2,5-disubstituted 3-methylpyrazine and 2,5,6-trisubstituted 3-methylpyrazine as allosteric SHP2 inhibitors

Abstract

To provide inhibitors of SHP2 and pharmaceutical compositions comprising the same.SOLUTION: For example, a compound of the following formula is illustrated.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Application No. 62 / 361,249, filed on 12 July 2016, and U.S. Provisional Application No. 62 / 449,523, filed on 23 January 2017, the contents of which are incorporated herein by reference in their entirety.

[0002] This disclosure relates to inhibitors of the protein tyrosine phosphatase SHP2 that are useful in treating diseases or disorders. More specifically, this disclosure relates to compounds and compositions that inhibit SHP2, methods for treating diseases associated with SHP2, and methods for synthesizing these compounds. [Background technology]

[0003] SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPNl1 gene, which contributes to multiple cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is involved in signal transduction via the Ras-mitogen-activated protein kinase, JAK-STAT, or phosphoinositol 3-kinase-AKT pathways.

[0004] SHP2 possesses two N-terminal Src homologous domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains regulate the intracellular localization and functional regulation of SHP2. The molecule exists in an inactive autoinhibitory conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. For example, stimulation by cytokines or growth factors leads to exposure of the catalytic site, resulting in enzymatic activation of SHP2.

[0005] Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human diseases such as Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloblastic leukemia, and cancers of the breast, lung and colon. SHP2 therefore represents a highly attractive target for the development of novel therapies for the treatment of various diseases. The compounds of the present disclosure meet the need for small molecules that inhibit the activity of SHP2. Summary of the Invention Problems to be Solved by the Invention

[0006] The present disclosure relates to compounds that can inhibit the activity of SHP2. The present disclosure further provides a process for the manufacture of the compounds disclosed herein, pharmaceutical preparations containing such compounds, and methods of using such compounds and compositions in the management of diseases or disorders associated with ectopic activity of SHP2. Means for Solving the Problems

[0007] One aspect of the present disclosure is Formula I: [Chemical Formula] (Wherein: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Y m , a , a , a , a , a , a , m , a , a is -S- or a direct bond; Y 2 is -NR a -, -(CR <^ a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R a )-, -N(R a )C(O)-, -S(O)2N(R a )-, -N(R a )S(O)2-, -N(R a)C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The bond on the right side of the section is R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Also -CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, oxo -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2 R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R6 、 -S(O)R 5 、 -NR 5 S(O)NR 5 R 6 、 -NR 5 S(O)R 6 、 optionally substituted with a complex ring, aryl or heteroaryl; wherein, heterocyclyl or heteroaryl is not attached via a nitrogen atom; R a is independently, in each occurrence, -H, -D, -OH, -C3-C8 cycloalkyl or - C1-C6 alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more -NH2, wherein two R a can be combined together with the carbon atom to which they are both attached to form a 3- to 8-membered cycloalkyl; R b is independently, in each occurrence, -H, -D, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C2-C6 alkenyl, or a heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or complex ring is one or more -OH, halogen, -NO2, oxo -CN, -R 、 -OR 5 、 -NR 5 R 5 、 -SR 6 、 -S(O)2NR 5 R 5 、 -S(O)2R 6 、 -NR 5 S(O)2NR 5 R 5 、 -NR 6 S(O)2R 5 、 -S(O)NR 6 R 5 、 -S (O)R 5 、 -NR 5 S(O)NR 5 R 6 、 -NR 5 、 -S(O)R5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 These are independently C1-C6 alkyl or 3- to 12-membered monocyclic or polycyclic compounds. It is a heterocycle, where each alkyl or heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle may have one or more -C1-C6 alkyl, -OH, or -NH2 groups. It has been replaced; R 4 These are independently -H, -D, or -C1~C6 alkyl groups, where each alkyl group is , optionally substituted with one or more -OH, -NH2, halogen or oxo or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic It can form heterocycles ranging from 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo molecule; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. This relates to compounds of the same, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers.

[0008] Another aspect of this disclosure is Formula II: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The bond on the right side of the section is R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Also -CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, oxo -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2 R5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6, optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 These are independently C1-C6 alkyl or 3- to 12-membered monocyclic or polycyclic compounds. It is a heterocycle, where each alkyl or heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle may have one or more -C1-C6 alkyl, -OH, or -NH2 groups. It has been replaced; R 4 These are independently -H, -D, or -C1~C6 alkyl groups, where each alkyl group is , optionally substituted with one or more -OH, -NH2, halogen or oxo or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic It can form heterocycles ranging from 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo molecule; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. This relates to compounds of the same, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers.

[0009] Another aspect of this disclosure is Formula III: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a)O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The bond on the right side of the section is R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Also -CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, oxo -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2 R 5 , -NR 5S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6, optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 These are independently C1-C6 alkyl or 3- to 12-membered monocyclic or polycyclic compounds. It is a heterocycle, where each alkyl or heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle may have one or more -C1-C6 alkyl, -OH, or -NH2 groups. It has been replaced; R 4 These are independently -H, -D, or -C1~C6 alkyl groups, where each alkyl group is , optionally substituted with one or more -OH, -NH2, halogen or oxo or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic It can form heterocycles ranging from 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo molecule; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is one Or possibly substituted with -OH, -SH, -NH2, -NO2 or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. This relates to compounds of the same, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers.

[0010] One aspect of this disclosure is formula I-V1: [ka] (In the formula: A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are monocyclic or polycyclic structures with 5 to 12 members; Y 1 is -S-, direct bond, -NH-, -S(O)2-, -S(O)2-NH-, -C( =CH2)-, -CH-, or -S(O)-; Y 2 -NR a -and here, Y 2 The bond on the left side is pyrazine, as depicted. It is bonded to the ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds.12 Cycloalkyl or monocyclic or polycyclic A cyclic heterocycle is formed with 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo; where the heterocycle is optionally substituted with -S(O)2- Including; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, -OR 6 , halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 , -CO2R 5 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 monocyclic or polycyclic hetero Rocyclyl, spiroheterocyclyl, heteroaryl, or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, =O, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independently -NH2, -OR b -CN, -C1~C6 alkyl, -C2~C6 alke Nyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, halogen, -C(O)OR b Selected from the group consisting of -C3~C8 cycloalkyl, aryl, N, S, P and O. A heterocyclyl containing 1 to 5 heteroatoms, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each a Lukyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may contain one or more -OH, halogen, or -NO2 , oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R b These are independent of each other, and in each occurrence, -H, -D, -OH, -C1~C6 alkyl, -C3~C8 alkyl Chloalkyl, -C2~C6 alkenyl, -(CH2) n -A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, heterocyclic, heteroaryl, or -(CH2) n -aryl is one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) nThey may be substituted with OH, -C1~C6 alkyl, -CF3, -CHF2, or -CH2F; R 3 These are independently -H, -C1~C6 alkyl, and 3- to 12-membered monocyclic or polycyclic compounds. Heterocyclic compounds, 5- to 12-membered spiroheterocyclic compounds, C3-C8 cycloalkyl compounds or -(CH2) n -R b Here, each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is 1 One or more -C1~C6 alkyl, -OH, -NH2, -OR b , -NHR b ,-( CH2) n OH may be substituted with heterocyclyl or spiroheterocyclyl; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 It is -NO2, -CF3, or -CN; R 7 and R 8 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OR b , or a monocyclic or polycyclic complex ring with 3 to 12 members, where Each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle may be substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. This relates to compounds of the same, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0011] One aspect of this disclosure is formula I-V2: [ka] (In the formula: A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are monocyclic or polycyclic structures with 5 to 12 members; Y 1 is -S-, direct bond, -NH-, -S(O)2-, -S(O)2-NH-, -C( =CH2)-, -CH-, or -S(O)-; Y 2 -NR a -and here, Y 2 The bond on the left side is pyrazine, as depicted. It is bonded to the ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 3 R a These combine to form 3- to 12-membered polycyclic heterocycles or 5- to 12-membered spiroheterocycles, where each heterocycle or spiroheterocycle contains one or more -C1-C6 alkyl, halogen, -OH, -OR b -NH2, -NHR b heterogeneous Ru, heterocyclyl, -(CH2) n NH2, -(CH2) n OH, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , -CF3, -CHF2, -CH2F or =O are sometimes substituted; R 1Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, -OR 6 , halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 , -CO2R 5 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 monocyclic or polycyclic hetero Rocyclyl, spiroheterocyclyl, heteroaryl, or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, =O, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independently -NH2, -OR b -CN, -C1~C6 alkyl, -C2~C6 alke Nyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, halogen, -C(O)OR b Selected from the group consisting of -C3~C8 cycloalkyl, aryl, N, S, P and O. A heterocyclyl containing 1 to 5 heteroatoms, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl contains one or more -OH, halogen, -NO2 , oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; Rb These are independent of each other, and in each occurrence, -H, -D, -OH, -C1~C6 alkyl, -C3~C8 alkyl Chloalkyl, -C2~C6 alkenyl, -(CH2) n -A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, heterocyclic, heteroaryl, or -(CH2) n -aryl is one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) n They may be substituted with OH, -C1~C6 alkyl, -CF3, -CHF2, or -CH2F; R 4 These are independently -H, -D, -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 hydroxyalkyl, -CF2OH, -CHFOH, -NH-NHR 5 , -NH-OR 5 , -O-NR 5 R6 , -NHR 5 , -OR 5 ,-NHC(O)R 5 ,-NHC(O)NHR 5 , -NHS(O)2R 5 , -NHS(O)2NHR 5 -S(O)2OH, -C(O)OR 5 , -NH(CH2) n OH, -C(O)NH(CH2) n OH, -C(O)NH(CH2) n R b , -C(O)R b -NH2, -OH, -CN, -C(O)NR 5 R 6 -S(O)2NR 5 R 6 A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of C3-C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, cycloalkyl, or heterocyclyl contains one or more -OH, -NH2, -OR b , optionally substituted with halogen or oxo; where each aryl or Heteroaryls are, in the case of one or more -OH, -NH2, or halogens It has been replaced; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 It is -NO2, -CF3, or -CN; R 7 and R 8Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OR b , or a monocyclic or polycyclic complex ring with 3 to 12 members, where Each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle may be substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. This invention relates to compounds of the same, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers.

[0012] One aspect of this disclosure is formula IW: [ka] (In the formula: A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are monocyclic or polycyclic structures with 5 to 12 members; Y 1 is -S-, direct bond, -NH-, -S(O)2-, -S(O)2-NH-, -C( =CH2)-, -CH-, or -S(O)-; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a)C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, -OR 6 , halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 , -CO2R 5 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 monocyclic or polycyclic hetero Rocyclyl, spiroheterocyclyl, heteroaryl, or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, =O, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, halogen, -C(O)OR b , 1 to 5 selected from the group consisting of -C3~C8 cycloalkyl, aryl, N, S, P and O A heterocyclyl containing a heteroatom, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl contains one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O) R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, each occurrence is either -H, -D, -OH, -C3~C8 cycloalkyl, -C1~C6 alkyl, 3- to 12-membered heterocyclyl, or -(CH2) n -Aryl Here, each alkyl or cycloalkyl group is composed of one or more -NH2 groups. It is replaced by a combination, or here, two R a Both of them are attached Together with carbon atoms, they can combine to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, and in each occurrence, -H, -D, -OH, -C1~C6 alkyl, -C3~C8 alkyl Chloalkyl, -C2~C6 alkenyl, -(CH2) n -A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, heterocyclic, heteroaryl, or -(CH2) n -aryl is one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) n They may be substituted with OH, -C1~C6 alkyl, -CF3, -CHF2, or -CH2F; R 3 These are independently -H, -C1~C6 alkyl, and 3- to 12-membered monocyclic or polycyclic compounds. Heterocyclic compounds, 5- to 12-membered spiroheterocyclic compounds, C3-C8 cycloalkyl compounds or -(CH2) n -R b Here, each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is 1 One or more -C1~C6 alkyl, -OH, -NH2, -OR b , -NHR b ,-( CH2) n OH, heterocyclyl, or spiroheterocyclyl may be substituted; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle contains one or more -C1-C6 alkyl, halogen, -OH, or -OR b , -N H2, -NHR b heteroaryl, heterocyclyl, -(CH2) n NH2, -(CH2) n OH, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , -CF3, -CHF2, -CH2F or =O are sometimes substituted; R 4 These are independently -H, -D, -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 hydroxyalkyl -CF2OH, -CHFOH -NH-NHR 5 , -NH-OR 5 , -O-NR 5 R 6 , -NHR 5 , -OR 5 ,-NHC(O)R 5 ,-NHC(O)NHR 5 , -NHS(O)2R 5 , -NHS(O)2NHR 5 -S(O)2OH, -C(O)OR 5 , -NH(CH2) n OH, -C(O)NH(CH2) n OH, -C(O)NH(CH2) n R b , -C(O)R b -NH2, -OH, -CN, -C(O)NR 5 R 6 -S(O)2NR 5 R 6 A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of C3-C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, cycloalkyl, or heterocyclyl contains one or more -OH, -NH2, -OR b, optionally substituted with halogen or oxo; where each aryl or Heteroaryls are, in the case of one or more -OH, -NH2, or halogens It has been replaced; or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic A heterocycle can be formed with 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo; where the heterocycle has -S(O)2- Includes by combination; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 It is -NO2, -CF3, or -CN; R 7 and R 8 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OR b , or a monocyclic or polycyclic complex ring with 3 to 12 members, where Each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle may be substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. This invention relates to compounds of the same, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers.

[0013] One aspect of this disclosure is formula IX: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 1 is -S- or a direct bond; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl , -C4 to C8 cycloalkenyl, -C2 to C6 alkynyl, -C3 to C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 , -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 , -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 , and also is -CO2R 5 , where each alkyl, alkenyl, cycloalkenyl, alkynyl or cycloalkyl is optionally substituted with one or more of -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 , -S(O)2NR 5 R 6 , -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 , -S(O)NR 5 R 6 , -S(O) R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with a heterocycle, aryl or heteroaryl; R2 is independently -OR b , -CN, -C1-C6 alkyl, -C2-C6 alkenyl, -C4-C8 cycloalkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, aryl, heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more of -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 , -S(O)2NR 5 R 6 , -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 , -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with a heterocycle, aryl or heteroaryl; wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom; R a is independently, in each occurrence, -H, -D, -OH, -C3-C8 cycloalkyl or - C1-C6 alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more of -NH2, and wherein two R a can combine with the carbon atom to which they are both attached to form a 3- to 8-membered cycloalkyl; R bThese are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 These are independently -H, -C1~C6 alkyl, or 3- to 12-membered monocyclic or It is a polycyclic heterocycle, where each alkyl or heterocycle has one or more -C atoms. 1-C6 alkyl, -OH or -NH2 may be substituted; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle may have one or more -C1-C6 alkyl, -OH, or -NH2 groups. It has been replaced; R 4independently, -H, -D, -C1-C6 alkyl, -NH-NHR 5 , -NH-OR 5 , -O-NR 5 R 6 , -NHR 5 , -OR 5 , -NHC(O)R 5 , -NHC(O)NHR 5 , -NHS(O)2R 5 , -NHS(O)2NHR 5 , -S(O)2OH, -C(O)OR 5 , -C(O)NR 5 R 6 , -S(O)2NR 5 R 6 , C3-C8 cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more -OH, -NH2, halogen or oxo; wherein each aryl or heteroaryl is optionally substituted with one or more -OH, -NH2 or halogen; or R and R a and R 4 together with the atom(s) to which they are attached, are combined to form a monocyclic or polycyclic C3-C 12 cycloalkyl or a monocyclic or polycyclic 3- to 12-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with oxo; wherein the heterocycle optionally contains -S(O)2- in the heterocycle; R and R 5 and R 6Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. This relates to compounds of the same, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers.

[0014] One aspect of this disclosure is formula IY: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 1 is -S- or a direct bond; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a)-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Also -CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, oxo -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2 R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) n OH, -C1~C6 alkyl, -CF3, -CHF2 or -CH2 F is sometimes substituted; R 3 These are independently -H, -C1~C6 alkyl, and 3- to 12-membered monocyclic or polycyclic compounds. Heterocyclic, C3-C8 cycloalkyl or -(CH2) n -R b And here, each Alki A heterocyclic or cycloalkyl group is defined as one or more -C1-C6 alkyl, -OH, -NH2, -OR b , -NHR b ,-(CH2) n OH, heterocyclyl or spirohete It is sometimes replaced by rocicryl; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles with 3 to 12 members or spiroheterocycles with 5 to 12 members, where each heterocycle or spiroheterocycle is one or more -C1~C6 alkyl, -OH, -NH2, heteroaryl , heterocyclyl, -(CH2) n NH2, -COOR b -CONHR b , -CONH(C H2) n COOR b , -NHCOOR b -CF3, -CHF2, or -CH2F depending on the case It has been replaced; R 4 These are independently -H, -D, -C1~C6 alkyl, and -NH-NHR 5 , -NH-OR 5 , -O-NR5 R 6 , -NHR 5 , -OR 5 ,-NHC(O)R 5 ,-NHC(O)NHR 5 , -NHS(O)2R 5 , -NHS(O)2NHR 5 -S(O)2OH, -C(O)OR 5 , -NH(CH2) n OH, -C(O)NH(CH2) n OH, -C(O)NH(CH2) n R b , -C(O)R b -NH2, -OH, -CN, -C(O)NR 5 R 6 -S(O)2NR 5 R 6 A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of C3-C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, cycloalkyl, or heterocyclyl contains one or more -OH, -NH2, They are optionally substituted with halogens or oxos; where each aryl or heteroaryl is optionally substituted with one or more -OH, -NH2 or halogens. or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic A heterocycle can be formed with 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo; where the heterocycle has -S(O)2- Includes by combination; R 5 and R 6Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. This relates to compounds of the same, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers.

[0015] One aspect of this disclosure is formula IZ: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 1 is -S-, direct bond, -NH-, -S(O)2-, -S(O)2-NH-, -C( =CH2)-, -CH-, or -S(O)-; Y 2 -NR a -,-(CR a 2) m -, -C(R a)2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S (O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N(R a )-,-O C(O)N(R a )-,-N(R a )C(O)O-, -C(O)N(R a )O-, -N(R a )C(S)-, or -C(S)N(R a )- and; here, Y 2 The bond on the left side is bonded to the pyrazine ring, as depicted, Y 2 The connection on the right side of the section is as depicted. R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R5 ,Also -CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, oxo -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2 R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b -NH2, -CN, -C1~C6 alkyl, -C2~C6 alchemy Nyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, halogen, -C(O)OR b Selected from the group consisting of -C3~C8 cycloalkyl, aryl, N, S, P and O. A heterocyclyl containing 1 to 5 heteroatoms, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl contains one or more -OH, halogen, -NO2 , oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -OH, -C3~C8 cycloalkyl or -C1~C6 alkyl This is a kill, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2s, where two R a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6, -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) n OH, -C1~C6 alkyl, -CF3, -CHF2 or -CH2 F is sometimes substituted; R 3 These are independently -H, -C1~C6 alkyl, and 3- to 12-membered monocyclic or polycyclic compounds. Heterocyclic, C3-C8 cycloalkyl or -(CH2) n -R b And here, each Alki A heterocyclic or cycloalkyl group may have one or more -C1-C6 alkyl groups, or -OH groups. -NH2, -OR b , -NHR b ,-(CH2) n OH, heterocyclyl or spirohete It is sometimes replaced by rocicryl; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles with 3 to 12 members or spiroheterocycles with 5 to 12 members, where each heterocycle or spiroheterocycle is one or more -C1~C6 alkyl, -OH, -NH2, heteroaryl , heterocyclyl, -(CH2) n NH2, -COOR b -CONHR b , -CONH(C H2) n COOR b , -NHCOOR b -CF3, -CHF2, or -CH2F depending on the case It has been replaced; R 4These are independently -C1~C6 alkyl and -NH-NHR 5 , -NH-OR 5 , -O-NR 5 R 6 , -NHR 5 , -OR 5 ,-NHC(O)R 5 ,-NHC(O)NHR 5 , -NHS(O )2R 5 , -NHS(O)2NHR 5 -S(O)2OH, -C(O)OR 5 , -NH(CH2 ) n OH, -C(O)NH(CH2) n OH, -C(O)NH(CH2) n R b , -C(O)R b -NH2, -OH, -C(O)NR 5 R 6 -S(O)2NR 5 R 6 C3-C8 cycloal A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of alkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, cycloalkyl, or heterocyclyl contains one or more -OH, -NH2, halogen, or oxo They are optionally substituted; where each aryl or heteroaryl is optionally substituted with one or more -OH, -NH2 or halogens; R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic Forms a heterocycle of 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo group; where the heterocycle optionally contains -S(O)2- ; R 5and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. This relates to compounds of the same, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers.

