group may be the same or different.
• the alkoxy may be, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, and the like.
• alkoxyalkoxy refers to an alkoxy bonded to an alkoxy group.
• Alkoxyalkoxy may include, for example, methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, and the like.
• amino refers to -NH 2 .
• amine group means a substituent in which one, two or all three hydrogens of ammonia are replaced with organic functional groups, and includes all primary amines, secondary amines and tertiary amines, A term that includes an amino group.
• nitro refers to -NO 2 .
• cyano is -CN, and refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.
• carboxy refers to -COOH.
• Salts of carboxyls refer to the conjugate bases of carboxylic acids.
• sulfonyl refers to the -SO 2 - group.
• cycloalkyl refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic hydrocarbon group.
• Cyclic ring groups may contain 3 to 20 carbon atoms, such as 5 to 10, 3 to 8, or 3 to 6 carbon atoms.
• a monocyclic ring group can be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl, and the like.
• Bicyclic ring groups are, for example, bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, or bicyclo[2.2 .2] octyl and the like.
• a tricyclic ring group can be, for example, adamantyl.
• aryl also includes groups in which an aromatic ring is fused to one or more carbon rings.
• the C 6 -C 30 aryl may be, for example, C 6 -C 15 or C 6 -C 10 aryl.
• Aryl can be phenyl, naphthyl, or tetrahydronaphthyl.
• arylalkyl refers to an alkyl substituted with an aryl.
• aryloxy refers to an aryl bonded to an oxygen atom.
• heteroaryl refers to a monocyclic or bicyclic aromatic compound that contains one or more heteroatoms, the remaining ring atoms being carbon.
• the heteroaryl may include, for example, 1 to 5, 1 to 3, 1 or 2 hetero atoms, and may include 5 to 10 ring members.
• Heteroaryl includes, for example, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl.
• heteroarylalkyl refers to an alkyl substituted with a heteroaryl.
• heteroaryloxy refers to a heteroaryl bonded to an oxygen atom.
• heterocycloalkyl or “heterocyclyl” refers to a saturated or partially unsaturated cyclic hydrocarbon containing at least one heteroatom.
• a heterocyclyl ring group can be a single ring group, two ring groups, or three ring groups.
• the two ring groups may be a spiro-ring group, a bridged-ring group, and a fused-ring group.
• the heterocyclyl ring group may contain 3 to 20, 3 to 10, 3 to 8, 3 to 7, 5 to 7, 4 to 6, or 5 to 6 ring atoms.
• the heteroatom may be any one or more selected from the group consisting of N, O and S, for example, 1, 2 or 3 heteroatoms.
• the heterocycloalkyl is aziridinyl, oxiranyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, dihydropyranyl , morpholinyl, thiomorpholinyl or oxazolidinyl and the like.
• heterocycloalkylalkyl refers to an alkyl substituted with a heterocycloalkyl.
• heterocycloalkyloxy refers to a heterocycloalkyl bonded to an oxygen atom.
• the heteroatom may be at least one selected from the group consisting of N, O, P, and S.
• the heteroatom may be one, two or three heteroatoms selected from the group consisting of N, O and S.
• substituted or unsubstituted refers to what is introduced in place of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and "substituent” refers to an introduced atomic group.
• Isomer of the term “stereoisomer” refers to a compound having the same molecular formula but not the same connection method or spatial arrangement of constituent atoms in a molecule. Isomers include, for example, structural isomers, and stereoisomers. The stereoisomers may be diastereomers or enantiomers. Enantiomers refer to isomers that do not overlap with their mirror images, such as the relationship between left and right hands, and are also called optical isomers. Enantiomers are classified as R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents differ from each other on the chiral central carbon.
• Diastereomers are stereoisomers that are not mirror images, and are isomers that result from differences in the arrangement of atoms in space.
• the diastereomers may be divided into cis-trans isomers and conformational isomers or conformers.
• solvate refers to a compound solvated in an organic or inorganic solvent.
• the solvate is, for example, a hydrate.
• salt refers to inorganic and organic acid addition salts of a compound.
• the pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.
• the inorganic acid salt may be a hydrochloride, bromate, phosphate, sulfate, or bisulfate salt.