[0016] Another aspect of this disclosure relates to a method for treating SHP2 modulation-related diseases in a subject requiring such treatment, comprising administering an effective amount of one or more of the compounds disclosed herein (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) to the subject.

[0017] Another aspect of this disclosure relates to a method for inhibiting SHP2. The method involves using an effective amount of one or more compounds disclosed herein (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) to inhibit SHP2. This includes administering the drug to patients who require it.

[0018] Another aspect of this disclosure relates to a pharmaceutical composition comprising one or more compounds disclosed herein (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise excipients, diluents, or surfactants. The pharmaceutical composition may be effective in treating diseases associated with SHP2 modulation in subjects requiring it.

[0019] Another aspect of the present disclosure relates to a method for treating a disease associated with SHP2 modulation in a subject requiring such treatment, comprising administering an effective amount of a pharmaceutical composition comprising one or more of the compounds disclosed herein (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) to the subject.

[0020] Another aspect of this disclosure relates to a method for inhibiting SHP2, comprising administering an effective amount of a pharmaceutical composition comprising one or more of the compounds disclosed herein (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) to a patient in need.

[0021] Another aspect of the present disclosure relates to one or more of the compounds disclosed herein (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) for use in treating or preventing diseases associated with SHP2 modulation. One aspect of the present disclosure relates to a pharmaceutical composition comprising one or more of the compounds disclosed herein (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) and a pharmaceutically acceptable carrier for use in treating or preventing diseases associated with SHP2 modulation.

[0022] Another aspect of this disclosure relates to the use of one or more of the compounds disclosed herein (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) in the manufacture of a pharmacopoeia for treating or preventing diseases associated with SHP2 modulation. Another aspect of this disclosure relates to the use of a pharmaceutical composition comprising one or more of the compounds disclosed herein (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) and a pharmaceutically acceptable carrier in the manufacture of a pharmacopoeia for treating or preventing diseases associated with SHP2 modulation.

[0023] Another aspect of this disclosure relates to one or more of the compounds disclosed herein (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) for pharmaceutically use. Another aspect of this disclosure relates to one or more of the compounds disclosed herein ( The present invention relates to pharmaceutical compositions comprising, for example, compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers. In some embodiments, the pharmaceuticals are used to treat or prevent diseases associated with SHP2 modulation.

[0024] This disclosure also provides compounds and pharmaceutical compositions that are useful in inhibiting SHP2. [Modes for carrying out the invention]

[0025] In the first embodiment, a compound of formula I is described: [ka] In the formula, A, R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 And n are described as above.

[0026] In another embodiment, a compound of formula II is described: [ka] In the formula, A, R 1 , R 2 , R 3 , R 4 , Y 2 And n are described as above.

[0027] In another embodiment, a compound of formula III is described: [ka] In the formula, A, R 1 , R 2 , R 3 , R 4 , Y 2 And n are described as above.

[0028] One aspect of this disclosure is formula I-V1: [ka] Regarding the compound, in the formula, A, R 1 , R 3 , R 4 , Y 1 , Y 2 And n are as described above. It can be done.

[0029] One aspect of this disclosure is formula I-V2: [ka] Regarding the compound, in the formula, A, R 1 , R 3 , R 4 , Y 1 , Y 2 And n are as described above. It can be done.

[0030] One aspect of this disclosure is formula IW: [ka] Regarding the compound, in the formula, A, R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 And n are described as above.

[0031] One aspect of this disclosure is formula IX: [ka] Regarding the compound, in the formula, A, R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 And n are as described above. It will be published.

[0032] One aspect of this disclosure is formula IY: [ka] Regarding the compound, in the formula, A, R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 And n are described as above.

[0033] One aspect of this disclosure is formula IZ: [ka] Regarding the compound, in the formula, A, R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 And n are described as above.

[0034] Details of this disclosure are described in the appendix below. Similar or equivalent methods and materials described herein may be used in the practice or testing of this disclosure, but only exemplary methods and materials are described herein. Other features, purposes and advantages of the disclosure are evident from the description and claims. In this specification and the appendix claims, singular forms include plural forms unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to whom this disclosure belongs. All patents and publications referenced in this specification are incorporated herein by reference in their entirety.

[0035] Each embodiment described herein may be interpreted individually or in combination with any one or more other embodiments.

[0036] definition In this disclosure, the parts of speech "a" and "an" are used to refer to one or more than one (i.e., at least one) grammatical objects of the part of speech. For example, "an "Element" means one element or more than one element.

[0037] The term "and / or" is used in this disclosure to mean either "and" or "or" unless otherwise indicated.

[0038] The events described thereafter may be "optional" or "depending on the circumstances." A situation may or may not occur, and the description includes cases in which an event or situation occurs and cases in which it does not. For example, "optionally substituted aryl" includes both "aryl" and "substituted aryl" as defined herein. With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible and / or inherently unstable.

[0039] The term "optionally substituted" is understood to mean that a given chemical part (e.g., an alkyl group) can (but is not required to) bond to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group could be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group could have substituents other than hydrogen. For example, it could bond to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" means that a given chemical part has the potential to contain other functional groups, but does not necessarily have any further functional groups.

[0040] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one or two aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When two aromatic rings are present (bicyclic, etc.), the aromatic rings of the aryl group can be joined (e.g., biphenyl) or condensed (e.g., naphthyl) at a single point. The aryl group may optionally be substituted at any attachment point with one or more substituents, e.g., one to five substituents. Exemplary substituents include, but are not limited to, -H, halogens, -O-C1~C6 alkyl, -C1-C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1~C6 alkyl, -C(O)C1~C6 Lukil, -OC(O)OC1-C6 alkyl, -NH2, -NH(C1~C6 alkyl), - Examples include N(C1~C6 alkyl)2, -S(O)2-C1~C6 alkyl, -S(O)NHC1-C6 alkyl, and -S(O)N(C1~C6 alkyl)2. These substituents are themselves The body can be replaced depending on the circumstances.

[0041] Unless otherwise specifically defined, “heteroaryl” means a monovalent or polyvalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, S, P, and O, with the remaining ring atoms being C. Heteroaryl, as defined herein, also means a bicyclic heteroaromatic group in which the heteroatoms are selected from N, S, P, and O. Aromatic radicals are optionally independently substituted with one or more substituents as described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranil, isothiazolyl, thiazolyl, thiadiazolyl, benzo[d]imidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, 1-Methyl-1H-indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanil, thiochromanil, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzooxanil, quinolinyl, isoquinoli Nyl, 1,6-naphthilidinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthilidinyl, thieno[2,3-b]pyradinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, isoindorin-1-one, indorin-2-one, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyridinyl, tetrahydropyrrolo[1,2-a]pyridinyl, 3,4-dihydro-2H-1λ 2 -Piroro[2,1- b) Pyrimidine, dibenzo[b,d]thiophene, pyridine-2-one, flo[3,2-c]pyridinyl, flo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiadinyl, 2-methylbenzo[d]oxazolyl, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidyl, 2,3-dihydrobenzofuranyl, benzoxazolyl, benzoisoxazolyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, flo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthilidinyl, flo[3,2-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, 1-methyl-1H-benzo[d][1,2,3]triazolyl, imidazo[1, 2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, quinoxalinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, 1,3-dihydro-2H-benzo[d]imidazole-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 3,4-dihydro-2H- Examples include benzo[b][1,4]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, benzo[d][1,3]dioxolyl, pyrazolo[1,5-a]pyridinyl, and their derivatives.

[0042] "Alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon. C1-C6 alkyl groups contain one to six carbon atoms. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, and neopentyl.

[0043] The term "alkenyl" refers to an aliphatic hydrocarbon group that contains a carbon-carbon double bond and has approximately 2 to 6 carbon atoms in its chain, which can be linear or branched. Certain alkenyl groups have 2 to 4 carbon atoms in their chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are attached to a linear alkenyl chain. Illustrative alkenyl groups include ethenyl, propenyl, n-butenyl, and i-butenyl. C2-C6 alkenyl groups are alkenyl groups that contain between 2 and 6 carbon atoms.

[0044] The term "alkynyl" refers to an aliphatic hydrocarbon group that contains a carbon-carbon triple bond and can be linear or branched, having approximately 2 to 6 carbon atoms in the chain. Certain alkynyl groups have 2 to 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are attached to a linear alkynyl chain. Illustrative alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. C2-C6 alkynyl groups are alkynyl groups that contain between 2 and 6 carbon atoms.

[0045] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms. Examples of cycloalkyl groups, without limitation, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, and cycloocta. Examples include nyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. C3-C8 cycloalkyls are cycloalkyl groups containing between 3 and 8 carbon atoms. Cycloalkyl groups can be condensed (e.g., decalin) or crosslinked (e.g., norbornane).

[0046] The term "cycloalkenyl" refers to a monocyclic, non-aromatic, unsaturated carbon ring containing 4 to 18 carbon atoms. Examples of cycloalkenyl groups, without limitation, include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and norborenyl. C4-C8 cycloalkenyls are cycloalkenyl groups containing between 4 and 8 carbon atoms.

[0047] In some embodiments, the terms “heterocyclyl,” “heterocycloalkyl,” or “heterocyclic” refer to monocyclic or polycyclic rings with 3 to 24 members that contain carbon and heteroatoms selected from oxygen, phosphorus, nitrogen, and sulfur, and lack delocalized π electrons (aromatic) shared between ring carbons or heteroatoms. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl. Heterocyclyl or heterocycloalkyl rings can also be condensed or crosslinked, and may, for example, be bicyclic rings.

[0048] In some embodiments, “heterocyclyl” or “heterocycloalkyl” or “heterocycle” is a saturated, partially saturated, or unsaturated monocyclic or bicyclic ring containing 3 to 24 atoms, at least one of which is selected from nitrogen, sulfur, or oxygen, and is carbon or nitrogen-linked unless otherwise specified, where the -CH2- group is -C The (O)- group may be replaced by an (O)- group, or the ring sulfur atom may be oxidized to form an S- oxide. A "heterocyclyl" can be a saturated, partially saturated, or unsaturated monocyclic or bicyclic ring containing five or six atoms, at least one of which is selected from nitrogen, sulfur, or oxygen, and unless otherwise specified, is carbon or nitrogen-linked, where the -CH2- group is replaced by -C(O)- The ring sulfur atom can be replaced in some cases, or it can be oxidized in some cases to form an S-oxide (singular or plural). Non-limiting examples and appropriate values ​​of the term "heterocyclyl" are thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl, 1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl, 2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinyl, 5,6-dihydrourasilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl, 4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl These include 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridadinyl, pyridyl, 4-pyridonyl, quinolyl, and 1-isoquinolonyl.

[0049] As used herein, the terms "halo" or "halogen" mean a fluoro, chloro, bromo, or iodine group.

[0050] The term "carbonyl" refers to a functional group containing a carbon atom double-bonded to an oxygen atom. In this specification, it may be abbreviated as "oxo," C(O), or C=O.

[0051] A "spiro ring" or "spiro ring system" refers to a carbogenic bicyclic ring system in which two rings are connected by a single atom. These rings may differ in size and properties, or they may be identical in size and properties. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, and spirodecane. One or both rings in a spiro ring can be fused to another carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring. One or more carbon atoms in a spiro ring can be substituted with heteroatoms (e.g., O, N, S, or P). C5~C 12 A spiro ring is a spiro ring containing between 5 and 12 carbon atoms. One or more of the carbon atoms can be replaced by heteroatoms.

[0052] The terms “spirocyclic heterocycle,” “spiroheterocyclyl,” or “spiroheterocycle” are understood to mean a spirocycle in which at least one of the rings is heterocycle (for example, at least one of the rings is furanyl, morpholinyl, or piperazinyl). A spirocyclic heterocycle may contain between 5 and 12 atoms, at least one of which is a heteroatom selected from N, O, S, and P.

[0053] This disclosure also includes pharmaceutical compositions comprising an effective amount of one or more disclosed compounds and a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier, diluent or excipient” includes, but is not limited to, any adjuvant, carrier, excipient, flow enhancer, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, surfactant or emulsifier.

[0054] This disclosure includes pharmaceutically acceptable salts of the compounds described herein. Typical "pharmaceutically acceptable salts" include, but are not limited to, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, hydrogen tartrate, borate, bromide, butyrate, calcium salt, calcium edetate, cansylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estrulate, esylate, finalate, gluceptate, gluconate, glutamate, glycolyl arsanate, hexafluorophosphate, hexylresorcinate, hydravaminate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactate, lactate, Examples include bionates, laurates, magnesium salts, malates, maleates, mandelates, mesylates, methyl bromides, methylnitrates, methyl sulfates, mucinates, napsylates, nitrates, N-methylglucamine ammonium salts, 3-hydroxy-2-naphthoates, oleates, oxalates, palmitates, pamoates (1,1-methene-bis-2-hydroxy-3-naphthoates, einvonates), pantothenates, phosphates / diphosphates, picrates, polygalactuloses, propionates, p-toluenesulfonates, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicylates, slamates, tannates, tartrates, theoclates, tosylates, triethiozides, and valersates.

[0055] "Pharmacologically acceptable salts" include both acid addition salts and base addition salts. "Pharmacologically acceptable acid addition salts" are those that are not biologically or otherwise undesirable and contain inorganic acids, such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. In addition, organic acids, for example, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonate, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptanoic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid This refers to salts formed from hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid, which retain the biological efficacy and properties of the free base.

[0056] "Pharmacologically acceptable base addition salts" refer to salts that retain the biological efficacy and properties of a free acid, and are not biologically or otherwise undesirable. These salts are produced by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. For example, inorganic salts include, but are not limited to, ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. Examples of salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins, such as salts of ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0057] The term "tautomer" refers to a series of compounds that have the same number and type of atoms but differ in their bonding connectivity and are in equilibrium with each other. A "tautomer" is a single member of this series of compounds. Typically, a single tautomer is depicted, but it is understood that this single structure represents all possible tautomers that may exist. An example is enol-ketone tautomerism. Where a ketone is depicted, it is understood that both the enol and ketone forms are part of this disclosure.

[0058] For example, the compounds disclosed herein may exist in tautomer forms. In some embodiments of the compounds disclosed herein (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ), R 2 It is oxygen Often, the tautomers of the compound are in equilibrium: [ka] It can exist in that form.

[0059] This disclosure includes prodrugs of the compounds described herein. As used herein, the term "prodrug" means a compound that can be converted in vivo to the disclosed compound by metabolic means (e.g., by hydrolysis). Furthermore, as used herein, a prodrug is a drug that is inactive in the body but is converted to an active compound either during or after absorption from the gastrointestinal tract. The conversion of a prodrug to an active compound in the body can be carried out chemically or biologically (i.e., using enzymes).

[0060] This disclosure includes solvates of the compounds described herein. The term “solvate” refers to a variable stoichiometric complex formed by a solute and a solvent. Such solvents for the purposes of this disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0061] This disclosure includes isomers of the compounds described herein. The term "isomer" refers to compounds having the same composition and molecular weight but different physical and / or chemical properties. Structural differences may be in composition (geometric isomers) or in the ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, the compounds of this disclosure may have one or more chiral carbon atoms and may arise as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0062] The term “stereoisomer” refers to a set of compounds that have the same number and type of atoms and share the same bonding connectivity between those atoms, but differ in their three-dimensional structure. The term “stereoisomer” refers to any member of this set of compounds. For example, stereoisomers may be enantiomers or diastereomers. This disclosure includes stereoisomers of compounds described herein.

[0063] In addition, this disclosure encompasses all geometric and positional isomers. For example, if a compound of this disclosure incorporates a double bond or a fused ring, both cis and trans forms, as well as mixtures thereof, are included within the scope of this disclosure. If the compound contains a double bond, the substituent may have an E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration.

[0064] The term "enantiomer" refers to a pair of stereoisomers that are mirror images of each other and cannot be superimposed. The term "enantiomer" also refers to a single member of this pair of stereoisomers. The term "racemic" refers to a 1:1 mixture of a pair of enantiomers. This disclosure includes enantiomers of the compounds described herein. Each compound disclosed herein includes all enantiomers that conform to the general structure of the compound. The compounds are available in racemic or enantiomerically pure forms, or in terms of stereochemistry. It may be any other form. In some embodiments, the compound is an (S)-enantiomer. In other embodiments, the compound is an (R)-enantiomer. In other embodiments, the compound is an (+) or (-) enantiomer.

[0065] In some embodiments, the compounds and compositions of this disclosure can be enriched to primarily provide one enantiomer of the compounds described herein. An enantiomerically enriched mixture may, for example, contain at least 60 mol percent, or more preferably at least 75, 80, 85, 90, 95, 96, 97, 98, 99, 99.5, or even 100 mol percent, of one enantiomer. In some embodiments, a compound described herein enriched with one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance constitutes less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, in the composition or compound mixture, compared to the amount of the other enantiomer. For example, if a composition or compound mixture contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, it can be said that it contains only 98 mol percent of the first enantiomer and 2 mol percent of the second enantiomer.

[0066] The term “diastereomer” refers to a set of stereoisomers that cannot be superimposed by rotation around a single bond. For example, compounds containing cis and trans double bonds, endo and exo substitutions on bicyclic ring systems, and multiple chiral centers with different relative stereochemistrys are considered diastereomers. The term “diastereomer” refers to any member of this set of compounds. In some of the examples presented, the synthetic route may produce a single diastereomer or a mixture of diastereomers. This disclosure includes diastereomers of the compounds described herein.

[0067] In some embodiments, the compounds and compositions of the Disclosure may be enriched primarily to provide one diastereomer of a compound disclosed herein. A diastereomerically enriched mixture may, for example, contain at least 60 mol percent, or more preferably at least 75, 99, 95, 96, 97, 98, 99, or even 100 mol percent, of one diastereomer.

[0068] The compounds described herein further include all pharmaceutically acceptable isotope-labeled compounds. A “isotope-labeled” or “radiolabeled” compound is one in which one or more atoms are replaced or substituted by atoms having an atomic mass or mass number different from that typically found in nature (i.e., spontaneously occurring). For example, in some embodiments, in the compounds described herein, a hydrogen atom is replaced or substituted by one or more deuterium or tritium atoms. Certain isotope-labeled compounds in this disclosure, e.g., those incorporating radioisotopes, are useful in studies of drug and / or substrate tissue distribution. Radioisotope tritium, i.e. 3 H, and carbon 14, i.e. 14 C is one of those pairs It is particularly useful for this purpose in terms of ease of insertion and easy detection means. Heavier isotopes, such as deuterium, i.e. 2 Substitution with H results in greater metabolic stability, e.g., in vivo half-life. This can enable certain therapeutic benefits resulting from an increase in or a reduction in dosage requirements, and is therefore preferable in some situations. Suitable isotopes that can be incorporated into the compounds described herein include, but are not limited to, the following: 2 H(deuterium) (Also written as D) 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N,15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I is an example. Positron-emitting isotopes, for example 11 C, 18 F, 15 O and 13 Substitution with N in positron emission tomography It may be useful in (PET) studies.

[0069] When used in relation to a compound, "effective amount" means an amount effective to treat or prevent a disease in the subject as described herein.

[0070] When used in this disclosure, the term "carrier" includes carriers, excipients, and diluents and means a material, composition, or vehicle involved in holding a pharmaceutical agent or transporting it from one organ or part of a body to another, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.

[0071] With respect to the subject, the term "to treat" refers to improving at least one symptom of the disorder of the subject. Treating includes curing, improving, or at least partially relieving the disorder.

[0072] With respect to the subject, the terms “prevent” or “prevent” mean preventing the disease or disorder from afflicting the subject. Prevention includes preventive measures. For example, prevention includes administering one or more of the compounds disclosed herein to the subject before the subject becomes afflicted with the disease, and the administration prevents the subject from becoming afflicted with the disease.

[0073] The term “disability” is used in this disclosure to mean the terms “disease,” “condition,” or “illness,” unless otherwise indicated, and is interchangeable between the two terms.

[0074] When used in this disclosure, the terms “administer,” “dosing,” or “administer” mean directly administering to one or more disclosed compounds, pharmaceutically acceptable salts of one or more disclosed compounds, or compositions comprising one or more disclosed compounds, or administering to a prodrug derivative or analogue of a compound, or pharmaceutically acceptable salt of a compound or composition, which may form an equivalent amount of the active compound in the body of the subject.

[0075] "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cattle, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus macaque.

[0076] Compounds of the Disclosure In one or more embodiments of the compound of formula I, the compound is of formula IA: [ka] (In the formula: A is an aryl; Y 1 is -S- or a direct bond; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-, -N(R a)S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The bond on the right side of the section is R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Also -CO2R 5Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O) R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5, -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 These are independently C1-C6 alkyl or 3- to 12-membered monocyclic or polycyclic compounds. It is a primary ring, where each alkyl or heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle may have one or more -C1-C6 alkyl, -OH, or -NH2 groups. It has been replaced; R 4 These are independently -H, -D, or -C1~C6 alkyl groups, where each alkyl group is , optionally substituted with one or more -OH, -NH2, halogen or oxo or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic It can form heterocycles ranging from 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo molecule; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8, -NO2 or -CN; R 7 and R 8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. This also includes pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof.

[0077] In one or more embodiments of the compound of formula I, the compound is of formula IB: [ka] (In the formula: A is a heteroaryl; Y 1 is -S- or a direct bond; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(Ra )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The bond on the right side of the section is R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Also -CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O) R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3These are independently C1-C6 alkyl or 3- to 12-membered monocyclic or polycyclic compounds. It is a heterocycle, where each alkyl or heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle may have one or more -C1-C6 alkyl, -OH, or -NH2 groups. It has been replaced; R 4 These are independently -H, -D, or -C1~C6 alkyl groups, where each alkyl group is , optionally substituted with one or more -OH, -NH2, halogen or oxo or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic It can form heterocycles ranging from 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo molecule; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN. We are; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. This also includes pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof.

[0078] In one or more embodiments of the compound of formula IW, the compound is of formula I-W1: [ka] (In the formula: A is a heterocycloalkyl, aryl, or heteroaryl, where heterocycloalkyl, aryl, and heteroaryl are monocyclic or polycyclic structures with 5 to 12 members; Y 1 is -S- or a direct bond; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH- or -( CR a 2) m O-; here Y 2 The bond on the left side is bonded to the pyrazine ring, as depicted, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 1 These are independent of each other, and in each occurrence, -H, -C1~C6 alkyl, -OH, -OR6 , halogen, -CN, -NR 5 R 6 -S(O)2R 5 , -NR 5 C(O)R 6 These are monocyclic or polycyclic heterocyclyl, spiroheterocyclyl, heteroaryl, or oxo, where each alkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is one or more -OH, halogen, oxo, =O, -CN, -R 5 , -OR 5 , -NR 5 R 6 Or -S(O)2R 5 It is sometimes replaced by; R 2 These are independent, -OR b -CN, -C1~C6 alkyl, -C2~C6 alkenyl, halogen, -C(O)OR b , -C3~C8 cycloalkyl or aryl; where each Alkyl, cycloalkyl, or aryl groups contain one or more -OH, halogen, or -OR groups. 5 or -NR 5 R 6 It is sometimes replaced by; R a Independently, in each occurrence, -H or -C1~C6 alkyl, where each a Kill is sometimes replaced by one or more -NH2, or here, 2 The R a They combine with the carbon atoms to which they are attached, ranging from 3 to 8 members. It can form a cycloalkyl group; R b Independently, in each occurrence, -H, -C1~C6 alkyl, -C3~C8 cycloalkyl, -(CH2) n-A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, cycloalkyl, -(CH2) n -aryl, heterocyclyl, or heteroaryl is one or more -OH, halogen, -R 5 , -OR 5 , -NR 5 R 6 , -NR 5 C(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) n OH, -CF3, -CHF2, or -CH2 F is sometimes substituted; R 3 These are independently -H, -C1~C6 alkyl, and 3- to 12-membered monocyclic or polycyclic compounds. Heterocyclic compounds, 5- to 12-membered spiroheterocyclic compounds, C3-C8 cycloalkyl compounds or -(CH2) n -R b Here, each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is 1 One or more -C1~C6 alkyl, -OH, -NH2, -OR b , -NHR b ,-( CH2) n OH, heterocyclyl, or spiroheterocyclyl may be substituted; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle contains one or more -C1-C6 alkyl, halogen, -OH, or -OR b , -N H2, -NHR b heteroaryl, heterocyclyl, -(CH2) n NH2, -(CH2) n OH, -COORb -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , -CF3, -CHF2, -CH2F or =O are sometimes substituted; R 4 These are independently -H, -C1~C6 alkyl, -C1~C6 haloalkyl, and -C1~C6 hydroxyl Droxyalkyl-CF2OH,-CHFOH-NHR 5 , -OR 5 , -NHC(O) R 5 ,-NHC(O)NHR 5 , -C(O)OR 5 , -NH(CH2) n OH, -C(O)N H(CH2) n OH, -C(O)NH(CH2) n R b , -C(O)R b NH2, -OH, - CN, -C(O)NR 5 R 6 -S(O)2NR 5 R 6 C3-C8 cycloalkyl, aryl A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, cycloalkyl, or heterocyclyl contains one or more -OH, -NH2, -OR b , optionally substituted with halogens or oxos; where each aryl or heteroaryl is optionally substituted with one or more -OH, -NH2 or halogens; or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic A heterocycle can be formed with 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo; where the heterocycle has -S(O)2- Includes by combination; R 5 and R 6 Independently, in each occurrence, -H, -C1~C6 alkyl, -C3~C8 cycloalkyl, monocyclic or polycyclic 3- to 12-membered heterocycle, -OR 7 , halogen, -NR 7 R 8 or -CN; R 7 and R 8 These are independent of each other, in each occurrence: -H, -C1~C6 alkyl, -C3~C8 cycloalkyl, -OR b , or a monocyclic or polycyclic complex ring with 3 to 12 members, here Each alkyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -NH2, or -CN groups; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers.

[0079] In one or more embodiments of the compound of formula I-W1, Y 2 Ha-(CR a 2) m -In one or more embodiments of the compound of formula I-W1, Y 2 -NR a - is

[0080] In one or more embodiments of a compound of formula IW or I-W1, the compound is of formula I-W2: [ka] That is the case.

[0081] In one or more embodiments of formula I-W2, A is a heterocycloalkyl. In one or more embodiments of formula I-W2, A is an aryl. In one or more embodiments of formula I-W2, A is a heteroaryl. In one or more embodiments of formula I-W2, A is a pyridinyl.

[0082] In one or more embodiments of formula I-W2, n is independently 0, 1, 2, or 3 in each occurrence.

[0083] In one or more embodiments of formula I-W2, R 1 They are independent, in each appearance, in the field -C1~C6 alkyl, halogen, or -NR substituted by compounding 5 R 6 In certain such embodiments, R 5 and R 6 Both are -H. In one or more embodiments of formula I-W2, R 1 These are independent, in each appearance, methyl, fluoro, and cyanoacrylate. It is either rolo or -NH2.

[0084] In one or more embodiments of formula I-W2, R 2 is OR b In certain such embodiments, R b H or, in some cases, -C1~C6 is substituted. It is a kill. In one or more embodiments of formula I-W2, R 2 is -CN In one or more embodiments of formula I-W2, R 2 It may be replaced depending on the case. It is a C1-C6 alkyl group. In certain such embodiments, R 2 is methyl be.

[0085] In one or more embodiments of formula I-W2, R4 is one or more -C1~C6 alkyl groups, which may be substituted with -OH, -NH2, halogens, or oxos. It is. In one or more embodiments of formula I-W2, R 4 is one or that It is a -C1~C6 alkyl group substituted with more than one -OH group. 4 is -CH2-OH. In one or more embodiments of formula I-W2, R 4 is -H. In one or more embodiments of formula I-W2, R 4 is -CN. In one or more embodiments of formula I-W2, R 4 It is a -C1-C6 haloalkyl or -C1-C6 hydroxyalkyl. One of formulas I-W2 or so In the embodiments described above, R 4 It is either -CF2OH or -CHFOH.

[0086] In one or more embodiments of formula I-W2, R 3 is one or more -C1~C6 alkyl, -OH, -NH2, -OR b , -NHR b ,-(CH2) n OH, Haeta It is a C1-C6 alkyl group that is optionally substituted with rocyclyl or spiroheterocyclyl. In one or more embodiments of formula I-W2, R 3 is one or it The above -C1~C6 alkyl, -OH, -NH2, -OR b , -NHR b or -(CH2) n These are -C1~C6 alkyl groups that may be substituted with OH groups.

[0087] In one or more embodiments of formula I-W2, R 3 It may be replaced depending on the case. It is a monocyclic or polycyclic heteroring with 3 to 12 members. In certain such embodiments, R a is -H. In one or more embodiments of formula I-W2, R 3 R is a monocyclic heteroring of three to twelve members, which may be substituted depending on the case. In certain such embodiments, R a is -H. In one or more embodiments of formula I-W2 In R 3 It is a polycyclic heteroalgebra with 3 to 12 members, which may be substituted depending on the case. In certain embodiments, R a is -H. One or more of the equations I-W2. In the embodiment, R 3 These are polycyclic spiros with 5 to 12 members, which are sometimes substituted. It is a complex algebra. In certain such embodiments, R a is -H.

[0088] In one or more embodiments of formula I-W2, R 3 and R a These combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, -OH, -NH2, halogen, heteroaryl, heterocyclyl, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , 3- to 12-member monocyclic complexes which are optionally substituted with -CF3, -CHF2, or -CH2F It forms a ring.

[0089] In one or more embodiments of formula I-W2, R 3 and R a These combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, -OH, -NH2, halogen, heteroaryl, heterocyclyl, -(CH2)n NH2, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , 3- to 12-membered polycyclic complexes, optionally substituted with -CF3, -CHF2, or -CH2F It forms a ring.

[0090] In one or more embodiments of formula I-W2, R 3 and R a These combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, -OH, -NH2, halogen, heteroaryl, heterocyclyl, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b 5- to 12-membered spirocomplexes, optionally substituted with -CF3, -CHF2, or -CH2F It forms a ring.

[0091] In one or more embodiments of formula I-W2, R 3 and R a These combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, -OH, -NH2, halogen, heteroaryl, heterocyclyl, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , 10 to 12 member spiroconjugates, optionally substituted with -CF3, -CHF2, or -CH2F It forms an elementary ring.

[0092] In one or more embodiments of formula I-W2, R a and R 4These atoms, along with the atoms to which they are attached, combine to form optionally substituted monocyclic or polycyclic 3- to 12-membered cycloalkyl groups. In certain such embodiments, the cycloalkyl group is oxo-substituted.

[0093] In one or more embodiments of formula I-W2, R a and R 4 These atoms, along with the atoms to which they are attached, combine to form a monocyclic or polycyclic 3- to 12-membered heterocycle, which may be substituted. In certain such embodiments, the heterocycle is substituted with an oxo.

[0094] In one or more embodiments of a compound of formula IW or I-W1, the compound is of formula I-W3: [ka] And in the formula: B, together with the nitrogen atom to which it is attached, forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, where the heterocycle or spiroheterocycle contains one or more -C1-C6 alkyl, halogen, -OH, -OR b ,- (CH2) n OH, -CONHR b ,-(CH2) n NH2, -NHR b , heteroaryl, he The heterocycle is optionally substituted with -CF3, -CHF2, -CH2F, =O, or -NH2. In certain such embodiments, the heterocycle or spiroheterocycle is one or more -C1-C6 alkyl, halogen, -OH, -OR b -CONHR b These are sometimes substituted with heteroaryl, -CF3, -CHF2, -CH2F, or -NH2.

[0095] In one or more embodiments of formula I-W3, A is a heterocycloalkyl. In one or more embodiments of formula I-W3, A is an aryl. In one or more embodiments of formula I-W3, A is a heteroaryl. In one or more embodiments of formula I-W3, A is a pyridinyl.

[0096] In one or more embodiments of formula I-W3, n is independently 0, 1, 2, or 3 in each occurrence.

[0097] In one or more embodiments of formula I-W3, R 1 They are independent, in each occurrence, - C1-C6 alkyl, halogen, or -NR 5 R 6 In certain such embodiments, R 5 and R 6 Both are -H. In one or more embodiments of formula I-W3, R 1 Independently, in each occurrence, it is methyl, fluoro, chloro, or -NH2.

[0098] In one or more embodiments of formula I-W3, R 2 is OR b In certain such embodiments, R b H or, in some cases, -C1~C6 is substituted. It is a kill. In one or more embodiments of formula I-W3, R 2 is -CN In one or more embodiments of formula I-W3, R 2 It may be replaced depending on the case. It is a C1-C6 alkyl group. In certain such embodiments, R 2 is methyl be.

[0099] In one or more embodiments of formula I-W3, R 4 is one or more -C1~C6 alkyl groups, which may be substituted with -OH, -NH2, halogens, or oxos. It is. In one or more embodiments of formula I-W3, R 4 Depending on the circumstances, The replaced -C1~C6 alkyl is substituted with one or more -OH groups. In certain such embodiments, R 4 is -CH2-OH. In one or more embodiments of formula I-W3, R 4 is -H. One of the equations I-W3 is also In more embodiments, R 4 is -CN. One or more of the formulas I-W3. In the embodiment, R 4 -C1~C6 haloalkyl or -C1~C6 hydroxyal It is a kill. In one or more embodiments of formula I-W3, R 4 is -CF2OH Alternatively, it is -CHFOH.

[0100] In one or more embodiments of a compound of formula IW or I-W1, the compound is of formula I-W4: [ka] That is the case.

[0101] In one or more embodiments of formula I-W4, A is a heterocycloalkyl. In one or more embodiments of formula I-W4, A is an aryl. In one or more embodiments of formula I-W4, A is a heteroaryl. In one or more embodiments of formula I-W4, A is a pyridinyl.

[0102] In one or more embodiments of formula I-W4, n is independently 0, 1, 2, or 3 in each occurrence.

[0103] In one or more embodiments of formula I-W4, R 1They are independent, in each occurrence, - C1-C6 alkyl, halogen, or -NR 5 R 6 In certain such embodiments, R 5 and R 6 Both are -H. In one or more embodiments of formula I-W4, R 1 Independently, in each occurrence, it is methyl, fluoro, chloro, or -NH2.

[0104] In one or more embodiments of formula I-W4, R 2 is OR b In certain such embodiments, R b H or, in some cases, -C1~C6 is substituted. It is a kill. In one or more embodiments of formula I-W4, R 2 is -CN In one or more embodiments of formula I-W4, R 2 It may be replaced depending on the case. It is a C1-C6 alkyl group. In certain such embodiments, R 2 is methyl be.

[0105] In one or more embodiments of formula I-W4, R 4 is one or more -C1~C6 alkyl groups, which may be substituted with -OH, -NH2, halogens, or oxos. It is. In one or more embodiments of formula I-W4, R 4 is one or that It is a -C1~C6 alkyl group substituted with more than one -OH group. 4 is -CH2-OH. In one or more embodiments of formula I-W4, R 4 is -H. In one or more embodiments of formula I-W4, R 4 is -CN. In one or more embodiments of formula I-W4, R4 It is a -C1-C6 haloalkyl or -C1-C6 hydroxyalkyl. One of formulas I-W4 or the same In the embodiments described above, R 4 It is -CF2OH or -CHFOH.

[0106] In one or more embodiments of formula I-W4, R 3 is one or more -C1~C6 alkyl, -OH, -NH2, -OR b , -NHR b ,-(CH2) n OH, Haeta It is a C1-C6 alkyl group that is optionally substituted with rosicyl or spiroheterocyclyl. In one or more embodiments of formula I-W4, R 3 is one or it The above -C1~C6 alkyl, -OH, -NH2, -OR b , -NHR b or -(CH2) n These are -C1~C6 alkyl groups that may be substituted with OH groups.

[0107] In one or more embodiments of formula I-W4, R 3 It may be replaced depending on the case. It is a monocyclic or polycyclic heteroring with 3 to 12 members. In certain such embodiments, R a is -H. In one or more embodiments of formula I-W4, R 3 R is a monocyclic heteroring of three to twelve members, which may be substituted depending on the case. In certain such embodiments, R a is -H. In one or more embodiments of formula I-W4 In R 3 It is a polycyclic heteroalgebra with 3 to 12 members, which may be substituted depending on the case. In certain embodiments, R a is -H. One or more of the equations I-W4. In the embodiment, R3 These are polycyclic spiros with 5 to 12 members, which are sometimes substituted. It is a complex algebra. In certain such embodiments, R a is -H.

[0108] In one or more embodiments of formula I-W4, R 3 and R a These combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, -OH, -NH2, halogen, heteroaryl, heterocyclyl, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , 3- to 12-member monocyclic complexes which are optionally substituted with -CF3, -CHF2, or -CH2F It forms a ring.

[0109] In one or more embodiments of formula I-W4, R 3 and R a These combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, -OH, -NH2, halogen, heteroaryl, heterocyclyl, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , 3- to 12-membered polycyclic complexes, optionally substituted with -CF3, -CHF2, or -CH2F It forms a ring.

[0110] In one or more embodiments of formula I-W4, R 3 and R aThese combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, -OH, -NH2, halogen, heteroaryl, heterocyclyl, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b 5- to 12-membered spirocomplexes, optionally substituted with -CF3, -CHF2, or -CH2F It forms a ring.

[0111] In one or more embodiments of formula I-W4, R 3 and R a These combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, -OH, -NH2, halogen, heteroaryl, heterocyclyl, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , 10 to 12 member spiroconjugates, optionally substituted with -CF3, -CHF2, or -CH2F It forms an elementary ring.

[0112] In one or more embodiments of formula I-W4, R a and R 4 These atoms, along with the atoms to which they are attached, combine to form optionally substituted monocyclic or polycyclic 3- to 12-membered cycloalkyl groups. In certain such embodiments, the cycloalkyl group is oxo-substituted.

[0113] In one or more embodiments of formula I-W4, R a and R 4These atoms, along with the atoms to which they are attached, combine to form a monocyclic or polycyclic 3- to 12-membered heterocycle, which may be substituted. In certain such embodiments, the heterocycle is substituted with an oxo.

[0114] In one or more embodiments of the compound of formula IW or I-W1, the compound is of formula I-W5: [ka] And in the formula: B, together with the nitrogen atom to which it is attached, forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, where the heterocycle or spiroheterocycle contains one or more -C1-C6 alkyl, halogen, -OH, -OR b ,- (CH2) n NH2, -(CH2) n OH, -CONHR b , -NHR b , heteroaryl, he The heterocycle is optionally substituted with -CF3, -CHF2, -CH2F, =O, or -NH2. In certain such embodiments, the heterocycle or spiroheterocycle is one or more -C1-C6 alkyl, halogen, -OH, -OR b -CONHR b These are sometimes substituted with heteroaryl, -CF3, -CHF2, -CH2F, or -NH2.

[0115] In one or more embodiments of formula I-W5, A is a heterocycloalkyl. In one or more embodiments of formula I-W5, A is an aryl. In one or more embodiments of formula I-W5, A is a heteroaryl. In one or more embodiments of formula I-W5, A is a pyridinyl.

[0116] In one or more embodiments of formula I-W5, n is independently 0, 1, 2, or 3 in each occurrence.