• the organic acid salt is formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edisyl salt, trichloroacetic acid, trifluoroacetate , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate may be an acid salt.
• the metal salt may be a calcium salt, sodium salt, magnesium salt, strontium salt, or potassium salt.
• Src homology region 2 domain-containing phosphatase-2 may be an inhibitor for SHP2).
• Src homology region 2 domain-containing phosphatase-2 may be a protein belonging to protein tyrosine phosphatase (PTP).
• the SHP2 may also be called PTPN11 (tyrosine-protein phosphatase non-receptor type 11), PTP-1D (protein-tyrosine phosphatase 1D), or PTP-2C (protein-tyrosine phosphatase 2C).
• the SHP2 may include two tandem SH2 domains at the N-terminus together with SPP1.
• the SHP2 is Uniprot No. 2 in humans.
• the amino acid sequence of Q06124 or Uniprot No. It may be a protein comprising the amino acid sequence of P35235.
• the SHP2 may be wild type SHP2 or SHP2 mutant.
• the inhibitor for SHP2 may be an inhibitor that inhibits the expression or activity of SHP2.
• Another aspect provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to one aspect, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof.
• Src homology region 2 domain-containing phosphatase-2 comprising a compound according to one aspect, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition for preventing or treating a disease associated with abnormal activity of SHP2) is provided.
• the disease associated with the abnormal activity of SHP2 may be selected from the group consisting of cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis, and eye disorder.
• the cancer is ovarian cancer, cervical cancer, endometrial cancer, uterine sarcoma, vulvar cancer, breast cancer, skin cancer, head and neck cancer, pancreatic cancer, lung cancer, colon cancer, colorectal cancer, stomach cancer, prostate cancer, bladder cancer, urethral cancer, liver cancer, kidney cancer , skin cancer, cerebrospinal tumor, brain cancer, thymoma, mesothelioma, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, biliary tract cancer, testicular cancer, germ cell tumor, thyroid cancer, parathyroid cancer, lymphoma, myelodysplastic syndromes (MDS), myelofibrosis (myelofibrosis), acute leukemia, chronic leukemia, multiple myeloma, endocrine cancer, and sarcoma.
• MDS myelodysplastic syndromes
• the cancer metastasis refers to the spread of a tumor from a primary site to other parts of the body, where it settles and proliferates. Cancer metastasis can spread cancer cells to blood vessels, lymph vessels, or tissues.
• the cardiovascular disease refers to a disease occurring in the heart or major arteries (eg, aorta, pulmonary artery, carotid artery, cerebrovascular artery, renal artery, lower extremity artery).
• the cardiovascular disease may be selected from the group consisting of hypertension, ischemic heart disease, coronary artery disease, angina pectoris, myocardial infarction, atherosclerosis (arteriosclerosis), cerebrovascular disease, stroke, arrhythmia, acute heart failure, chronic heart failure, and hypotension. .
• the immune disorder refers to a state in which a normal immune response is not achieved.
• the immune disorder may be selected from the group consisting of acquired immunodeficiency, autoimmune disease, systemic lupus erythematosus, scleroderma, Sjogren's syndrome, polymyositis, dermatomyositis, polymyalgia rheumatica, temporal arteritis, polyarteritis nodosa, and Behçet's syndrome. .
• the fibrosis refers to a condition in which fibrous tissue excessively increases in a part of a tissue or organ.
• the fibrosis may be selected from the group consisting of liver fibrosis, cystic fibrosis, myelofibrosis, endomyocardial muscle fibrosis, and retroperitoneal fibrosis.
• the ocular disorders refer to disorders affecting various structures of the eye.
• the ocular disorder may be selected from the group consisting of endophthalmitis, degenerative myopia, degenerative disorders of the eye, low intraocular pressure of the eye, intraocular foreign body, hemoglobin, and ocular dislocation.
• Noonan syndrome Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias (JMML), neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, From the group consisting of colorectal cancer, head cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, anaplastic large cell lymphoma, glioblastoma, pancreatic cancer, biliary tract cancer, uterine cancer, endometrial cancer, liver cancer, and Neurofibromatosis type 1 can be chosen
• prevention refers to all activities of suppressing or delaying the onset of diseases associated with SHP2 by administration of the pharmaceutical composition.