[0117] In one or more embodiments of formula I-W5, R 1 They are independent, in each appearance, in the field -C1~C6 alkyl, halogen, or -NR substituted by compounding 5 R 6 In certain such embodiments, R 5 and R 6 Both are -H. In one or more embodiments of formula I-W5, R 1 These are independent, in each appearance, methyl, fluoro, and cyanoacrylate. It is either rolo or -NH2.

[0118] In one or more embodiments of formula I-W5, R 2 is OR b In certain such embodiments, R b H or, in some cases, -C1~C6 is substituted. It is a kill. In one or more embodiments of formula I-W5, R 2 is -CN In one or more embodiments of formula I-W5, R 2 It may be replaced depending on the case. It is a C1-C6 alkyl group. In certain such embodiments, R 2 is methyl be.

[0119] In one or more embodiments of formula I-W5, R 4 is one or more -C1~C6 alkyl groups, which may be substituted with -OH, -NH2, halogens, or oxos. It is. In one or more embodiments of formula I-W5, R 4 -C1~C6a It is a lukil, which is substituted with one or more -OH groups. In certain such embodiments, R 4 It is -CH2-OH. One or more of formulas I-W5 In one embodiment, R 4 is -H. In one or more embodiments of formula I-W5 And, R 4 is -CN. In one or more embodiments of formula I-W5, R 4 is a -C1-C6 haloalkyl or -C1-C6 hydroxyalkyl. In one or more embodiments of formula I-W5, R 4 It is either -CF2OH or -CHFOH.

[0120] This disclosure provides compounds of formula I-W2 or I-W4 having one, two, three, four or more of the following features: a) A is a heterocycloalkyl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e)R 3 and R a They combine with the atoms to which they are attached, and may be substituted with one or more -C1-C6 alkyl, -OH, -NH2, or halogen atoms. It forms monocyclic or polycyclic heterocyclic rings of 3 to 12 members; and f)R 4 It is -CH2-OH.

[0121] This disclosure provides compounds of formula I-W2 or I-W4 having one, two, three, four or more of the following features: a) A is an aryl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e)R 3 and R a They combine with the atoms to which they are attached, and may be substituted with one or more -C1-C6 alkyl, -OH, -NH2, or halogen atoms. It forms monocyclic or polycyclic heterocyclic rings of 3 to 12 members; and f)R 4 It is -CH2-OH.

[0122] This disclosure provides compounds of formula I-W2 or I-W4 having one, two, three, four or more of the following features: a) A is a heteroaryl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e)R 3 and R a They combine with the atoms to which they are attached, and may be substituted with one or more -C1-C6 alkyl, -OH, -NH2, or halogen atoms. It forms monocyclic or polycyclic heterocyclic rings of 3 to 12 members; and f)R 4 It is -CH2-OH.

[0123] This disclosure provides compounds of formula I-W2 or I-W4 having one, two, three, four or more of the following features: a) A is pyridinyl; b) n is independently 1 or 2 in each occurrence; c)R1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e)R 3 and R a They combine with the atoms to which they are attached, and may be substituted with one or more -C1-C6 alkyl, -OH, -NH2, or halogen atoms. It forms monocyclic or polycyclic heterocyclic rings of 3 to 12 members; and f)R 4 It is -CH2-OH.

[0124] This disclosure provides compounds of formula I-W2 or I-W4 having one, two, three, four or more of the following features: a) A is a heterocycloalkyl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e)R 3 and R a They combine with the atoms to which they are attached, and may be substituted with one or more -C1-C6 alkyl, -OH, -NH2, or halogen atoms. It forms a 5-member to 12-member spiroheterocyclic ring; and f)R 4 It is -CH2-OH.

[0125] This disclosure provides compounds of formula I-W2 or I-W4 having one, two, three, four or more of the following features: a) A is an aryl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e)R 3 and R a They combine with the atoms to which they are attached, and may be substituted with one or more -C1-C6 alkyl, -OH, -NH2, or halogen atoms. It forms a 5-member to 12-member spiroheterocyclic ring; and f)R 4 It is -CH2-OH.

[0126] This disclosure provides compounds of formula I-W2 or I-W4 having one, two, three, four or more of the following features: a) A is a heteroaryl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e)R 3 and R a They combine with the atoms to which they are attached, and may be substituted with one or more -C1-C6 alkyl, -OH, -NH2, or halogen atoms. It forms a 5-member to 12-member spiroheterocyclic ring; and f)R 4 It is -CH2-OH.

[0127] This disclosure provides compounds of formula I-W2 or I-W4 having one, two, three, four or more of the following features: a) A is pyridinyl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e)R 3 and R a They combine with the atoms to which they are attached, and may be substituted with one or more -C1-C6 alkyl, -OH, -NH2, or halogen atoms. It forms a 5-member to 12-member spiroheterocyclic ring; and f)R 4 It is -CH2-OH.

[0128] This disclosure provides compounds of formula I-W3 or I-W5 having one, two, three, four or more of the following features: a) A is a heterocycloalkyl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e) B is one or more -C1~C6 alkyl, -OH, -NH2 or halogen It is a monocyclic or polycyclic heterocyclic ring of 3 to 12 members, which may be substituted in some cases; and f)R 4 It is -CH2-OH.

[0129] This disclosure provides compounds of formula I-W3 or I-W5 having one, two, three, four or more of the following features: a) A is an aryl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e) B is one or more -C1~C6 alkyl, -OH, -NH2 or halogen It is a monocyclic or polycyclic heterocyclic ring of 3 to 12 members, which may be substituted in some cases; and f)R 4 It is -CH2-OH.

[0130] This disclosure provides compounds of formula I-W3 or I-W5 having one, two, three, four or more of the following features: a) A is a heteroaryl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e) B is one or more -C1~C6 alkyl, -OH, -NH2 or halogen It is a monocyclic or polycyclic heterocyclic ring of 3 to 12 members, which may be substituted in some cases; and f)R 4 It is -CH2-OH.

[0131] This disclosure provides compounds of formula I-W3 or I-W5 having one, two, three, four or more of the following features: a) A is pyridinyl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e) B is one or more -C1~C6 alkyl, -OH, -NH2 or halogen It is a monocyclic or polycyclic heterocyclic ring of 3 to 12 members, which may be substituted in some cases; and f)R 4 It is -CH2-OH.

[0132] This disclosure relates to formulas I-W3 having one, two, three, four or more of the following features. Or provides I-W5 compounds: a) A is a heterocycloalkyl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e) B is one or more -C1~C6 alkyl, -OH, -NH2 or halogen It is a 5- to 12-member spiroheterocyclic ring that is substituted in some cases; and f)R 4 It is -CH2-OH.

[0133] This disclosure provides compounds of formula I-W3 or I-W5 having one, two, three, four or more of the following features: a) A is an aryl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e) B is one or more -C1~C6 alkyl, -OH, -NH2 or halogen It is a 5- to 12-member spiroheterocyclic ring that is substituted in some cases; and f)R 4 It is -CH2-OH.

[0134] This disclosure provides compounds of formula I-W3 or I-W5 having one, two, three, four or more of the following features: a) A is a heteroaryl; b) n is independently 1 or 2 in each occurrence; c)R 1 Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e) B is one or more -C1~C6 alkyl, -OH, -NH2 or halogen It is a 5- to 12-member spiroheterocyclic ring that is substituted in some cases; and f)R 4 It is -CH2-OH.

[0135] This disclosure provides compounds of formula I-W3 or I-W5 having one, two, three, four or more of the following features: a) A is pyridinyl; b) n is independently 1 or 2 in each occurrence; c)R 1Independently, in each occurrence, -C1~C6 alkyl, halo It is either -OCH3 or -NH2; d)R 2 This is a -C1~C6 alkyl group, for example, methyl, which may be substituted depending on the case; e) B is one or more -C1~C6 alkyl, -OH, -NH2 or halogen It is a 5- to 12-member spiroheterocyclic ring that is substituted in some cases; and f)R 4 It is -CH2-OH.

[0136] In one or more embodiments of the compound of formula IW, the compound is of formula I-W6: [ka] (In the formula: A is a monocyclic or polycyclic heteroaryl with 5 to 12 members; Y 1 is -S-; Y 2 -NR a -and; here Y 2 The bond on the left side is pyrazine, as depicted. It is bonded to the ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 3 R a These combine to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle contains one or more -C1~C6 alkyl, -OH, -NH2, heteroaryl, heterocyclic Lil, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COO R b , -NHCOOR b, may be replaced by -CF3, -CHF2, or -CH2F. the law of nature; R 1 These are independent of each other, appearing as -H, -C1~C6 alkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 , -C(O)R 5 or -CO2R 5 and; R 2 It is a C1-C6 alkyl group; R b Independently, in each occurrence, is either -H or -C1~C6 alkyl; R 4 These are -H, -C1~C6 alkyl, -C1~C6 haloalkyl, and -C1~C6 hydroxyl Alkyl, -CF2OH, -CHFOH, -C(O)NH(CH2) n OH, -C(O)N H(CH2) n R b , -C(O)R b -C(O)NR 5 R 6 It is -OH or -CN, where alkyl is one or more -OH, -NH2, halogen or oxo. It is replaced by; or R 5 and R 6 Each of these is independently, in each occurrence, -H or -C1~C6 alkyl; n is independent of other variables in each occurrence, and is either 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers.

[0137] In one or more embodiments of the compound of formula IW, the compound is of formula I-W7: [ka] (In the formula: A is a monocyclic or polycyclic heteroaryl with 5 to 12 members; Y 1 It is a direct bond; Y 2 -NR a -and; here Y 2 The bond on the left side is pyrazine, as depicted. It is bonded to the ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 3 R a These combine to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle contains one or more -C1~C6 alkyl, -OH, -NH2, heteroaryl, heterocyclic Lil, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COO R b , -NHCOOR b , may be replaced by -CF3, -CHF2, or -CH2F. the law of nature; R 1 These are independent of each other, appearing as -H, -C1~C6 alkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 , -C(O)R 5 or -CO2R 5 and; R 2 It is a C1-C6 alkyl group; R b Independently, in each occurrence, is either -H or -C1~C6 alkyl; R 4 These are -H, -C1~C6 alkyl, -C1~C6 haloalkyl, and -C1~C6 hydroxyl Alkyl, -CF2OH, -CHFOH, -C(O)NH(CH2) n OH, -C(O)N H(CH2) n R b , -C(O)R b -C(O)NR 5 R 6 It is -OH or -CN, where alkyl is one or more -OH, -NH2, halogen or oxo. It is replaced by; or R 5 and R 6 Each of these is independently, in each occurrence, -H or -C1~C6 alkyl; n is independent of other variables in each occurrence, and is either 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers.

[0138] In one or more embodiments of the compound of formula II, the compound is of formula II-A: [ka] That is the case.

[0139] In one or more embodiments of the compound of formula II-A, the compound is of formula II-A1: [ka] And in the formula: B, together with the nitrogen atom to which it is attached, forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, where the heterocycle or spiroheterocycle may consist of one or more -C1-C6 alkyl, -OH, or -NH2 groups. It has been replaced.

[0140] In one or more embodiments of the compound of formula II-A, the compound is of formula II-A2: [ka] That is the case.

[0141] In one or more embodiments of the compound of formula II-A, the compound is of formula II-A3: [ka] That is the case.

[0142] In one or more embodiments of the compound of formula II, the compound is of formula II-B: [ka] That is the case.

[0143] In one or more embodiments of the compound of formula II-B, the compound is of formula II-B1: [ka] And in the formula: B, together with the carbon atoms to which it is attached, forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, where the heterocycle or spiroheterocycle may consist of one or more -C1-C6 alkyl, -OH, or -NH2 groups. It has been replaced.

[0144] In one or more embodiments of the compound of formula II-B, the compound is of formula II-B2: [ka] That is the case.

[0145] In one or more embodiments of the compound of formula II-B, the compound is of formula II-B3: [ka] That is the case.

[0146] In one or more embodiments of the compound of formula II-B, the compound is of formula II-B4: [ka] That is the case.

[0147] In one or more embodiments of the compound of formula II-B, the compound is of formula II-B5: [ka] That is the case.

[0148] In one or more embodiments of the compound of formula II-B, the compound is of formula II-B6: [ka] That is the case.

[0149] In one or more embodiments of the compound of formula II, the compound is of formula II-C: [ka] And in the formula: B forms a monocyclic or polycyclic heterocycle with 3 to 12 members, where the heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2 groups. Yes, they are.

[0150] In one or more embodiments of the compound of formula II-C, the compound is of formula II-C1: [ka] That is the case.

[0151] In one or more embodiments of the compound of formula II, the compound is of formula II-D: [ka] And in the formula: B forms a monocyclic or polycyclic heterocycle with 3 to 12 members, where the heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2 groups. Yes, they are.

[0152] In one or more embodiments of the compound of formula II-D, the compound is of formula II-D1: [ka] That is the case.

[0153] In one or more embodiments of the compound of formula II, the compound is of formula II-E: [ka] That is the case.

[0154] In one or more embodiments of the compound of formula II, the compound is of formula II-F: [ka] That is the case.

[0155] In one or more embodiments of the compound of formula II, the compound is of formula II-G: [ka] And in the formula, R 2 It is either aryl or heteroaryl.

[0156] In one or more embodiments of the compound of formula III, the compound is of formula III-A: [ka] That is the case.

[0157] In one or more embodiments of the compound of formula III-A, the compound is of formula III-A1: [ka] And in the formula: B, together with the nitrogen atom to which it is attached, forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, where the heterocycle or spiroheterocycle may consist of one or more -C1-C6 alkyl, -OH, or -NH2 groups. It has been replaced.

[0158] In one or more embodiments of the compound of formula III-A, the compound is of formula III-A2: [ka] That is the case.

[0159] In one or more embodiments of the compound of formula III-A, the compound is of formula III-A3: [ka] That is the case.

[0160] In one or more embodiments, the compounds of the present disclosure (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ) are: [ka] [ka] [ka] [ka] Furthermore, a selection of pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof may be used.

[0161] In one or more embodiments, the compounds of the present disclosure (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ) are: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] Furthermore, a selection of pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof may be used.

[0162] In one or more embodiments, the compounds of the present disclosure (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ) are: [Table 31] Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 [Table 49] [Table 50] [Table 51] [Table 52] [Table 53] [Table 54] [Table 55] [Table 56] [Table 57] [Table 58] [Table 59] [Table 60] Furthermore, a selection of pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof may be used.

[0163] In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl group. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, A is a heterocycloalkyl group. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, A is an aryl group. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, A is a heteroaryl group. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, A is a pyridinyl group.

[0164] In one or more embodiments of formulas I, I-V1, I-V2, IW, IX, IY, or IZ, Y 1 is -S-. Equations I, I-V1, I-V2, IW, I- In one or more embodiments of X, IY, or IZ, Y 1 This is a direct bond. In one or more embodiments of formulas I-V1, I-V2, IW, or IZ, Y 1 is -NH-. One or the other of formulas I-V1, I-V2, IW or IZ In the embodiments described above, Y 1 is -C(=CH2)-. In one or more embodiments of formulas I-V1, I-V2, IW, or IZ, Y 1 is -S(O2)-. In one or more embodiments of formulas I-V1, I-V2, IW, or IZ, Y 1 It is -S(O2)-NH-.

[0165] In one or more embodiments of formulas I, II, III, IW, IX, IY, or IZ, Y 2 -NR a- is. In one or more embodiments of formulas I, II, III, IW, IX, IY, or IZ, Y 2 Ha-(CR a 2) m - is. In one or more embodiments of formulas I, II, III, IW, IX, IY, or IZ, Y 2 is -C(O)-. Equations I, II, III, IW, IX, I- In one or more embodiments of Y or IZ, Y 2 -C(R a )2NH- or -(CR a 2) m It is O-. Formulas I, II, III, IW, IX, IY or In one or more embodiments of IZ, Y 2 is -C(O)N(R a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(S)- or -C(S)N(R a )- is. Equations I, II, III, IW, IX, In one or more embodiments of IY or IZ, Y 2 is -N(R a )C(O)N(R a )-,-N(R a )C(S)N(R a )-,-OC(O)N(R a )-,-N(R a )C(O)O- or -C(O)N(R a )O-. In one or more embodiments of formulas I, II, III, IW, IX, or IY, Y 2 is -C(O)O -, -OC(O)- or -OC(O)O-

[0166] In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R1 These are independent, in each occurrence, -H, depending on the case. The replaced -C1~C6 alkyl, halogen, -OH, -CN and -NR 5 R 6 Selected from: In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 1 These are independent, in each occurrence, -H, in the case More substituted -C1~C6 alkyl, halogen, -OH and -NR 5 R 6 Selected from: In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 1 These are independent, in each occurrence, -H, depending on the case Substituting -C1~C6 alkyl, halogen and -NR 5 R 6 Selected from: In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 1 Independently, in each appearance, -H, methyl, fluoro, Selected from chloro, bromo, and -NH2. Formulas I, II, III, I-V1, IV 2. In one or more embodiments of IW, IX, IY, or IZ, R 1 Independently, in each occurrence, is selected from -H, methyl, fluoro, chloro, and -NH2. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 1 is -H. 1 In some embodiments where the alkyl group is C1-C6 alkyl, the alkyl group is substituted with a halogen. In certain such embodiments, the halogen is fluoro.

[0167] In one or more embodiments of formulas I-V1, I-V2, or IW, R 1 teeth It's oxo.

[0168] In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 1 -S(O)2R 5 That is. A certain type In one embodiment, R 5 It is a C1-C6 alkyl group.

[0169] In one or more embodiments of formulas I-V1, I-V2, or IW, R 1 teeth It is a heteroaryl. 1 In certain such embodiments where is a heteroaryl Therefore, heteroaryl is R 5 It is replaced by R 5 It is a C1-C6 alkyl group.

[0170] In one or more embodiments of I-V1, I-V2, or IW, R 1 teeth- C(O)NR 5 R 6 In certain such embodiments, R 5 and R 6 Both are -H.

[0171] In one or more embodiments of formulas I-V1, I-V2, or IW, R 1 teeth , in some cases, is a heterocyclyl which is substituted. In one or more embodiments of formulas I-V1, I-V2, or IW, R 1 In some cases, the spirochete is replaced. It is telosikrill.

[0172] In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 1 -NR 5 R 6 That is. In the application form, R 5 Independently, in each occurrence, is -H or -C1~C6 alkyl, and R 6 Independently, each occurrence is a -C1-C6 alkyl, -C3-C8 cycloalkyl, or a monocyclic or polycyclic heterocycle with 3 to 12 members.

[0173] In one or more embodiments of formulas I-V1, I-V2, or IW, R 1 teeth -OR 6 In certain such embodiments, R 6 These are independent, and in each occurrence, -C It is a 1-C6 alkyl, -C3-C8 cycloalkyl, or a monocyclic or polycyclic 3- to 12-membered heterocycle. In certain such embodiments, R 6 It is -CH3.

[0174] In one or more embodiments of formulas I, II, III, IW, I-V1, I-V2, IX, IY, or IZ, R 2 は-OR b That is. R 2 ga-OR b In certain embodiments where R may be, b is -H. 2 ga-OR b In the case of In a particular embodiment, R b These are -C1~C6 alkyl groups which may be substituted in some cases. ru.

[0175] In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 2 -C1~C6 are substituted in some cases. It is R. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 2 is -CN. Equations I and II, In one or more embodiments of III, I-V1, I-V2, IW, IX, IY, or IZ, R 2 These are -C2~C6 alkenyls that are substituted in some cases. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 2 -C4~C8 is sometimes replaced. It is a chloralkenyl. In one or more embodiments of formulas I, II, III, IW, I-V1, I-V2, IX, IY, or IZ, R 2 It may be replaced depending on the circumstances. It is a C2-C6 alkynyl. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 2 is, It is a C3-C8 cycloalkyl that is substituted by a compound. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 2 This is an aryl that is substituted in some cases. Formulas I, II, III, I- In one or more embodiments of V1, I-V2, IW, IX, IY, or IZ, R 2 This consists of 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O. A heterocycline containing, optionally substituted, R 2 This consists of 1 to 5 heterogenes selected from the group consisting of N, S, P, and O. It is a heteroaryl compound containing, optionally substituted, the derivative. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R 2 It is methyl. One of the formulas I-V1, I-V2, IW, or IZ. In other embodiments, R 2It is a halogen. Formula I-V1 or I-V2 In one or more embodiments, R 2 It is -NH2.

[0176] In one or more embodiments of formulas I-V1, I-V2, IW, or IZ, R 2 is -C(O)OR b In certain such embodiments, R b In some cases, These are more substituted C1-C6 alkyl groups.

[0177] In one or more embodiments of formulas I, II, III, IW, IX, or IY, R a is -H. One of equations I, II, III, IW, IX, or IY In other embodiments, R a is -OH. Equations I, II, III, IW, In one or more embodiments of IX or IY, R a This may be replaced depending on the circumstances. It is a C3-C8 cycloalkyl group. In one or more embodiments of formula I, II, III, IW, IX, or IY, R a It is sometimes replaced. -C1~C6 alkyl

[0178] In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R b is -H. Equations I, II, III, IV 1. In one or more embodiments of I-V2, IW, IX, IY, or IZ In R b These are -C1~C6 alkyl groups that may be substituted depending on the case. Formulas I, II, I In one or more embodiments of II, I-V1, I-V2, IW, IX, IY, or IZ, R bThese are -C3~C8 cycloalkyls which may be substituted in some cases. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R b -C2~C6 are substituted in some cases. It is an alkenyl. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, R b are N, S, P and O It is an optionally substituted heterocycline containing 1 to 5 heteroatoms selected from the group. In one or more embodiments of I-V1, I-V2, or IW, R b This consists of 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O. It is a heteroaryl that contains, optionally substituted, R. In one or more embodiments of I-V1, I-V2, or IW, b It is sometimes replaced. -(CH2) n - It is Ariel.

[0179] In one or more embodiments of formulas I-V1, I-V2, or IW, R b teeth Independently, each occurrence is a heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -H, -D, -C1~C6 alkyl, -C3~C8 cycloalkyl, -C2~C6 alkenyl, or N, S, P and O; where each alkyl, cycloalkyl, alkenyl or heterocycle contains one or more -OH, halogen, -NO2, oxo, - CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6, -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) n OH, -C1~C6 alkyl, -CF3, -CHF2, or -CH2F may be used as substitutes depending on the case.

[0180] In one or more embodiments of formula IY or IZ, R b Each is independent, The appearance is a heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -H, -D, -C1~C6 alkyl, -C3~C8 cycloalkyl, -C2~C6 alkenyl, or N, S, P and O; where each alkyl, cycloalkyl, alkenyl or heterocycle is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2)n Optionally substituted with OH, -C1~C6 alkyl, -CF3, -CHF2, or -CH2F It is.

[0181] In one or more embodiments of formulas I, II, III, I-V1, IW, IX, IY, or IZ, R 3 These are -C1~C6 alkyl groups which may be substituted in some cases. In one or more embodiments of formulas I, II, III, I-V1, IW, IX, IY, or IZ, R 3 This is a monoring with 3 to 12 members, which may be substituted depending on the case. It is a heterocyclic ring of formula or polycyclic form. In one or more embodiments of formulas I, II, III, I-V1, IW, IX, IY, or IZ, R 3 It may be replaced depending on the case. It is a monocyclic heteroring with 3 to 12 members. In one or more embodiments of formulas I, II, III, I-V1, IW, IX, IY, or IZ, R 3 In some cases, It is a more substituted 3- to 12-membered polycyclic heteroring. In one or more embodiments of formulas I-V1 or IW, R 3 These are 5 to 12 members, which may be replaced depending on the circumstances. It is a spiroheterocyclic ring of a certain number of members. In one or more embodiments of formula I-V1 or IW, R 3 This includes one or more -C1~C6 alkyl, -OH, -NH2, -OR b , -NHR b ,-(CH2) n In some cases, OH, heterocyclyl, or spiroheterocyrill These are substituted C1-C6 alkyl groups.

[0182] In one or more embodiments of formulas I, II, III, I-V2, IW, IX, or IY, R 4 is -H. Equations I, II, III, I-V2, IW, IX Or, in one or more embodiments of IY, R 4 It may be replaced depending on the case. It is a C1-C6 alkyl group. In one or more embodiments of formula I-V2 or IW, R 4 is one or more -OH, -NH2, -OR b , halogen or It is an oxo-substituted -C1~C6 alkyl. In one or more embodiments of formula I, II, III, IW, IX, or IY, R 4 It is substituted with -OH It is a C1-C6 alkyl group. In one or more embodiments of formulas I, II, III, I-V2, IW, IX, or IY, R 4 is -CH2-OH. In one or more embodiments of formulas I-V2, IW, or IY, R 4 is -CN In one or more embodiments of formulas I-V2, IW, IX, or IY, R 4 It is a heteroaryl that is substituted in some cases. Formula I-V2 or IW In one or more embodiments, R 4 is a -C1-C6 haloalkyl or -C1-C6 hydroxyalkyl. One or more embodiments of formulas I-V2 or IW. In R 4 It is either -CF2OH or -CHFOH.

[0183] In one or more embodiments of formulas I-V2, IW, or IY, R 4 teeth- C(O)R b In certain such embodiments, R b It is a heterocyclyl that is sometimes substituted.

[0184] In one or more embodiments of formulas I-V2, IW, or IY, R 4 teeth- C(O)NH(CH2)n R b In certain such embodiments, R b is a heterocyclyl that is substituted depending on the case, and n is 0.

[0185] In one or more embodiments of formulas I-V2, IW, or IY, R 4 teeth- C(O)NH(CH2) n It is OH. In certain such embodiments, n is 0.

[0186] In one or more embodiments of formulas I-V2, IW, or IY, R 4 teeth- NH(CH2) n It is OH. In certain such embodiments, n is 2.

[0187] In one or more embodiments of formulas I-V2, IW, IX, or IY, R 4 Ha-NHR 5 In certain such embodiments, R 5 is -H.

[0188] In one or more embodiments of formulas I-V2, IW, IX, or IY, R 4 は-OR 5 In certain such embodiments, R 5 is -H.

[0189] In one or more embodiments of formulas I-V2, IW, IX, or IY, R 4 is -C(O)OR 5 In certain such embodiments, R 5 -C1~C6 It is alkyl.

[0190] In one or more embodiments of formulas I-V2, IW, IX, or IY, R 4 -C(O)NR 5 R6 In certain such embodiments, R 5 and R 6 Both are -H.

[0191] In one or more embodiments of formulas I, II, III, IW, IX, or IY, Y 2 ga-NR a - or - (CR a 2) m -If R 3 and R a Those Together with the attached atoms, it combines and, in some cases, substitutes to form a 3- to 12-member monocyclic heterocycle. 2 ga-NR a - or - (CR a 2) m -Formula I in the case of - In one or more embodiments of II, III, IW, IX, or IY, R 3 and R a These, together with the atoms to which they are attached, combine to form a 3- to 12-membered polycyclic heterocycle, which may be substituted. 2 ga-NR a - or - (CR a 2) m - If one of the formulas I, II, III, IW, IX or IY is - In further embodiments, R 3 and R a These, along with the atoms to which they are attached, combine to form a 5- to 12-membered spiroheterocyclic ring, which may be substituted.

[0192] Y 2 ga-NR a - or - (CR a 2) m - If one or more of the formulas IW are In one embodiment, R 3 and R aThese combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, halogen, -OH, -OR b -NH2, -NHR b heteroaryl, heterocyclyl, -(CH2) n NH2, -(CH2) n OH, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , 3- to 12-membered cells, which are sometimes substituted with -CF3, -CHF2, -CH2F or =O It forms a monocyclic heteroring. In certain such embodiments, the 3- to 12-member monocyclic heteroring is -OR b It is replaced with R b is -H, -C1~C6 alkyl or C3~ It is a C8 cycloalkyl group.

[0193] Y 2 ga-NR a - or - (CR a 2) m - If one or more of the formulas IW are In one embodiment, R 3 and R a These combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, halogen, -OH, -OR b -NH2, -NHR b heteroaryl, heterocyclyl, -(CH2) n NH2, -(CH2) n OH, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , 3- to 12-membered cells, which are sometimes substituted with -CF3, -CHF2, -CH2F or =O It forms a polycyclic heteroring. In certain such embodiments, the 3- to 12-membered polycyclic heteroring is -ORb It is replaced with R b is -H, -C1~C6 alkyl or C3~ It is a C8 cycloalkyl group.

[0194] Y 2 ga-NR a - or - (CR a 2) m - If one or more of the formulas IW are In one embodiment, R 3 and R a These combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, halogen, -OH, -OR b -NH2, -NHR b heteroaryl, heterocyclyl, -(CH2) n NH2, -(CH2) n OH, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , 5- to 12-membered cells, which are sometimes substituted with -CF3, -CHF2, -CH2F or =O It forms a spiroheterocycle. In certain such embodiments, the 5-membered to 12-membered spiroheterocycle is -OR b It is replaced with R b is -H, -C1~C6 alkyl or C3~ It is a C8 cycloalkyl group.

[0195] Y 2 ga-NR a - or - (CR a 2) m - If one or more of the formulas IW are In one embodiment, R 3 and R a These combine with the atoms to which they are attached to form one or more -C1~C6 alkyl, halogen, -OH, -OR b -NH2, -NHR bheteroaryl, heterocyclyl, -(CH2) n NH2, -(CH2) n OH, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b 10 to 12 members, which may be substituted with -CF3, -CHF2, -CH2F or =O. It forms a spiroheterocycle. In certain such embodiments, the 10- to 12-membered spiroheterocycle is -OR b It is replaced with R b These are -H, -C1-C6 alkyl, or C3-C8 cycloalkyl.

[0196] Y 2 ga-NR a - or - (CR a 2) m -Formulas I, II, III, IW, I -In one or more embodiments of X or IY, R a and R 4 These are monocyclic or substituted monocyclic or cyclic compounds that combine with the atoms to which they are attached, and may be substituted. It forms a polycyclic cycloalkyl group with 3 to 12 members. 2 ga-NR a - or - (CR a 2) m - If this is the case, then one of the formulas I, II, III, IW, IX, IY, or IZ In other embodiments, R a and R 4 These atoms, along with the atoms to which they are attached, combine to form monocyclic or polycyclic heterocycles with 3 to 12 members, which may be substituted.

[0197] Y 2 When is -C(O)-, the formulas I, II, III, IW, IX, or IY In one or more embodiments, R 3Depending on the circumstances, one of the three members is replaced. It is a two-membered monoring or polyring complex ring.

[0198] Y 2 -C(R a )If the formula is 2NH-, then one of the formulas IW, IX, or IY or In the embodiments described above, R 3 is -H and two R a These, together with the carbon atoms to which they are attached, form 3- to 8-membered cycloalkyl groups.

[0199] Y 2 ga-NR a -In one or more embodiments of formula IW, R a is -H, and R 3 This includes one or more -C1~C6 alkyl, -OH, -NH2, -OR b , -NHR b ,-(CH2) n It is a C1-C6 alkyl group optionally substituted with an OH, heterocyclyl, or spiroheterocyclyl. In certain such embodiments, R 3 It is substituted with -NH2, a heterocyclyl, or a spiroheterocyclyl.

[0200] Y 2 ga-NR a -In one or more embodiments of formula IW, R a is -H, and R 3 These are monocyclic or polycyclic heterocyclic rings with 3 to 12 members, and 5 to 12 members. It is a spiroheterocycle or C3-C8 cycloalkyl group, where heterocycle, spiroheterocycle and C3-C8 cycloalkyl group are one or more -C1-C6 alkyl, -OH, -NH2, -OR groups. b , -NHR b ,-(CH2) n OH, heterocyclyl, or spirohetero It is sometimes substituted with a cyclil.

[0201] Y 2 ga-(CR a 2) m -In one or more embodiments of formula I, II, III, IW, IX, or IY, R a is -H, m is 1, R 3 A complex ring is a monocyclic or polycyclic ring with 3 to 12 members, which may be substituted depending on the case.

[0202] In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, n is independently 0, 1, 2, or 3 in each occurrence. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, n is 1. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, n is 2. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, n is 0. In one or more embodiments of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, n is 3.

[0203] In one variation of equations I, II, III, IW, IX, or IY, R 2 is a C1-C6 alkyl group, and R 4 is -H. In certain examples of equations I, II, III, IW, IX, or IY, R 2 is a C1-C6 alkyl group, and R 4 is a C1-C6 alkyl group. In certain examples of formulas I, II, III, IW, IX, or IY, R 2 is a C1-C6 alkyl group, and R 4 is one or more -OH, -NH2, halo It is a C1-C6 alkyl group substituted with a gen or oxo group. In certain examples of formulas I, II, III, IW, IX, or IY, R 2It is a C1-C6 alkyl group, R 4 These are -C1~C6 alkyl groups substituted with -OH.

[0204] In one variation of equations I, II, III, IW, IX, or IY, R 2 ha-O R b And R 4 is -H. In certain examples of equations I, II, III, IW, IX, or IY, R 2 は-OR b And R 4 These are C1-C6 alkyl groups. Formulas I and II In certain examples of III, IW, IX, or IY, R 2 は-OR b And R 4 R is a -C1-C6 alkyl group substituted with one or more -OH, -NH2, halogen, or oxo groups. In certain examples of formulas I, II, III, IW, IX, or IY, R 2 は-OR b And R 4 This is a -C1~C6 ammonium compound substituted with -OH. It's a kill.

[0205] In one variation of equations I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, Y 1 is -S-, and A is a monocyclic or polycyclic atom with 5 to 12 members. It is a cycloalkyl compound. In certain examples of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, Y 1 is -S-, and A is heterocycloal It is a kill. In certain examples of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, Y 1 is -S-, and A is aryl. Equations I and II In certain examples of III, I-V1, I-V2, IW, IX, IY, or IZ, Y 1A is -S- and A is a heteroaryl.

[0206] In one variation of equations I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, Y 1 A is a direct bond, and A is a monocyclic or polycyclic compound with 5 to 12 members. It is a cycloalkyl. In certain examples of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, Y 1 This is a direct bond, and A is heterocyclo It is alkyl. In certain examples of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, Y 1 The bond is direct, and A is an aryl group. Equation I In certain examples of II, III, I-V1, I-V2, IW, IX, IY, or IZ, Y 1 The bond is direct, and A is a heteroaryl group.

[0207] Method for synthesizing the disclosed compound The compounds disclosed herein can be prepared by a variety of methods, including standard chemistry. Suitable synthetic routes are illustrated in the scheme shown below.

[0208] Any compound of the formulas described herein can be prepared by methods known in the art of organic synthesis, as partially illustrated by the following synthesis schemes and examples. In the schemes described below, protecting groups for sensitive or reactive groups are used where necessary according to general principles or chemistry. Protecting groups are handled according to standard methods of organic synthesis (TW Greene and PGMWuts, "Protective Groups in Organic Synthesis," 3rd edition, Wiley, New York 1999). These groups are removed at a convenient stage in the compound synthesis using methods readily apparent to those skilled in the art. The selection process, as well as the reaction conditions and the order in which they are carried out, are consistent with the preparation of the compounds of this disclosure.

[0209] Those skilled in the art will recognize whether a stereocenter is present in any of the compounds of this disclosure. Therefore, this disclosure includes both possible stereoisomers (unless otherwise specified in synthesis) and includes not only racemic compounds but also individual enantiomers and / or diastereomers. Where a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by the separation of the final product or any convenient intermediate. Separation of the final product, intermediate, or starting material can be achieved by any suitable method known in the art. For example, see "Stereoch" by ELEliel, SHWilen, and LNMander. See "Emistry of Organic Compounds" (Wiley-Interscience, 1994).

[0210] Manufacturing of compounds The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0211] The compounds of this disclosure can be prepared by a number of methods well known to those skilled in the art of organic synthesis. For example, the compounds of this disclosure can be prepared by the methods described below, along with synthetic methods known in the art of synthetic organic chemistry or variations thereof recognized by those skilled in the art. These methods include, but are not limited to, the methods described below.

[0212] Scheme 1. General synthesis of 2-amino-5-thioaryl-(or thioheteroaryl)-6-methylpyrazine [ka] The general synthesis of 2-amino-5-thioaryl-(or thioheteroaryl)-6-methylpyrazine is outlined in Scheme 1. 2-bromo-5-chloro-3-methylpyrazine can be coupled to a substituted aryl or heteroaryl 1-thiol in the presence of a copper catalyst (e.g., CuI). The resulting thioether can then be coupled to a substituted primary or secondary amine to obtain 2-amino-5-thioaryl-(or thioheteroaryl)-6-methylpyrazine. Additional deprotection and / or functionalization steps may be required to produce the final compound.

[0213] Scheme 2. General synthesis of 2-amino-5-aryl (or heteroaryl)-6-methylpyrazine [ka] The general synthesis of 2-amino-5-aryl (or heteroaryl)-6-methylpyrazine is outlined in Scheme 2. 2-bromo-5-chloro-3-methylpyrazine is synthesized in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2) using substituted aryl or heteroaryl compounds. It can be coupled to a loarylboronic acid. The resulting biaryl intermediate can then be coupled to a substituted primary or secondary amine to obtain 2-amino-5-aryl (or heteroaryl)-6-methylpyrazine. Additional deprotection and / or functionalization steps may be required to produce the final compound.

[0214] Scheme 3. General synthesis of 3-amino-6-aryl-5-methylpyrazinyl-2-methanol and 3-amino-5-methyl-6-arylsulfanylpyrazinyl-2-methanol [ka] The general synthesis of 3-amino-6-aryl-5-methylpyrazine-2-methanol and 3-amino-5-methyl-6-arylsulfanylpyrazine-2-methanol is outlined in Scheme 3. Ethyl 6-bromo-3-chloro-5-methylpyrazine-2-carboxylate can be coupled to a substituted primary or secondary amine. The resulting aminopyrazine intermediate can be coupled to a substituted aryl or heteroarylboronic acid or in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2) It can be coupled to a substituted arylthiol, followed by a reduction step. Additional deprotection and / or functionalization steps may be required to produce the final compound.

[0215] [ka] Alternatively, the aminopyrazine intermediate can be produced by coupling ethyl 3-chloro-5-methylpyrazine-2-carboxylate to a substituted primary or secondary amine, and subsequent bromination using NBS or an alternative brominating agent.

[0216] Methods using the disclosed compounds and compositions Methods and Uses of This Disclosure Another aspect of the present disclosure relates to a method for treating diseases associated with SHP2 modulation in subjects requiring such treatment. The method involves administering an effective amount of one or more compounds of the present disclosure (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) or one or more pharmaceutical compositions of the present disclosure to a patient requiring treatment for a disease or disorder associated with SHP2 modulation. In some embodiments, the disease may be, but is not limited to, Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung, and colon. SHP2 is an important downstream signaling molecule for various receptor tyrosine kinases, including the receptors for platelet-derived growth factor (PDGF-R), fibroblast growth factor (FGF-R), and epidermal growth factor (EGF-R). SHP2 is a signaling molecule. It is also a crucial downstream signaling molecule for the activation of the mitogen-activated protein (MAP) kinase pathway, which can lead to cell transformation, a prerequisite for cancer development. Knockdown of SHP2 significantly inhibited cell growth in lung cancer cell lines with SHP2 mutations or EML4 / ALK metastases, as well as in EGFR-amplified breast and esophageal cancers. Furthermore, SHP2 is activated downstream of oncogenes in gastric carcinoma, anaplastic large cell lymphoma, and glioblastoma.

[0217] In addition, SHP2 plays a role in transmitting signals derived from immune checkpoint molecules, including, but not limited to, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). In this context, modulation of SHP2 function can lead to immune activation, specifically an anti-cancer immune response.

[0218] Another aspect of the present disclosure relates to a method for inhibiting SHP2. The method involves administering an effective amount of one or more compounds of the present disclosure (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) or one or more pharmaceutical compositions of the present disclosure to a patient in need.

[0219] This disclosure relates to compounds or compositions disclosed herein that can modulate (e.g., inhibit) the activity of SHP2. This disclosure also relates to the therapeutic use of such compounds and compositions.