• treatment refers to all activities that improve or beneficially change symptoms of SHP2-related diseases by administration of the pharmaceutical composition.
• the pharmaceutical composition may include a pharmaceutically acceptable carrier.
• the carrier is used as a meaning including an excipient, diluent or auxiliary agent.
• Such carriers include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl fibre, It may be one selected from the group consisting of Rolidone, water, physiological saline, a buffer such as PBS, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil.
• the composition may include fillers, anti-agglomerating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, or combinations thereof.
• the pharmaceutical composition may be prepared in any dosage form according to conventional methods.
• the composition may be formulated as, for example, an oral dosage form (eg, powder, tablet, capsule, syrup, pill, or granule), or a parenteral dosage form (eg, injection).
• the composition may be prepared as a systemic formulation or topical formulation.
• the solid preparation for oral administration may be tablets, pills, powders, granules, or capsules.
• the solid formulation may further include an excipient.
• the excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin.
• the solid preparation may further include a lubricant such as magnesium stearate or talc.
• the oral liquid formulation may be a suspension, internal solution, emulsion, or syrup.
• the liquid formulation may include water or liquid paraffin.
• the liquid formulation may contain excipients such as wetting agents, sweetening agents, flavoring agents, or preservatives.
• preparations for parenteral administration may be sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried or suppositories.
• Non-aqueous solvents or suspensions may include vegetable oils or esters.
• the vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil.
• the ester may be, for example, ethyl oleate.
• the base of the suppository may be witepsol, macrogol, tween 61, cacao butter, laurin fat, or glycerogelatin.
• the pharmaceutical composition includes the compound according to one aspect, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof as an active ingredient of the pharmaceutical composition.
• Active ingredient refers to a physiologically active substance used to achieve pharmacological activity (eg, treatment of diseases associated with abnormal activity of SHP2).
• the pharmaceutical composition may contain an effective amount of a compound according to one aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
• the term "effective amount" refers to an amount sufficient to exhibit the effect of preventing or treating a disease when administered to a subject in need of such prevention or treatment.
• the effective amount can be appropriately selected by those skilled in the art depending on the cell or organism to be selected.
• a preferred dosage of the pharmaceutical composition varies depending on the condition and body weight of the subject, the severity of the disease, the type of drug, the route and period of administration, but can be appropriately selected by those skilled in the art.
• the effective amount can be about 0.5 ⁇ g to about 2 g, about 1 ⁇ g to about 1 g, about 10 ⁇ g to about 500 mg, about 100 ⁇ g to about 100 mg, or about 1 mg to about 50 mg per pharmaceutical composition.
• the compound, its stereoisomer, solvate, or pharmaceutically acceptable salt can be used in an amount of, for example, about 0.0001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 100 mg/kg. It may be divided into 1 to 24 times per day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times per 1 month to 12 months.
• the compound, its stereoisomer, solvate, or pharmaceutically acceptable salt is from about 0.0001% to about 10% by weight, or from about 0.001% to about 1% by weight, based on the total weight of the composition. can be included
• the administration method may be oral or parenteral administration.
• the method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes.
• the composition may be administered systemically or topically, and may be administered alone or in combination with other pharmaceutically active compounds.
• Another aspect provides a method for preventing or treating a disease associated with abnormal activity of SHP2, comprising administering to a subject a compound according to one aspect, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof. .
• the compounds, stereoisomers, solvates, pharmaceutically acceptable salts, SHP2, diseases associated with abnormal SHP2 activity, prevention, and treatment are as described above.
• the subject may be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat, ape, or cat.
• the subject may be an individual suffering from, or highly likely to suffer from, symptoms associated with a disease associated with abnormal activity of SHP2.
• the method may further include administering to the subject a known active ingredient having an effect of preventing or treating a disease related to SHP2.
• the known active ingredient may be administered to the subject simultaneously, separately, or sequentially with the compound according to one aspect, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.
• the administration method may be oral or parenteral administration.
• the method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes.
• the pharmaceutical composition may be administered systemically or topically, and may be administered alone or in combination with other pharmaceutically active compounds.