[0220] One or more of the disclosed compounds or compositions can be administered in an effective amount to treat or prevent a disorder and / or prevent its onset in a subject. In some embodiments, SHP2 is inhibited after treatment with less than 1000 nM of the compounds of the disclosure. In some embodiments, SHP2 is inhibited after treatment with about 10 nm to about 100 nm of the compounds of the disclosure. In some embodiments, SHP2 is inhibited after treatment with 10 nM to 100 nM of the compounds of the disclosure. In some embodiments, SHP2 is inhibited after treatment with less than 10 nM of the compounds of the disclosure.

[0221] Another aspect of this disclosure relates to one or more compounds of the Disclosure (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) or one or more compositions of the Disclosure for use in treating or preventing diseases associated with SHP2 modulation. In some embodiments, the diseases are Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung, and colon. SHP2 is an important downstream signaling molecule for various receptor tyrosine kinases, including the receptors for platelet-derived growth factor (PDGF-R), fibroblast growth factor (FGF-R), and epidermal growth factor (EGF-R). SHP2 is also an important downstream signaling molecule for the activation of the mitogen-activated protein (MAP) kinase pathway, which can lead to cell transformation, a prerequisite for the development of cancer. SHP2 knockdown significantly inhibited cell growth in lung cancer cell lines with SHP2 mutations or EML4 / ALK metastases, as well as in EGFR-amplified breast and esophageal cancer cells. Furthermore, SHP2 is activated downstream of oncogenes in gastric carcinoma, anaplastic large cell lymphoma, and glioblastoma.

[0222] In another embodiment, the Disclosure relates to the use of one or more of the compounds of the Disclosure (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) in the manufacture of a pharmaceutical product for treating or preventing a disease. In terms of administration methods, the disease is associated with SHP2 modulation.

[0223] In another embodiment, the Disclosure relates to one or more compounds of the Disclosure (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) for use as pharmaceutically acceptable. In some embodiments, the pharmaceutically acceptable compounds are used to treat or prevent diseases associated with SHP2 modulation.

[0224] In one embodiment, the Disclosure relates to one or more compositions comprising one or more compounds of the Disclosure (e.g., compounds of formulas I, II, III, I-V1, I-V2, IW, IX, IY, or IZ, and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers) for use as pharmaceuticals. In some embodiments, the pharmaceuticals are used to treat or prevent diseases associated with SHP2 modulation.

[0225] Pharmaceutical compositions and administration modes disclosed herein Another aspect of the present disclosure relates to a pharmaceutical composition comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise excipients, diluents, or surfactants.

[0226] Each composition can be manufactured according to conventional mixing, granulation, or coating methods, and the pharmaceutical compositions may contain the disclosed compound in amounts of about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% by weight or volume.

[0227] The administration of the disclosed compounds and pharmaceutical compositions can be achieved through any mode of administration of the therapeutic agent. These modes include systemic or topical administration, such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration.

[0228] Depending on the intended mode of administration, the disclosed compounds or pharmaceutical compositions may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, or suspensions, sometimes in unit doses and consistent with conventional pharmaceutical practices. Similarly, they may also be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, and in all forms well known to those skilled in the pharmaceutical art.

[0229] Exemplary pharmaceutical compositions include one or more compounds of the present disclosure and pharmaceutically acceptable carriers, for example, but not limited to, a) diluents, for example, purified water, triglyceride oils, for example, hydrogenated or partially hydrogenated vegetable oils, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, for example, EPA or DHA, or their esters or triglycerides, or mixtures thereof, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants, for example , silica, talcum, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for use in tablets; c) binders, e.g., aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, e.g., glucose or beta-lactose, corn sweeteners, natural or synthetic gums, e.g., acacia, tragacanth or sodium alginate d) Thorium, wax and / or polyvinylpyrrolidone, if desired; d) Disintegrants, e.g., starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) Absorbents, colorants, flavorings and sweeteners; f) Emulsifiers or dispersants, e.g., Tween 80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafac, Labrafil, Peseol, Transktol, Capmul MCM, Capmul PG-12, Captex 355, Gelcia, Vitamin ETGPS or other acceptable emulsifiers; and / or g) Tablets and gelatin capsules containing agents that enhance the absorption of the compound, e.g., cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200.

[0230] Liquids, particularly injectable compositions, can be prepared by means of dissolution, dispersion, etc. For example, one or more disclosed compounds may be dissolved in or mixed with a pharmaceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerin, or ethanol, to form an injectable isotonic solution or suspension. Proteins, such as albumin, chylomicron particles, or serum proteins, may be used to solubilize the disclosed compounds.

[0231] One or more disclosed compounds or compositions may be formulated as suppositories that can be prepared from fatty emulsions or suspensions; or as carriers using polyalkylene glycols such as propylene glycol.

[0232] One or more disclosed compounds or compositions may also be administered in the form of liposome delivery systems such as small monolayer vesicles, macrolayer vesicles, and multilayer vesicles. Liposomes can be formed from a variety of phospholipids containing cholesterol, stearylamine, or phosphatidylcholine. In some embodiments, the membrane of lipid components forms a lipid layer that encapsulates the drug when hydrated with an aqueous solution of the drug, as described in U.S. Patent No. 5,262,564, the contents of which are incorporated herein by reference.

[0233] One or more of the disclosed compounds or compositions can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Examples of such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspanamide-phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, one or more of the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled drug release, such as polylactic acid, polyepsilon caprolactone, polyhydroxybutyrate, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. In some embodiments, one or more of the disclosed compounds are not covalently bonded to polymers, such as polycarboxylic acid polymers or polyacrylates.

[0234] One or more disclosed compounds or compositions can be delivered by parenteral administration. Parenteral injection administration is generally used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectable preparations can conventionally be prepared as either a solution, suspension, or solid form suitable for dissolution in a liquid before injection.

[0235] The administration regimen of this disclosure The administration regimen utilizing the disclosed compound may take into account the patient's type, species, age, weight, sex and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal or hepatic function; and The drugs are selected according to various factors, including the specific disclosed compounds used. A physician or veterinarian with normal skills in the profession can easily determine and prescribe the effective amount of drugs needed to prevent, counteract, or inhibit the progression of the condition.

[0236] The effective dosage of the disclosed compound, when used for the indicated effect, ranges from about 0.5 mg to about 5000 mg, depending on what is needed to treat the condition. Compositions for in vivo or in vitro use may contain about 0.5 mg, 5 mg, 20 mg, 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1250 mg, 2500 mg, 3500 mg, or 5000 mg of the disclosed compound, or may range from one amount to another in the list of doses. In some embodiments, the composition is in the form of a tablet that can be cut.

[0237] If desired, an effective daily dose of one or more compounds or compositions of this disclosure may be administered as one, two, three, four, five, six or more subdoses, optionally in unit dosage forms, administered separately at appropriate intervals throughout the day. In some embodiments of this disclosure, one or more compounds or compositions or mixtures thereof may be administered twice or three times daily. In some embodiments, one or more compounds or compositions of this disclosure may be administered once daily.

[0238] In some embodiments, one or more compounds or compositions described herein may be used alone or together, co-administered, or used in combination with another type of therapeutic agent. Co-administration or use in combination refers to any form of administration of two or more different therapeutic compounds or compositions such that a second compound or composition is administered while a previously administered therapeutic compound or composition is still effective in the body. For example, different therapeutic compounds or compositions may be administered simultaneously, sequentially, or by separate dosing of the individual components of the treatment, either in the same formulation or in separate formulations. In some embodiments, different therapeutic compounds or compositions may be administered to each other within one hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or one week. Thus, an individual receiving such treatment may benefit from the combined effects of different therapeutic compounds or compositions.

[0239] kit In some embodiments, the disclosure also provides a pharmaceutical package or kit comprising one or more containers filled with at least one compound or composition of the disclosure. Relating to such containers (one or more) may be a notice in a form prescribed by a government agency regulating the manufacture, use, or sale of a pharmaceutical or biological product, which reflects (a) authorization by the agency for manufacture, use, or sale for human administration, (b) instructions for use, or both. In some embodiments, the kit comprises at least two containers, at least one of which contains at least one compound or composition of the disclosure. In some embodiments, the kit comprises at least two containers, each of which contains at least one compound or composition of the disclosure.

[0240] In some embodiments, the kit includes additional materials to facilitate the delivery of the target compound and composition. For example, the kit may include one or more such as catheters, tubes, infusion bags, and syringes. In some embodiments, the compound and composition are packaged in a lyophilized form, and the kit includes at least two containers: a container containing the lyophilized compound or composition and an appropriate amount of water, buffer, or freeze-dried liquid. Includes a container containing other liquids suitable for reconstituting the dry material.

[0241] The foregoing applies to any of the compounds, compositions, methods, and uses described herein. This disclosure specifically envisions any combination of the features of these compounds, compositions, methods, and uses (alone or in combination) with the features described for the various kits described in this section.

[0242] Exemplary Embodiments Some embodiments of this disclosure are, as follows, Embodiment I:

[0243] Embodiment I-1. Formula I: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 1 is -S- or a direct bond; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a)C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The bond on the right side of the section is R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkeni -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 ,- S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Ma taha-CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, or oxo -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2 R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 These are independently C1-C6 alkyl or 3- to 12-membered monocyclic or polycyclic compounds. It is a heterocycle, where each alkyl or heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles with 3 to 12 members or spiroheterocycles with 5 to 12 members, where each heterocycle or spiroheterocycle is optionally substituted with -C1-C6 alkyl, -OH, or -NH2; R 4 These are independently -H, -D, or -C1~C6 alkyl groups, where each alkyl group is , optionally substituted with one or more -OH, -NH2, halogen or oxo or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic It can form heterocycles ranging from 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo molecule; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Compounds thereof, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0244] Embodiment I-2. The compound of Embodiment I-1, wherein A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl group.

[0245] Embodiment I-3. The chemical of Embodiment I-1 or I-2, wherein A is a heterocycloalkyl group. Compound.

[0246] Embodiment I-4. One of the compounds from Embodiments I-1 to I-3, wherein A is an aryl compound.

[0247] Embodiment I-5. One of the compounds from Embodiments I-1 to I-4, wherein A is a heteroaryl compound.

[0248] Embodiment I-6. Y 1 One of the embodiments I-1 to I-5 is -S-. Compound.

[0249] Embodiment I-7. Y 1 One of embodiments I-1 to I-6 is a direct bond. compound.

[0250] Embodiment I-8. Y 2 ga-NR a-A compound which is any one of embodiments I-1 to I-7.

[0251] Embodiment I-9. Y 2 ga-(CR a 2) m -A compound from any one of embodiments I-1 to I-8.

[0252] Embodiment I-10. Y 2 Any of embodiments I-1 to I-9, where is -C(O)-. A type of compound.

[0253] Embodiment I-11. Y 2 -C(R a )2NH- or -(CR a 2) m A compound that is O-, one of any of embodiments I-1 to I-10.

[0254] Embodiment I-12. Y 2 -C(O)N(R a )-,-N(R a )C(O)-, -S(O )2N(R a )-,-N(R a )S(O)2-, -N(R a )C(S)-, or -C(S) N(R a )- one of the compounds from Embodiments I-1 to I-11.

[0255] Embodiment I-13. Y 2 ga-N(R a )C(O)N(R a )-,-N(R a )C(S)N(R a )-,-OC(O)N(R a )-,-N(R a )C(O)O-, or -C(O)N( R a A compound that is O-, one of any two compounds from Embodiments I-1 to I-12.

[0256] Embodiment I-14. Y2 -C(O)O-, -OC(O)-, or -OC(O)O- A compound, which is one of the embodiments I-1 to I-13.

[0257] Embodiment I-15. R 2 ga-OR b A compound, which is one of the embodiments I-1 to I-14.

[0258] Embodiment I-16. R 2 Embodiments I-1 to I-15, in which the element is C1-C6 alkyl. Any one of the following compounds.

[0259] Embodiment I-17. R 2 One of embodiments I-1 to I-16, wherein -CN A compound of [this].

[0260] Embodiment I-18. R 2 Embodiments I-1 to I-17, in which the compound is a C2-C6 alkenyl. One of the following compounds.

[0261] Embodiment I-19. R 2 Embodiments I-1 to I -18 of the following compounds.

[0262] Embodiment I-20. R 2 Embodiments I-1 to I-19, in which the compound is -C2~C6 alkynyl. One of the following compounds.

[0263] Embodiment I-21. R 2 Embodiments I-1 to I- are C3-C8 cycloalkyl. One of the 20 compounds.

[0264] Embodiment I-22. R 2 is any one of embodiments I-1 to I-21 A type of compound.

[0265] Embodiment I-23. R 2 However, 1 to 5 elements selected from the group consisting of N, S, P, and O A compound from any one of Embodiments I-1 to I-22, which is a heterocyclyl containing a heteroatom.

[0266] Embodiment I-24. R 2 However, 1 to 5 elements selected from the group consisting of N, S, P, and O A compound from any one of embodiments I-1 to I-23, which is a heteroaryl compound containing a heteroatom.

[0267] Embodiment I-25. R a One of embodiments I-1 to I-24 where is -H compound.

[0268] Embodiment I-26. R a One of embodiments I-1 to I-25, wherein is -OH A compound of [this].

[0269] Embodiment I-27. R a Embodiments I-1 to I- are C3-C8 cycloalkyl. One of the 26 compounds.

[0270] Embodiment I-28. R a Embodiments I-1 to I-27, wherein the alkyl group is C1-C6 alkyl. Any one of the following compounds.

[0271] Embodiment I-29. R b One of embodiments I-1 to I-28 where is -H compound.

[0272] Embodiment I-30. R b Embodiments I-1 to I-29, wherein the element is C1-C6 alkyl. Any one of the following compounds.

[0273] Embodiment I-31. R b Embodiments I-1 to I- are C3-C8 cycloalkyl. One of the 30 compounds.

[0274] Embodiment I-32. R b Embodiments I-1 to I-31, in which the compound is a C2-C6 alkenyl. One of the following compounds.

[0275] Embodiment I-33. R b However, 1 to 5 elements selected from the group consisting of N, S, P, and O A compound from any one of embodiments I-1 to I-32, which is a heterocyclyl containing a heteroatom.

[0276] Embodiment I-34. R 3 Embodiments I-1 to I-33, wherein the element is C1-C6 alkyl. Any one of the following compounds.

[0277] Embodiment I-35. R 3 However, real complex rings are monocyclic or polycyclic rings with 3 to 12 members. One compound from application forms I-1 to I-34.

[0278] Embodiment I-36. R 3 However, Embodiment I-1 is a monocyclic heteroring with 3 to 12 members. One of the compounds from I-35.

[0279] Embodiment I-37. R 3 However, Embodiment I-1 is a polycyclic heteroring with 3 to 12 members. One of the compounds from I-36.

[0280] Embodiment I-38. R 3 and R a However, any one of the compounds from Embodiments I-1 to I-37, wherein these atoms, together with the atoms to which they are attached, combine to form a monocyclic heterocycle of 3 to 12 members.

[0281] Embodiment I-39. R 3 and R a However, any one of the compounds from Embodiments I-1 to I-38, wherein these atoms, together with the atoms to which they are attached, combine to form a 3- to 12-membered polycyclic heterocycle.

[0282] Embodiment I-40. R 3 and R a However, any one of the compounds from Embodiments I-1 to I-39, wherein these atoms, together with the atoms to which they are attached, combine to form a 5- to 12-membered spiroheterocycle.

[0283] Embodiment I-41. R a and R 4 However, any one of the compounds from Embodiments I-1 to I-40, wherein these atoms, together with the atoms to which they are attached, combine to form a monocyclic or polycyclic cycloalkyl group consisting of 3 to 12 members.

[0284] Embodiment I-42. R a and R 4 However, any one of the compounds from Embodiments I-1 to I-41, wherein these atoms, together with the atoms to which they are attached, combine to form a monocyclic or polycyclic heterocycle of three to twelve members.

[0285] Embodiment I-43. Formula IA: [ka] (In the formula: A is an aryl; Y 1 is -S- or a direct bond; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(Ra )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The bond on the right side of the section is R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Also -CO2R 5Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O) R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5, -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 These are independently C1-C6 alkyl or 3- to 12-membered monocyclic or polycyclic compounds. It is a primary ring, where each alkyl or heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles with 3 to 12 members or spiroheterocycles with 5 to 12 members, where each heterocycle or spiroheterocycle is optionally substituted with -C1-C6 alkyl, -OH, or -NH2; R 4 These are independently -H, -D, or -C1~C6 alkyl groups, where each alkyl group is , optionally substituted with one or more -OH, -NH2, halogen or oxo or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic It can form heterocycles ranging from 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo molecule; R 5 and R 6 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloal Kill, monocyclic or polycyclic complex rings with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8, -NO2 or -CN; R 7 and R 8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Compounds thereof, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0286] Embodiment I-44. Formula IB: [ka] (In the formula: A is a heteroaryl; Y 1 is -S- or a direct bond; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(Ra )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The bond on the right side of the section is R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Also -CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6-S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O) R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may contain one or more -OH, halogen, -NO2, oxo, -CN, or -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 These are independently C1-C6 alkyl or 3- to 12-membered monocyclic or polycyclic compounds. It is a heterocycle, where each alkyl or heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles with 3 to 12 members or spiroheterocycles with 5 to 12 members, where each heterocycle or spiroheterocycle is optionally substituted with -C1-C6 alkyl, -OH, or -NH2; R 4 These are independently -H, -D, or -C1~C6 alkyl groups, where each alkyl group is , optionally substituted with one or more -OH, -NH2, halogen or oxo or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic It can form heterocycles ranging from 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo molecule; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Compounds thereof, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0287] Embodiment I-45. Formula II: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 2 -NR a -,-(CR a 2) m -, -C (O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N(R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C(O)O-, -C(O)N(R a )O-, -N (R a )C(S)-, -C(S)N(R a )-, or -OC(O)O-; where Y 2 The bond on the left side is bonded to the pyrazine ring, as depicted, Y 2 The bond on the right side of the section is R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkeni -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 ,- S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Ma taha-CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, or oxo -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2 R 5 , -NR 5 S(O)2NR 5 R 6, -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; Ra Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, -C2~C6 alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl A rhizome, alkenyl, or heterocycle may contain one or more -OH, halogen, -NO2, or hydroxyl groups. Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 These are independently C1-C6 alkyl or 3- to 12-membered monocyclic or polycyclic compounds. It is a heterocycle, where each alkyl or heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles with 3 to 12 members or spiroheterocycles with 5 to 12 members, where each heterocycle or spiroheterocycle is optionally substituted with -C1-C6 alkyl, -OH, or -NH2; R 4 These are independently -H, -D, or -C1~C6 alkyl groups, where each alkyl group is , optionally substituted with one or more -OH, -NH2, halogen or oxo or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic It can form heterocycles ranging from 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo molecule; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Compounds thereof, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0288] Embodiment I-46. Formula II-A: [ka] The compound of Embodiment I-45.

[0289] Embodiment I-47. Formula II-A1: [ka] (In the formula: B, together with the nitrogen atom to which it is attached, forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, where the heterocycle or spiroheterocycle is optionally substituted with -C1-C6 alkyl, -OH, or -NH2. The compound of Embodiment I-46.

[0290] Embodiment I-48. Formula II-A2: [ka] The compound of Embodiment I-46.

[0291] Embodiment I-49. Formula II-A3: [ka] The compound of Embodiment I-46.

[0292] Embodiment I-50. Formula II-B: [ka] The compound of Embodiment I-45.

[0293] Embodiment I-51. Formula II-B1: [ka] (In the formula: B, together with the carbon atoms to which it is attached, forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, where the heterocycle or spiroheterocycle is optionally substituted with -C1-C6 alkyl, -OH, or -NH2. The compound of Embodiment I-50.

[0294] Embodiment I-52. Formula II-B2: [ka] The compound of Embodiment I-50.

[0295] Embodiment I-53. Formula II-B3: [ka] The compound of Embodiment I-50.

[0296] Embodiment I-54. Formula II-B4: [ka] The compound of Embodiment I-50.

[0297] Embodiment I-55. Formula II-B5: [ka] The compound of Embodiment I-50.

[0298] Embodiment I-56. Formula II-B6: [ka] The compound of Embodiment I-50.

[0299] Embodiment I-57. Formula II-C: [ka] (In the formula: B forms a monocyclic or polycyclic heterocycle with 3 to 12 members, where the heterocycle is optionally substituted with -C1-C6 alkyl, -OH, or -NH2. The compound of Embodiment I-45.

[0300] Embodiment I-58. Formula II-C1: [ka] The compound of Embodiment I-57.

[0301] Embodiment I-59. Formula II-D: [ka] The compound of Embodiment I-57, here: B forms a monocyclic or polycyclic heterocycle with 3 to 12 members, where the heterocycle is optionally substituted with -C1-C6 alkyl, -OH, or -NH2.

[0302] Embodiment I-60. Formula II-D1: [ka] The compound of Embodiment I-57.

[0303] Embodiment I-61. Formula II-E: [ka] The compound of Embodiment I-45.

[0304] Embodiment I-62. Formula II-F: [ka] The compound of Embodiment I-45.

[0305] Embodiment I-63. Formula II-G: [ka] The compound of Embodiment I-45, In the formula, R 2 It is either aryl or heteroaryl.

[0306] Embodiment I-64. Formula III: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, and -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2The bond on the right side of the section is R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Also -CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O) R 5 , -NR 5 S(O)NR 5R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 Independently, in each occurrence, -C1~C6 alkyl or 3- to 12-membered monocyclic or The group is selected from polycyclic heterocycles, where each alkyl or heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2 groups. ;or R 3 R aCombined with these, a monocyclic or polycyclic heterocyclic ring with 3 to 12 members or Five- to twelve-membered spiroheterocycles can be formed, where each heterocycle or spiroheterocycle is optionally substituted with -C1-C6 alkyl, -OH, or -NH2; R 4 These are independently -H, -D, or -C1~C6 alkyl groups, where each alkyl group is , optionally substituted with one or more -OH, -NH2, halogen or oxo or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic It can form heterocycles ranging from 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo molecule; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Compounds thereof, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0307] Embodiment I-65. Formula III-A: [ka] The compound of Embodiment I-64.

[0308] Embodiment I-66. Formula III-A1: [ka] (In the formula, B, together with the nitrogen atom to which it is attached, forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, where the heterocycle or spiroheterocycle The heterocycle may be substituted with -C1-C6 alkyl, -OH, or -NH2 groups. The compound of Embodiment I-65.

[0309] Embodiment I-67. Formula III-A2: [ka] The compound of Embodiment I-65.

[0310] Embodiment I-68. Formula III-A3: [ka] The compound of Embodiment I-65.

[0311] Embodiment I-69. A compound selected from the group consisting of compounds 1 to 41, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof.

[0312] Embodiment I-70. A pharmaceutical composition comprising one or more compounds from any one of Embodiments I-1 to I-69 and a pharmaceutically acceptable carrier.

[0313] Embodiment I-71. A method for treating a disease associated with SHP2 modulation in a subject requiring it, comprising administering an effective amount of one or more compounds from any one of Embodiments I-1 to I-69 to the subject.

[0314] Embodiment I-72. The method of Embodiment I-71, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung, and colon.

[0315] Embodiment I-73. One or more compounds from any one of Embodiments I-1 to I-69 for use in treating or preventing diseases associated with SHP2 modulation.

[0316] Embodiment I-74. Use of one or more compounds from any one of Embodiments I-1 to I-69 in the manufacture of a pharmaceutical product for treating or preventing a disease associated with SHP2 modulation.

[0317] Embodiment I-75. Formula IX: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 1 is -S- or a direct bond; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R)a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkeni -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 ,- S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Ma taha-CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, or oxo -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2 R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a They are attached together Together with the carbon atoms present, they can combine to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 These are independently -H, -C1~C6 alkyl, or 3- to 12-membered monocyclic or polycyclic compounds. A cyclic heterocycle, where each alkyl or heterocycle is one or more -C1 ~C6 alkyl, -OH or -NH2 may be substituted; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles with 3 to 12 members or spiroheterocycles with 5 to 12 members, where each heterocycle or spiroheterocycle is optionally substituted with -C1-C6 alkyl, -OH, or -NH2; R 4 These are independently -H, -D, -C1~C6 alkyl, and -NH-NHR 5 , -NH-OR 5 , -O-NR 5 R 6 , -NHR 5 , -OR 5 ,-NHC(O)R 5 ,-NHC(O)NHR 5 , -NHS(O)2R 5 , -NHS(O)2NHR 5 -S(O)2OH, -C(O)OR 5 -C(O)NR 5 R 6 -S(O)2NR 5 R 6 C3-C8 cycloalkyl, aryl, N, S A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of P and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P and O, where each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more -OH, -NH2, halogen or oxo. Here, each aryl or heteroaryl is optionally substituted with one or more -OH, -NH2, or halogens; or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic A heterocycle can be formed with 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo; where the heterocycle has -S(O)2- Includes by combination; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Compounds thereof, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0318] Embodiment I-76. Formula IY: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 1 is -S- or a direct bond; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The joint on the right side of the section is R, as depicted.3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkeni -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 ,- S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Ma taha-CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, or oxo -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2 R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) n OH, -C1~C6 alkyl, -CF3, -CHF2 or -CH2 F is sometimes substituted; R 3 These are independently -H, -C1~C6 alkyl, and 3- to 12-membered monocyclic or polycyclic compounds. Heterocyclic, C3-C8 cycloalkyl or -(CH2) n -R b And here, each Alki A heterocyclic or cycloalkyl group is defined as one or more -C1-C6 alkyl, -OH, -NH2, -OR a , -NHR a ,-(CH2) n OH, heterocyclyl or spirohete It is sometimes replaced by rocicryl; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles with 3 to 12 members or spiroheterocycles with 5 to 12 members, where each heterocycle or spiroheterocycle is -C1~C6 alkyl, -OH, -NH2, heteroaryl, heterocyclyl, - (CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , -CF3, -CHF2, or -CH2F may be used as substitutes; R 4 These are independently -H, -D, -C1~C6 alkyl, and -NH-NHR 5 , -NH-OR 5 , -O-NR 5 R 6 , -NHR 5 , -OR 5 ,-NHC(O)R 5 ,-NHC(O)NHR 5 , -NHS(O)2R 5 , -NHS(O)2NHR 5 -S(O)2OH, -C(O)OR 5 , -NH(CH2) n OH, -C(O)NH(CH2) n OH, -C(O)NH(CH2) n R b , -C(O)R b -NH2, -OH, -CN, -C(O)NR 5 R 6 -S(O)2NR 5 R 6 A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of C3-C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, cycloalkyl, or heterocyclyl contains one or more -OH, -NH2, They are optionally substituted with halogens or oxos; where each aryl or heteroaryl is optionally substituted with one or more -OH, -NH2 or halogens. or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic A heterocycle can be formed with 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo; where the heterocycle has -S(O)2- Includes by combination; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Compounds thereof, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0319] Embodiment I-77. Formula IZ: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 1 is -S-, direct bond, -NH-, -S(O)2-, -S(O)2-NH-, -C( =CH2)-, -CH-, or -S(O)-; Y 2 -NR a -,-(CR a 2) m -, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S (O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N(R a )-,-O C(O)N(R a )-,-N(R a )C(O)O-, -C(O)N(R a )O-, -N(R a )C(S)-, or -C(S)N(R a )- and; here, Y 2 The bond on the left side is bonded to the pyrazine ring, as depicted, Y 2The connection on the right side of the section is as depicted. R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkeni -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 ,- S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 ,Ma taha-CO2R 5 Here, each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is one or more -OH, halogen, -NO2, or oxo -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2 R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b -NH2, -CN, -C1~C6 alkyl, -C2~C6 alchemy Nyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, halogen, -C(O)OR b Selected from the group consisting of -C3~C8 cycloalkyl, aryl, N, S, P and O. A heterocyclyl containing 1 to 5 heteroatoms, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl contains one or more -OH, halogen, -NO2 , oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R aIndependently, in each occurrence, -OH, -C3~C8 cycloalkyl or -C1~C6 alkyl This is a kill, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2s, where two R a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) n OH, -C1~C6 alkyl, -CF3, -CHF2 or -CH2 F is sometimes substituted; R 3 Independently, in each appearance, -H, -C1~C6 alkyl, and 3- to 12-membered monocyclic compounds are also k is a polycyclic heterocycle, C3-C8 cycloalkyl or -(CH2) n -Rb And here Each alkyl, heterocyclic, or cycloalkyl group may contain one or more -C1-C6 alkyl, -OH, -NH2, or -OR a , -NHR a ,-(CH2) n OH, heterocyclyl or Substituted in some cases with spiroheterocyrils; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles with 3 to 12 members or spiroheterocycles with 5 to 12 members, where each heterocycle or spiroheterocycle is -C1~C6 alkyl, -OH, -NH2, heteroaryl, heterocyclyl, - (CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , -CF3, -CHF2, or -CH2F may be used as substitutes; R 4 These are independently -C1~C6 alkyl and -NH-NHR 5 , -NH-OR 5 , -O-NR 5 R 6 , -NHR 5 , -OR 5 ,-NHC(O)R 5 ,-NHC(O)NHR 5 , -NHS(O )2R 5 , -NHS(O)2NHR 5 -S(O)2OH, -C(O)OR 5 , -NH(CH2 ) n OH, -C(O)NH(CH2) n OH, -C(O)NH(CH2) n R b , -C(O)R b -NH2, -OH, -C(O)NR 5 R 6 -S(O)2NR 5 R6 C3-C8 cycloal A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of alkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, cycloalkyl, or heterocyclyl contains one or more -OH, -NH2, halogen, or oxo They are optionally substituted; where each aryl or heteroaryl is optionally substituted with one or more -OH, -NH2 or halogens; R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic A cyclic heterocycle is formed with 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo; where the heterocycle is optionally substituted with -S(O)2- Including; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Compounds thereof, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0320] Embodiment I-78. A compound selected from the group consisting of compounds A-1 to A-141, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof.

[0321] Some embodiments of this disclosure are described below as Embodiment II:

[0322] Embodiment II-1. Formula IW: [ka] (In the formula: A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are monocyclic or polycyclic structures with 5 to 12 members; Y 1 is -S-, direct bond, -NH-, -S(O)2-, -S(O)2-NH-, -C( =CH2)-, -CH-, or -S(O)-; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a)C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, -OR 6 , halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 , -CO2R 5 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 monocyclic or polycyclic hetero Rocyclyl, spiroheterocyclyl, heteroaryl, or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, =O, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independent, -OR b -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, halogen, -C(O)OR b , 1 to 5 selected from the group consisting of -C3~C8 cycloalkyl, aryl, N, S, P and O A heterocyclyl containing a heteroatom, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl Or heteroaryls contain one or more -OH, halogens, -NO2, oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O) R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, each occurrence is either -H, -D, -OH, -C3~C8 cycloalkyl, -C1~C6 alkyl, 3- to 12-membered heterocyclyl, or -(CH2) n -Aryl Here, each alkyl or cycloalkyl group is composed of one or more -NH2 groups. It is replaced by a combination, or here, two R a Both of them are attached Together with carbon atoms, they can combine to form 3- to 8-membered cycloalkyl groups; R b These are independent of each other, and in each occurrence, -H, -D, -OH, -C1~C6 alkyl, -C3~C8 alkyl Chloalkyl, -C2~C6 alkenyl, -(CH2) n -A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, heterocyclic, heteroaryl, or -(CH2) n -aryl is one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) n They may be substituted with OH, -C1~C6 alkyl, -CF3, -CHF2, or -CH2F; R 3 These are independently -H, -C1~C6 alkyl, and 3- to 12-membered monocyclic or polycyclic compounds. Heterocyclic compounds, 5- to 12-membered spiroheterocyclic compounds, C3-C8 cycloalkyl compounds or -(CH2) n -R b Here, each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is 1 One or more -C1~C6 alkyl, -OH, -NH2, -OR b , -NHR b ,-( CH2) n OH, heterocyclyl, or spiroheterocyclyl may be substituted; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle contains one or more -C1-C6 alkyl, halogen, -OH, or -ORb , -N H2, -NHR b heteroaryl, heterocyclyl, -(CH2) n NH2, -(CH2) n OH, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , -CF3, -CHF2, -CH2F or =O are sometimes substituted; R 4 These are independently -H, -D, -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 hydroxyalkyl, -CF2OH, -CHFOH, -NH-NHR 5 , -NH-OR 5 , -O-NR 5 R 6 , -NHR 5 , -OR 5 ,-NHC(O)R 5 ,-NHC(O)NHR 5 , -NHS(O)2R 5 , -NHS(O)2NHR 5 -S(O)2OH, -C(O)OR 5 , -NH(CH2) n OH, -C(O)NH(CH2) n OH, -C(O)NH(CH2) n R b , -C(O)R b -NH2, -OH, -CN, -C(O)NR 5 R 6 -S(O)2NR 5 R 6 A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of C3-C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, cycloalkyl, or heterocyclyl contains one or more -OH, -NH2, -OR b, optionally substituted with halogen or oxo; where each aryl or Heteroaryls are, in the case of one or more -OH, -NH2, or halogens It has been replaced; or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic A heterocycle can be formed with 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo; where the heterocycle has -S(O)2- Includes by combination; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 It is -NO2, -CF3, or -CN; R 7 and R 8 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OR b , or a monocyclic or polycyclic complex ring with 3 to 12 members, where Each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle may be substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Compounds of, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers of.

[0323] Embodiment II-2. Formula I: [ka] (In the formula: A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y 1 is -S- or a direct bond; Y 2 -NR a -,-(CR a 2) m -, -C(O)-, -C(R a )2NH-, -(CR a 2) m O-, -C(O)N(R) a )-,-N(R a )C(O)-,-S(O)2N(R a )-,-N(R a )S(O)2-, -N(R a )C(O)N(R a )-,-N(R a )C(S)N( R a )-, -C(O)O-, -OC(O)-, -OC(O)N(R a )-,-N(R a )C (O)O-, -C(O)N(R) a )O-, -N(R a )C(S)-, -C(S)N(R a ) -, or -OC(O)O-; where Y 2 The connection on the left side is as depicted, It is bonded to the pyrazine ring, Y 2 The bond on the right side of the section is R 3 It is coupled to; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl , -C4-C8 cycloalkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 , -S(O)2NR 5 R 6 , -S (O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 , -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 , and also is -CO2R 5 , where each alkyl, alkenyl, cycloalkenyl, alkynyl or cycloalkyl is optionally substituted with one or more of -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 , -S(O)2NR 5 R 6 , -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 , -S(O)NR 5 R 6 , -S(O) R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , heterocyclic, aryl or heteroar yl and is optionally substituted; R2 These are independent, -OR b A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of -CN, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, -CN, -R 5 , -OR 5 , -N R 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R a Independently, in each occurrence, -H, -D, -OH, -C3~C8 cycloalkyl or - C1-C6 alkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -NH2 groups, where two R groups a These can combine with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl groups; R bThese are independent of each other, with each occurrence being -H, -D, -C1~C6 alkyl, and -C3~C8 cycloal A heterocyclyl containing one to five heteroatoms selected from the group consisting of alkyl, cycloalkyl, alkenyl, or N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, or heterocycle contains one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 3 These are independently C1-C6 alkyl or 3- to 12-membered monocyclic or polycyclic compounds. It is a heterocycle, where each alkyl or heterocycle is optionally substituted with one or more -C1-C6 alkyl, -OH, or -NH2; or R 3 R a These can be combined to form monocyclic or polycyclic heterocycles with 3 to 12 members or spiroheterocycles with 5 to 12 members, where each heterocycle or spiroheterocycle is optionally substituted with -C1-C6 alkyl, -OH, or -NH2; R 4 These are independently -H, -D, or -C1~C6 alkyl groups, where each alkyl group is , optionally substituted with one or more -OH, -NH2, halogen or oxo or R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic 3 A 12-membered heterocycle can be formed from the members, where the cycloalkyl or heterocycle is optionally substituted with an oxo molecule; R 5 and R 6 Each of these is independent, and in each occurrence, -H, -D, -C1~C6 alkyl, -C2~ C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkenyl Roalkyl, monocyclic or polycyclic heterocyclic rings with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 , -NO2 or -CN; R 7 and R 8 Independently, in each occurrence, is a -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, or monocyclic or polycyclic 3- to 12-membered heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; m is independently 1, 2, 3, 4, 5, or 6 in each occurrence; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The compound of Embodiment II-1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof.

[0324] Embodiment II-3. Formula I-W6: [ka] (In the formula: A is a monocyclic or polycyclic heteroaryl with 5 to 12 members; Y 1 is -S-; Y 2 -NR a -and; here Y 2 The bond on the left side is pyrazine, as depicted. It is bonded to the ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 3 R a These combine to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle contains one or more -C1~C6 alkyl, -OH, -NH2, heteroaryl, heterocyclic Lil, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COO R b , -NHCOOR b , may be replaced by -CF3, -CHF2, or -CH2F. the law of nature; R 1 These are independent of each other, appearing as -H, -C1~C6 alkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 , -C(O)R 5 or -CO2R 5 and; R 2 It is a C1-C6 alkyl group; R b Independently, in each occurrence, is either -H or -C1~C6 alkyl; R 4 These are -H, -C1~C6 alkyl, -C1~C6 haloalkyl, and -C1~C6 hydroxyl Alkyl, -CF2OH, -CHFOH, -C(O)NH(CH2) n OH, -C(O)N H(CH2) n R b , -C(O)R b -C(O)NR 5 R 6 It is -OH or -CN, where alkyl is one or more -OH, -NH2, halogen or oxo. It is replaced by; or R 5 and R 6 Each of these is independently, in each occurrence, -H or -C1~C6 alkyl; The compound of Embodiment II-1, wherein n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 in each occurrence) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof.

[0325] Embodiment II-4. Formula I-W7: [ka] (In the formula: A is a monocyclic or polycyclic heteroaryl with 5 to 12 members; Y 1 It is a direct bond; Y 2 -NR a -and; here Y 2 The bond on the left side is pyrazine, as depicted. It is bonded to the ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 3 R a These combine to form monocyclic or polycyclic heterocycles of 3 to 12 members or spiroheterocycles of 5 to 12 members, where each heterocycle or spiroheterocycle contains one or more -C1~C6 alkyl, -OH, -NH2, heteroaryl, heterocyclic Lil, -(CH2)n NH2, -COOR b -CONHR b -CONH(CH2) n COO R b , -NHCOOR b , may be replaced by -CF3, -CHF2, or -CH2F. the law of nature; R 1 These are independent of each other, appearing as -H, -C1~C6 alkyl, -OH, halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 , -C(O)R 5 or -CO2R 5 and; R 2 It is a C1-C6 alkyl group; R b Independently, in each occurrence, is either -H or -C1~C6 alkyl; R 4 These are -H, -C1~C6 alkyl, -C1~C6 haloalkyl, and -C1~C6 hydroxyl Alkyl, -CF2OH, -CHFOH, -C(O)NH(CH2) n OH, -C(O)N H(CH2) n R b , -C(O)R b -C(O)NR 5 R 6 It is -OH or -CN, where alkyl is one or more -OH, -NH2, halogen or oxo. It is replaced by; or R 5 and R 6 Each of these is independently, in each occurrence, -H or -C1~C6 alkyl; The compound of Embodiment II-1, wherein n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 in each occurrence) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof.