• a preferred dosage of the pharmaceutical composition varies depending on the condition and body weight of the patient, the severity of the disease, the type of drug, the route and period of administration, but can be appropriately selected by those skilled in the art.
• the dosage is, for example, in the range of about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 10 mg/kg, or about 0.1 mg/kg to about 1 mg/kg on an adult basis.
• the administration is once a day, 2 to 24 times a day, 1 to 2 times a day, 1 to 6 times a week, 1 to 10 times a week, 1 to 15 times a week, and 1 to 15 times a week. , 1 to 3 times every 4 weeks, or 1 to 12 times a year.
• Another aspect provides a compound according to one aspect, a stereoisomer or solvate thereof, or a pharmaceutically acceptable salt thereof, for use in preventing or treating a disease associated with abnormal activity of SHP2.
• the compounds, stereoisomers, solvates, pharmaceutically acceptable salts, SHP2, diseases associated with abnormal SHP2 activity, prevention, and treatment are as described above.
• Another aspect provides the use of a compound according to one aspect, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for preventing or treating a disease associated with abnormal activity of SHP2.
• the compounds, stereoisomers, solvates, pharmaceutically acceptable salts, SHP2, diseases associated with abnormal SHP2 activity, prevention, and treatment are as described above.
• SHP2 inhibitors pharmaceutical compositions for preventing or treating SHP2-related diseases including the same, methods for treating and preventing diseases using the same, and uses thereof can effectively prevent or treat SHP2-related diseases.
• Step 1 2-Methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propan-2-sulfanilamide
• Step 2 N-((3S,4S)-8-(5-Bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2- Methylpropane-2-sulfanilamide (intermediate I-3)
• 6-Bromo-5-chloroquinazolin-4(3H)-one (6.87 g, 26.47 mmol), ethyl-3-mercaptopropionate (4 mL, 34.41 mmol), Pd 2 (dba) 3 (1.21 g, 1.32 mmol) and xantphos (1.53 g, 2.65 mmol) were dissolved in 1,4-dioxane (66 mL, 0.4 M), and DIPEA (9.2 mL, 52.9 mmol) was added dropwise. After purging with nitrogen, the mixture was stirred at 140 ° C. for 16 hours. The reaction was terminated with H 2 O and extracted with EA.
• the EA layer was dried over MgSO 4 , filtered and concentrated to obtain ethyl 3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propionate (7.03 g, 91% ) was obtained.
• 6-amino-3-bromo-2-chlorobenzoic acid 250 mg, 1.0 mmol
• acetic anhydride 4 mL, 0.25 M
• NH 3 solution (28% in H 2 O) (4 mL, 0.25 M) was added to the compound, and the mixture was stirred at 100 ° C. for 12 hours.
• the solid precipitated during the reaction was filtered, washed with H 2 O and MeOH, and dried to obtain 6-bromo-5-chloro-2-methylquinazolin-4(3H)-one (203 mg, 74%). .
• Step 3 Ethyl 3-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propionate
• Step 1 Methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propanate
• Step 2 tert-butyl (1-(5-mercaptopyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (intermediate I-10)
• methyl 6-amino-3-bromo-2-chlorobenzoate 600 mg, 1.60 mmol was dissolved in triethyl ortho formate (0.4 mL, 2.40 mmol), and aniline (0.18 mL, 1.92 mmol) was added to the reaction mixture. ) and NH 4 Cl (43 mg, 0.80 mmol) were added dropwise and the reaction was stirred at 100 ° C for 16 h. The reaction was terminated with H 2 O and extracted with EA. The EA layer was dried over MgSO 4 , filtered and concentrated.
• Step 2 Methyl 3-((5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)thio)propanoate
• Step 1 tert-Butyl (1-(4-amino-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-methylpiperidin-4-yl)carbamate
• 6-Amino-3-methyl-1H-pyrimidine-2,4-dione 500 mg, 3.54 mmol
• BOP 1.57 g, 3.54 mmol
• DBU 1,8-Diazabicyclo[5.4.0]undec-7
• tert-butyl (4-methylpiperidin-4-yl)carbamate 758 mg, 3.54 mmol
• Step 2 tert-Butyl (1-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-methylpiperidin-4-yl ) carbamate (intermediate I-14)
• tert-butyl (1-(4-amino-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (260 mg, 950 ⁇ mol) was dissolved in ACN (3 mL, 0.25 M), and NIS (N-iodosuccinimide, 214 mg, 950 ⁇ mol) was added. The reaction solution was stirred for 1 hour at room temperature. A white precipitate was formed, and after confirming that the reaction material had completely disappeared by LCMS, the reaction was terminated with an aqueous solution of NaHCO 3 and extracted with EA. The EA layer was dried over MgSO 4 , filtered and concentrated. After separation by MPLC and concentration, intermediate I-14 (360 mg, 82%) was obtained. MS m/z: 464 [M+H] + .
• N-benzyl-3,4-dichloropicolinamide (92 mg, 0.33 mmol), ethyl-3-mercaptopropionate (63 ⁇ L, 0.495 mmol), Pd 2 (dba) 3 (18 mg, 0.02 mmol) and Xantphos (19 mg, 0.033 mmol) were dissolved in 1,4-dioxane (1 mL, 0.4 M), and DIPEA (115 ⁇ L, 0.66 mmol) was added. After purging with nitrogen, the mixture was stirred at 100 ° C. for 18 hours. The reaction was terminated with H 2 O and extracted with EA. The EA layer was dried over MgSO 4 , filtered and concentrated.
• Step 5 Ethyl 3-((2-benzyl-8-chloro-1-oxo-1,2,3,4-tetrahydro isoquinolin-7-yl)thio)propanoate
• Step 1 N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide
• Step 2 N-((S)-1′-(5-Bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)- 2-methylpropane-2-sulfinamide
• Step 2 2-Ethylhexyl 3-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate
• Step 3 Sodium 3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate
• Step 1 tert-Butyl 1-[(R)-tert-butylsulfinyl]iminospiro[indene-2,4'-piperidine]-1'-carboxylate
• Step 2 tert-Butyl (1R)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indene-2,4'-piperidine]-1'-carboxylate
• Step 2 tert-Butyl 4-[(3-bromo-2-pyridyl)methyl]-4-cyano-piperidine-1-carboxylate
• Step 3 tert-Butyl 5-oxospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate
• Step 4 tert-Butyl (5Z)-5-[(R)-tert-butylsulfinyl]iminospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxyl rate
• Step 5 tert-Butyl (5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine] -1'-Carboxylate and tert-butyl (5R)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'- piperidine]-1'-carboxylate
• Step 6 (R)-2-methyl-N-[(5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidin]-5-yl]propan-2 -sulfinamide and (R)-2-methyl-N-[(5R)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidin]-5-yl]propan- 2-sulfinamide
• Step 3 to Step 5 5-Chloro-6-((5-iodopyrazin-2-yl)thio)-3-(pyridin-3-ylmethyl)quinazolin-4(3H)-one
• Step 1 2-Ethylhexyl 3-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate
• Step 2 and Step 3 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one
• Step 2 tert-Butyl N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl] carbamate
• Step 3 2-Ethylhexyl 3-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane -8-yl) pyrazin-2-yl) thio) propanoate
• Step 4 Sodium 5-((3S,4S)-4-(tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazin-2 - Thiolate
• Step 1 Benzyl (2-chloro-6-nitrophenyl) sulfane
• N-iodosuccinimide N-iodosuccinimide
• Step 1 2-[(6-Bromo-7-chloro-2-tetrahydrofuran-3-yloxy-benzimidazol-1-yl)methoxy]ethyl-trimethyl-silane
• Step 3 6-Bromo-7-chloro-1-methyl-2-tetrahydrofuran-3-yloxy-benzimidazole and 5-bromo-4-chloro-1-methyl-2-tetrahydrofuran- 3-yloxy-benzimidazole
• Step 4 Ethyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-bromo-5-methyl-pyrazine- 2-Carboxylate
• Step 5 Ethyl 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl ]-5-methyl-pyrazine-2-carboxylate
• Step 6 tert-Butyl N-[(3S,4S)-8-[5-bromo-3-(hydroxymethyl)-6-methyl-pyrazin-2-yl]-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-yl]carbamate
• Step 1 6-(5-Bromopyrazin-2-yl)sulfanyl-5-chloro-3H-quinazolin-4-one
• Step 2 (R)-N-((S)-1'-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl )-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-yl)-2-methylpropane-2-sulfinamide
• 6-(5-bromopyrazin-2-yl)sulfanyl-5-chloro-3H-quinazolin-4-one 150 mg, 406 ⁇ mol
• dioxane 5 mL
• intermediate I-25 150 mg , 487 ⁇ mol
• [2-(2-aminophenyl)phenyl]-chloro-palladium [2-(2-aminophenyl)phenyl]-chloro-palladium
• Dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (RuPhos-Pd-G2) (31.5 mg, 40.6 ⁇ mol)
• 2-dicyclohexylphosphino-2',6' A mixture of -diisopropoxybiphenyl (RuPhos) (37.8 mg, 81.2 ⁇ mol) and K 2 CO 3 (168 mg, 1.22 mmol) was degassed and purged with N 2 three times, then the
• Step 1 tert-Butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'- carboxylate
• Step 3 (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl]-2-methylpropane-2-sulfinamide
• Step 3 O1-tert-butyl O4-ethyl 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylate
• reaction mixture was quenched with aqueous ammonium chloride solution (100 mL), diluted in water (200 ml) and extracted with EA (300 mL x 3). The combined organic layers were washed with brine (150 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0.1% FA) to give O1-tert-butyl O4-ethyl 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylate ( 14 g, 31% yield) as a yellow oil.
• Step 4 tert-Butyl 2-chloro-6-oxo-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate
• Step 1 tert-Butyl (6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1 '-Carboxylate
• Step 2 tert-Butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine ]-1'-carboxylate
• Step 3 (R)-2-methyl-N-[(6S)-spiro[4,6-dihydrocyclopenta[d]thiazol-5,4'-piperidin]-6-yl]propan- 2-sulfinamide
• Step 1 tert-Butyl (6Z)-6-[(S)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine ]-1'-carboxylate
• Step 2 tert-Butyl (6R)-6-[[(S)-tert-butylsulfinyl]amino]-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4 '-piperidine]-1'-carboxylate
• Step 3 tert-Butyl (6R)-6-[[(S)-tert-butylsulfanyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine ]-1'-carboxylate
• Step 4 (S)-2-Methyl-N-[(6R)-spiro[4,6-dihydrocyclopenta[d]thiazol-5,4'-piperidin]-6-yl]propan- 2-sulfinamide
• Step 2 tert-Butyl 2-chloro-4-oxo-spiro[6H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate
• Step 1 Methyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-bromo-pyrazine-2-carboxylate
• Step 2 Methyl 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl ]pyrazine-2-carboxylate
• Step 3 tert-Butyl N-[(3S,4S)-8-[5-bromo-3-(hydroxymethyl)pyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[ 4.5] decane-4-yl] carbamate
• Step 2 5-Amino-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazine-2-carbonitrile
• Step 3 tert-Butyl N-[(3S,4S)-8-(6-amino-3-cyano-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane -4-day] carbamate
• Step 4 tert-Butyl N-[(3S,4S)-8-(6-amino-3-carbamoyl-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane -4-day] carbamate
• Step 5 tert-Butyl N-[(3S,4S)-8-(6-amino-5-bromo-3-carbamoyl-pyrazin-2-yl)-3-methyl-2-oxa-8-aza Spiro[4.5]decan-4-yl]carbamate
• Step 1 tert-Butyl 6-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate
• reaction mixture was quenched at 25 ° C by addition of aqueous ammonium chloride (100 mL), then diluted with water (100 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by column chromatography to obtain tert-butyl 6-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (640 mg, 6% yield) as a yellow solid.
• Step 2 tert-Butyl (R,Z)-1-((tert-butylsulfinyl)imino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]- 1'-Carboxylate
• Step 3 tert-Butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine ]-1'-carboxylate
• Step 4 (R)-N-((S)-5-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl]-2-methylpropan-2 -Sulfinamide
• Step 2 tert-Butyl 6-hydroxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate
• Boc 2 O (1.97 g, 9.02 mmol) and NaOH (902 mg, 22.6 mmol) were added and the mixture was stirred at 25 ° C. for 1 hour.
• the reaction mixture was quenched at 25 ° C by addition of aqueous ammonium chloride solution (20 mL), then diluted with water (30 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
• step 1 of Preparation Example 47 (R) -2-methylpropane-2-sulfinamide was used instead of (S) -2-methylpropane-2-sulfinamide, and steps 2 and 4 were performed with the resulting intermediate.
• Intermediate I-64 (90mg, 66% yield) was prepared.
• Step 2 6-Bromo-3-((S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5, 4'-piperidine]-1'-yl)pyrazine-2-carboxamide
• Step 1 tert-Butyl (1R)-1-((tert-butylsulfinyl)amino)-8-azaspiro[4.5]decane-8-carboxylate
• Step 3 N-((R)-8-(5-Bromopyrazin-2-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide
• 6-bromo-5-chloroquinazolin-4(3H)-one 58.7 g, 226.1 mmol
• 1-bromo-2-methoxyethane 32 mL, 339.2 mmol
• cesium carbonate 147 g, 452.3 mmol
• DMF 565 mL, 0.4 M
• the reaction was terminated with an aqueous solution of NaHCO 3 and extracted with EA.
• the EA layer was dried over MgSO 4 , filtered and concentrated.
• Step 2 Ethyl 3-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate
• Step 3 Potassium 5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazoline-6-thiolate
• Preparation 72 N-((S)-1'-(6-chloro-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperi Din]-1-yl)-2-methylpropane-2-sulfinamide (intermediate I-74) and N-((S)-1′-(3-chloro-1,2,4-triazine-6- yl) -1,3-dihydrospiro [indene-2,4'-piperidin] -1-yl) -2-methylpropane-2-sulfinamide (intermediate I-75) synthesis
• Step 1 N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide
• Step 2 N-((S)-1'-(6-chloro-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine ]-1-yl)-2-methylpropane-2-sulfinamide (intermediate I-74) and N-((S)-1′-(3-chloro-1,2,4-triazin-6-yl )-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (intermediate I-75)
• Step 1 t-Butyl 4-(4-amino-1-methyl-6-oxo-pyrimidin-2-yl)piperazine-1-carboxylate
• Step 2 t-Butyl 4-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperazine-1-carboxylate
• Step 3 tert-Butyl 4-(4-amino-5-((2,3-dichlorophenyl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperazine -1-carboxylate
• 2,3-dichlorobenzenethiol (395 mg, 2.21 mmol), t-butyl 4-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl )piperazine-1-carboxylate (800 mg, 1.84 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (26.14 mg, 183.80 ⁇ mol) and K 3 PO 4 (780.28 mg) , 3.68 mmol) was dissolved in dioxane (15 mL), and then CuI (35.00 mg, 183.80 ⁇ mol) was added. The reaction mixture was stirred at 90 ° C.
• Step 1 t-Butyl N-[2-[4-(4-amino-1-methyl-6-oxo-pyrimidin-2-yl)-piperazin-1-yl]ethyl]carbamate
• 6-amino-3-methyl-1H-pyrimidine-2,4-dione 500 mg, 3.54 mmol
• BOP (1.57 g, 3.54 mmol
• DBU 539 mg, 3.54 mmol, 534.02 ⁇ L
• tert-butyl piperazine-1-carboxylate 812 mg, 3.54 mmol
• the reaction solution was stirred at room temperature for 16 hours. After confirming that the reaction material had completely disappeared by LCMS, brine (20 mL) and EtOAc (20 mL X 3) were added to the reaction solution and extraction was performed. The organic layer was dried over Na 2 SO 4 , filtered and concentrated.
• Step 2 t-Butyl N-[2-[4-(4-amino-5-iodo-1-methyl-6-oxo-pyrimidin-2-yl)-piperazin-1-yl]ethyl]carba mate
• Step 1 tert-Butyl (1-(4-amino-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate
• 6-amino-3-methylpyrimidine-2,4 (1H, 3H)-dione (300 mg, 2.13 mmol) and BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 942 mg, 2.13 mmol)
• DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene, 324 mg, 2.13 mmol, 0.32 mL
• 1-(tert-butyl) 2-methyl (S) -Piperazine-1,2-dicarboxylate 502.1 mg, 2.34 mmol
• Step 2 tert-butyl (1-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methylpiperidin-4-yl)carba mate
• Step 1 Methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorobenzoate
• intermediate I-1 (220 mg, 0.59 mmol), intermediate I-5 (110 mg, 0.53 mmol), Pd 2 (dba) 3 (50 mg, 0.053 mmol) and Zantphos (30 mg, 0.053 mmol) ) was dissolved in 1,4-dioxane (2.2 mL, 0.25 M), and then DIPEA (0.19 mL, 1.07 mmol) was added. After purging with nitrogen, the mixture was stirred at 100 ° C. for 1 hour. Washing with EA, filtration through celite, and the filtrate was concentrated.
• Step 1 Ethyl 3-((6-amino-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)thio)-2-chlorobenzoate
• Step 2 Ethyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-methyl-6-oxo-1 ,6-dihydropyrimidin-5-yl)thio)-2-chlorobenzoate
• Step 3 Ethyl 3-((4-amino-2-(4-amino-4-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5- yl)thio)-2-chlorobenzoate
• Step 1 tert-Butyl((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpipery din-4-yl)methyl)carbamate
• intermediate I-8 150 mg, 0.6 mmol
• intermediate I-2 154 mg, 0.4 mmol
• Pd 2 (dba) 3 36 mg, 0.04 mmol
• Zantphos 46 mg, 0.08 mmol
• 1,4-dioxane 1 mL, 0.4 M
• DIPEA 139 ⁇ L, 0.8 mmol
• Step 2 6-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloroquinazolin-4(3H)-one
• Example 4 The compound of Example 4 was synthesized in the same manner as in Example 3, but using Intermediate I-1 instead of Intermediate I-2.
• 1H NMR 400 MHz, DMSO
• Step 1 N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3 -Methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfanylamide
• intermediate I-8 (108 mg, 0.43 mmol), intermediate I-3 (170 mg, 0.39 mmol), Pd 2 (dba) 3 (36 mg, 0.04 mmol) and Zantphos (46 mg, 0.08 mmol) ) was dissolved in 1,4-dioxane (1 mL, 0.4 M), and then DIPEA (136 ⁇ L, 0.8 mmol) was added. After purging with nitrogen, the mixture was stirred at 100 ° C. for 4 hours. The reaction was terminated with H 2 O and extracted with EA. The EA layer was dried over MgSO 4 , filtered and concentrated.
• Step 2 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)- 5-Chloroquinazolin-4(3H)-one
• Step 1 tert-Butyl((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate
• intermediate I-2 200 mg, 0.52 mmol
• intermediate I-7 100 mg, 0.62 mmol
• Pd 2 (dba) 3 48 mg, 0.052 mmol
• Zantphos 30 mg, 0.052 mmol
• 1,4-dioxane 2.1 mL, 0.25 M
• DIPEA 0.18 mL, 1.04 mmol
• Step 2 tert-Butyl((1-(5-((2-chloro-3-(fluorosulfonyl)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl ) carbamate
• Step 3 3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorobenzenesulfonyl fluoride
• Example 7 The compound of Example 7 was synthesized in the same manner as in Example 6, but using Intermediate I-1 instead of Intermediate I-2.
• Step 3 tert-Butyl((3S,4S)-8-(5-((2-chloro-3-sulfamoylphenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-aza Spiro[4.5]decan-4-yl)carbamate
• Step 4 3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)- 2-Chlorobenzenesulfonamide
• Example 11 The compound of Example 11 was synthesized in the same manner as in Example 9, but using KHF 2 instead of ammonia.
• Example 12 3-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2- Synthesis of yl)thio)-2-chlorobenzenesulfonamide
• Step 1 3-((3-amino-2-chlorophenyl)thio)-6-chloropyrazin-2-amine
• Step 3 tert-Butyl((3S,4S)-8-(6-amino-5-((2-chloro-3-sulfamoylphenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa -8-azaspiro[4.5]decan-4-yl)carbamate
• Step 4 3-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl )thio)-2-chlorobenzenesulfonamide]
• Step 1 tert-Butyl((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpipery din-4-yl)methyl)carbamate

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