[0326] Embodiment II-5. Formula I-V1: [ka] (In the formula: A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are monocyclic or polycyclic structures with 5 to 12 members; Y 1 is -S-, direct bond, -NH-, -S(O)2-, -S(O)2-NH-, -C( =CH2)-, -CH-, or -S(O)-; Y 2 -NR a -and here, Y 2 The bond on the left side is pyrazine, as depicted. It is bonded to the ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R a and R 4 These, together with the atom(s) to which they are attached, combine to form monocyclic or polycyclic C3-C3 compounds. 12 Cycloalkyl or monocyclic or polycyclic A cyclic heterocycle is formed with 3 to 12 members, where the cycloalkyl or heterocycle is optionally substituted with an oxo; where the heterocycle is optionally substituted with -S(O)2- Including; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, -OR 6 , halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R 5 , -CO2R 5 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 monocyclic or polycyclic hetero Rocyclyl, spiroheterocyclyl, heteroaryl, or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is one or more -OH, halogen, -NO2, oxo, =O, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independently -NH2, -OR b -CN, -C1~C6 alkyl, -C2~C6 alke Nyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, halogen, -C(O)OR b Selected from the group consisting of -C3~C8 cycloalkyl, aryl, N, S, P and O. A heterocyclyl containing 1 to 5 heteroatoms, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl contains one or more -OH, halogen, -NO2 , oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R b These are independent of each other, and in each occurrence, -H, -D, -OH, -C1~C6 alkyl, -C3~C8 alkyl Chloalkyl, -C2~C6 alkenyl, -(CH2) n -A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, heterocyclic, heteroaryl, or -(CH2)n -aryl is one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) n They may be substituted with OH, -C1~C6 alkyl, -CF3, -CHF2, or -CH2F; R 3 These are independently -H, -C1~C6 alkyl, and 3- to 12-membered monocyclic or polycyclic compounds. Heterocyclic compounds, 5- to 12-membered spiroheterocyclic compounds, C3-C8 cycloalkyl compounds or -(CH2) n -R b Here, each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is 1 One or more -C1~C6 alkyl, -OH, -NH2, -OR b , -NHR b ,-( CH2) n OH may be substituted with heterocyclyl or spiroheterocyrillic. ; R 5 and R 6Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 It is -NO2, -CF3, or -CN; R 7 and R 8 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OR b , or a monocyclic or polycyclic complex ring with 3 to 12 members, where Each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle may be substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Compounds thereof, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.

[0327] Embodiment II-6. Formula I-V2: [ka] (In the formula: A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are monocyclic or polycyclic structures with 5 to 12 members; Y 1 is -S-, direct bond, -NH-, -S(O)2-, -S(O)2-NH-, -C( =CH2)-, -CH-, or -S(O)-; Y 2 -NR a -and here, Y 2The bond on the left side is pyrazine, as depicted. It is bonded to the ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 3 R a These combine to form 3- to 12-membered polycyclic heterocycles or 5- to 12-membered spiroheterocycles, where each heterocycle or spiroheterocycle contains one or more -C1-C6 alkyl, halogen, -OH, -OR b -NH2, -NHR b heterogeneous Ru, heterocyclyl, -(CH2) n NH2, -(CH2) n OH, -COOR b -CONHR b -CONH(CH2) n COOR b , -NHCOOR b , -CF3, -CHF2, -CH2F or =O are sometimes substituted; R 1 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, and -C2~C6 alkenyl -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OH, -OR 6 , halogen, -NO2, -CN, -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , -C(O)R5 , -CO2R 5 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 monocyclic or polycyclic hetero Rocyclyl, spiroheterocyclyl, heteroaryl, or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is one or more -OH groups, halogens -NO2, oxo, =O, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 ,-S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl rings; R 2 These are independently -NH2, -OR b -CN, -C1~C6 alkyl, -C2~C6 alke Nyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, halogen, -C(O)OR b Selected from the group consisting of -C3~C8 cycloalkyl, aryl, N, S, P and O. A heterocyclyl containing 1 to 5 heteroatoms, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl contains one or more -OH, halogen, -NO2 , oxo, -CN, -R 5 , -OR 5 , -NR 5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S(O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 , optionally substituted with heterocyclic, aryl, or heteroaryl atoms; where the heterocyclyl or heteroaryl atom is not attached via a nitrogen atom; R b These are independent of each other, and in each occurrence, -H, -D, -OH, -C1~C6 alkyl, -C3~C8 alkyl Chloalkyl, -C2~C6 alkenyl, -(CH2) n -A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, heterocyclic, heteroaryl, or -(CH2) n -aryl is one or more -OH, halogen, -NO2, or Kiso, -CN, -R 5 , -OR 5 , -NR5 R 6 , -SR 5 -S(O)2NR 5 R 6 -S(O)2R 5 , -NR 5 S(O)2NR 5 R 6 , -NR 5 S(O)2R 6 -S(O)NR 5 R 6 , -S (O)R 5 , -NR 5 S(O)NR 5 R 6 , -NR 5 S(O)R 6 -C(O)NR 5 R 6 , -NR 5 C(O)R 6 heterocyclic ring, aryl, heteroaryl, -(CH2) n They may be substituted with OH, -C1~C6 alkyl, -CF3, -CHF2, or -CH2F; R 4 These are independently -H, -D, -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 hydroxyalkyl, -CF2OH, -CHFOH, -NH-NHR 5 , -NH-OR 5 , -O-NR 5 R 6 , -NHR 5 , -OR 5 ,-NHC(O)R 5 ,-NHC(O)NHR 5 , -NHS(O)2R 5 , -NHS(O)2NHR 5 -S(O)2OH, -C(O)OR 5 , -NH(CH2) n OH, -C(O)NH(CH2) n OH, -C(O)NH(CH2) n R b , -C(O)R b -NH2, -OH, -CN, -C(O)NR 5 R 6 -S(O)2NR5 R 6 A heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of C3-C8 cycloalkyl, aryl, N, S, P, and O, or a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, cycloalkyl, or heterocyclyl contains one or more -OH, -NH2, -OR b , optionally substituted with halogen or oxo; where each aryl or Heteroaryls are, in the case of one or more -OH, -NH2, or halogens It has been replaced; R 5 and R 6 Independently, each occurrence is -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, monocyclic or polycyclic heterocycles with 3 to 12 members, -OR 7 , -SR 7 , halogen, -NR 7 R 8 It is -NO2, -CF3, or -CN; R 7 and R 8 Independently, in each occurrence, -H, -D, -C1~C6 alkyl, -C2~C6 alkenyl, -C4~C8 cycloalkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -OR b , or a monocyclic or polycyclic complex ring with 3 to 12 members, where Each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle may be substituted with one or more -OH, -SH, -NH2, -NO2, or -CN; n is independent of other variables in each occurrence, and is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Compounds of, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers of.

[0328] Embodiment II-7. R 2 A compound of Embodiment II-5 or II-6, wherein -NH2.

[0329] Embodiment II-8. One of the compounds from Embodiments II-1 to II-2 and II-5 to II-7, wherein A is a cycloalkyl compound.

[0330] Embodiment II-9. One of the compounds from Embodiments II-1 to II-2 and II-5 to II-7, wherein A is a heterocycloalkyl compound.

[0331] Embodiment II-10. One of the compounds from Embodiments II-1 to II-2 and II-5 to II-7, wherein A is an aryl compound.

[0332] Embodiment II-11. One of the compounds from Embodiments II-1 to II-2 and II-5 to II-7, wherein A is a heteroaryl compound.

[0333] Embodiment II-12. A compound from any one of Embodiments II-1 to II-7, wherein A is pyridinyl.

[0334] Embodiment II-13. One compound from Embodiments II-1 to II-12, wherein n is 1 or 2.

[0335] Embodiment II-14. R 1 Independently, in each appearance, -C1~C6 alkyl, halogen or -NR 5 R 6 The compound is one of any two embodiments II-1 to II-13.

[0336] Embodiment II-15. R 1 However, one compound from any of Embodiments II-1 to II-13, independently selected from methyl, fluoro, chloro, and -NH2.

[0337] Embodiment II-16. Y 1Embodiments II-1 to II-2 and II- One of the compounds from 5 to II-15.

[0338] Embodiment II-17. Y 1 Embodiments II-1 to II-2 and II are direct connections. One of the compounds from -5 to II-15.

[0339] Embodiment II-18. R 2 ga-OR b The compound is one of any two embodiments II-1 to II-6 and II-8 to II-17.

[0340] Embodiment II-19. R b The compound of Embodiment 18, wherein is -H.

[0341] Embodiment II-20. R b The compound of Embodiment 18, wherein the element is C1-C6 alkyl.

[0342] Embodiment II-21. R 2 Embodiments II-1 to II-6 and II- One of the compounds from 8 to II-17.

[0343] Embodiment II-22. R 2 Embodiments II-1 to II-6, where is C1-C6 alkyl. and one of the compounds II-8 to II-17.

[0344] Embodiment II-23. R 2 The compound of Embodiment II-22, wherein is methyl.

[0345] Embodiment II-24. R 2 Embodiments II-1 to II- are C2-C6 alkenyls. Compound 6 and one of the compounds II-8 to II-17.

[0346] Embodiment II-25. R 2Embodiments II-1 to II- Compound 6 and one of the compounds II-8 to II-17.

[0347] Embodiment II-26. R 4 However, one of the compounds from Embodiments II-1 to II-4 and II-6 to II-25, which is a -C1 to C6 alkyl that is optionally substituted with one or more -OH, -NH2, halogen or oxo groups.

[0348] Embodiment II-27. R 4 However, it is a -C1~C6 alkyl group that is substituted with -OH. Compound of application form II-26.

[0349] Embodiment II-28. R 4 The compound of Embodiment II-26, wherein -CH2-OH.

[0350] Embodiment II-29. R 4 Embodiments II-1 to II-4 and II-6 where -H One of the compounds from ~II-25.

[0351] Embodiment II-30. R 4 Embodiments II-1 to II-4 and II- One of the compounds from 6 to II-25.

[0352] Embodiment II-31. R 4 A compound from any one of embodiments II-1 to II-4 and II-6 to II-25, wherein is -CF2OH or -CHFOH.

[0353] Embodiment II-32. Y 2 ga-NR a -A compound which is one of embodiments II-1 to II-2 and II-7 to II-31.

[0354] Embodiment II-33. Y 2 ga-(CR a2) m -A compound which is one of embodiments II-1 to II-2 and II-7 to II-31.

[0355] Embodiment II-34. R 3 However, one or more -C1~C6 alkyl, -OH, - NH2, -OR b , -NHR b ,-(CH2) n OH, heterocyclyl, or spiroheterosyl A compound from any one of embodiments II-1 to II-2, II-5, and II-7 to II-33, which is a -C1 to C6 alkyl group optionally substituted with kyl.

[0356] Embodiment II-35. R a Embodiments II-1 to II-2, II-5, and o are -H. and one of the compounds II-7 to II-34.

[0357] Embodiment II-36. R 3 These are monocyclic or polycyclic complex rings with 3 to 12 members. One compound from among application forms II-1 to II-2, II-5, II-7 to II-33, and II-35.

[0358] Embodiment II-37. R 3 Embodiment II-1 is a monocyclic heteroring with 3 to 12 members. One of the following compounds: ~II-2, II-5, II-7~II-33, and II-35.

[0359] Embodiment II-38. R 3 Embodiment II-1 is a polycyclic heteroring having 3 to 12 members. One of the following compounds: ~II-2, II-5~II-33, and II-35.

[0360] Embodiment II-39. R 3 and R aHowever, when combined with the atoms to which they are attached, they form -C1~C6 alkyl, -OH, -NH2, heteroaryl, heterocyclic Lil, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COO R b , -NHCOOR b , may be replaced by -CF3, -CHF2, or -CH2F. A compound from any one of embodiments II-1 to II-4 and II-7 to II-33 that forms a monocyclic heterocycle with 3 to 12 members.

[0361] Embodiment II-40. R 3 and R a However, when combined with the atoms to which they are attached, they form -C1~C6 alkyl, -OH, -NH2, heteroaryl, heterocyclic Lil, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COO R b , -NHCOOR b , may be replaced by -CF3, -CHF2, or -CH2F. A compound from any one of embodiments II-1 to II-4 and II-6 to II-33 that forms a polycyclic heterocycle with 3 to 12 members.

[0362] Embodiment II-41. R 3 and R a However, when combined with the atoms to which they are attached, they form -C1~C6 alkyl, -OH, -NH2, heteroaryl, heterocyclic Lil, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COO R b , -NHCOORb , may be replaced by -CF3, -CHF2, or -CH2F. A compound from any one of embodiments II-1 to II-4 and II-6 to II-33 that forms a 5- to 12-membered spiroheterocycle.

[0363] Embodiment II-42. R 3 and R a However, when combined with the atoms to which they are attached, they form -C1~C6 alkyl, -OH, -NH2, heteroaryl, heterocyclic Lil, -(CH2) n NH2, -COOR b -CONHR b -CONH(CH2) n COO R b , -NHCOOR b , may be replaced by -CF3, -CHF2, or -CH2F. A compound of Embodiment II-41 that forms a 10- to 12-membered spiroheterocycle.

[0364] Embodiment II-43. R a and R 4 However, any of the compounds of Embodiments II-1 to II-2, II-7 to II-25, II-32 to II-34, and II-36 to II-38, which, when combined with the atoms to which they are attached, form a monocyclic or polycyclic 3- to 12-membered cycloalkyl group.

[0365] Embodiment II-44. R a and R 4 However, any of the compounds of Embodiments II-1 to II-2, II-7 to II-25, II-32 to II-34, and II-36 to II-38, which, when combined with the atoms to which they are attached, form a monocyclic or polycyclic heterocycle of 3 to 12 members.

[0366] Embodiment II-45. A compound selected from the group consisting of compounds 1 to 41 and compounds A-1 to A-309, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof.

[0367] Embodiment II-46. A pharmaceutical composition comprising one compound from Embodiments II-1 to II-45, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, and a pharmaceutically acceptable carrier.

[0368] Embodiment II-47. A method for treating a disease associated with SHP2 modulation in a subject requiring such treatment, comprising administering an effective amount of any one compound from Embodiments II-1 to II-45, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, to the subject.

[0369] Embodiment II-48. The method of Embodiment II-47, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung, and colon.

[0370] Embodiment II-49. One compound from Embodiments II-1 to II-45, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use as a pharmaceutical.

[0371] Embodiment II-50. Any one compound from Embodiments II-1 to II-45, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use in treating or preventing diseases associated with SHP2 modulation.

[0372] Embodiment II-51. Use of any one compound from Embodiments II-1 to II-45, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, in the manufacture of a pharmaceutical product for treating or preventing a disease associated with SHP2 modulation.

[0373] Embodiment II-52. A method for treating a disease associated with SHP2 modulation in a subject requiring the use of the pharmaceutical composition of Embodiment II-48, comprising administering an effective amount of the composition to the subject.

[0374] Embodiment II-53. The method of Embodiment II-52, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung, and colon.

[0375] Embodiment II-54. A pharmaceutical composition of Embodiment II-48 for use as a pharmaceutical.

[0376] Embodiment II-55. A pharmaceutical composition of Embodiment II-48 for use in treating or preventing diseases associated with SHP2 modulation.

[0377] Embodiment II-56. Use of the pharmaceutical composition of Embodiment II-48 in the manufacture of a pharmaceutical for treating or preventing diseases associated with SHP2 modulation. [Examples]

[0378] The present disclosure is further illustrated by the following examples and synthesis examples, but these should not be construed as limiting the present disclosure in scope or spirit to the specific procedures described herein. The examples are provided to illustrate certain embodiments and are not intended to limit the scope of the present disclosure in any way. It should also be understood that various other embodiments, modifications, and equivalents thereof suggested to those skilled in the art may be used without departing from the spirit of the present disclosure and / or the appended claims.

[0379] The following are the definitions used in the following examples and elsewhere in this specification: CH2Cl2, DCM: Methylene chloride, Dichloromethane CH3CN, MeCN acetonitrile CuI Copper(I) iodide DIPEA Diisopropylethylamine DMF (N,N-dimethylformamide) equiv equivalent ESI Electrospray Ionization HCl ethyl acetate hr time H2O (Water) HCl (hydrochloric acid) HPLC (High-Performance Liquid Chromatography) K3PO4 potassium phosphate (tribasic) LC-MS Liquid Chromatography-Mass Spectrometry MeOH methanol min Sodium sulfate (Na2SO4) NMP (N-methylpyrrolidone) NMR nuclear magnetic resonance Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]diq Lolopaladium(II) TLC (Thin-Layer Chromatography)

[0380] Examples 1-93 [Example 1] Synthesis of (R)-8-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-amine [ka]

[0381] Step 1. Synthesis of 5-chloro-2-((2,3-dichlorophenyl)thio)-3-methylpyrazine Under an inert atmosphere, at 20°C, 2,3-dichlorobenzenethiol (64.74 mg, 361.52 μmol, 1.5 equivalents), CuI (9.18 mg, 48.20 μmol, 0.2 equivalents), K3PO4 (102.32 mg, 482.02 μmol, 2 equivalents), and 1,10-phenanthroline (17.37 mg, 96.40 μmol, 0.4 equivalents) were sequentially added to a solution of 2-bromo-5-chloro-3-methylpyrazine (50 mg, 241.01 μmol, 1 equivalent) in dioxane (3 mL). The resulting mixture was stirred at 80°C for 0.5 hours. The reaction mixture was then cooled, and H2O (20 mL) was added to the solution. The aqueous phase was extracted with ethyl acetate (4 × 10 mL), the combined organic extract was washed with brine (2 × 10 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified to obtain 5-chloro-2-((2,3-dichlorophenyl)thio)-3-methylpyrazine (25.00 mg, yield 34%) as a pale yellow solid. LC-MS(ESI): m / z :C 11 The calculated [M+H] value for H7Cl3N2S is 304.94; the measured value is 305.0.

[0382] Step 2. Synthesis of N-((R)-8-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-yl)-2-methylpropane-2-sulfinamide Under an inert atmosphere, at 20°C, a solution of 5-chloro-2-((2,3-dichlorophenyl)thio)-3-methylpyrazine (25 mg, 81.80 μmol, 1 equivalent) and 2-methyl-N-((R)-8-azaspiro[4.5]decane-1-yl)propan-2-sulfinamide (42.28 mg, 163.61 μmol, 2 equivalents) in NMP (1 mL) was prepared by adding DIPEA (84.58 mg, 654.43 μmol, 114.30 μL, 8 equivalents). The mixture was then stirred at 120°C for 12 hours. The reaction mixture was then cooled, and H2O (20 mL) was added to the solution. The resulting aqueous phase was then converted to ethyl acetate (4 × 10 mL). Extracted with L). The combined organic extracts were washed with brine (2 x 10 mL) and anhydrous sodium 2 Dehydrate with SO4, filter, concentrate under reduced pressure to obtain crude N-((R)-8-(5-((2, 3-Dichlorophenyl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-yl)-2-methylpropane-2-sulfinamide (30 mg) was obtained as a dark brown solid and used directly in the next step without further purification. LC-MS(ESI):m / z:C 24 H 32 Cl2N4OS2's calculated [M+H] value: 527.14 Measured value: 527.1.

[0383] Step 3. Synthesis of (R)-8-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-amine Under an inert atmosphere, at 20°C, a solution of N-((R)-8-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-yl)-2-methylpropane-2-sulfinamide (30 mg, 56.86 μmol, 1 equivalent) in MeOH (1 mL) was added, and HCl (4 M, 3 mL) in MeOH was added. The resulting mixture was stirred at 20°C for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain the crude product. This crude residue was purified by preparative HPLC to obtain (R)-8-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-amine (7.01 mg, yield 29.12%) as a solid. 1 H NMR (400 MHz, methanol-d4) δ 8.12 (br s, 1 H), 7.34 (d, J = 7.72 Hz, 1 H), 7.12 (t, J = 7.94 Hz, 1 H), 6.69 (d, J = 7.72 Hz, 1 H), 4.45-4.27 (m, 2 H), 3.27-3.14 (m, 3H), 2.44 (s, 3H), 2.18-2.29 (m, 1H), 1.94-1.72 (m, 6H), 1.64-1.50 (m, 3H). LC-MS (ESI): m / z: [M + H] C 20 H 24 Calculated value of Cl2N4S: 423.11; Measured value: 423.1.

[0384] [Example 2] Synthesis of 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-amine [ka] 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-amine is 2-methyl-N-((R)-8-azaspiro[4.5]decane-1-yl)propane-2-sulfinamide tert-butyl(4- The synthesis was carried out in the same manner as in Example 1, except that it was replaced with methylpiperidine-4-yl)carbamate. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 4H), 7.48-7.46 (m, 1H), 7.26-7.22 (m, 1H), 6.75 (d, J = 8 Hz, 1H), 4.09-4.06 (m, 2H), 3.40 (m, 2H), 2.38 (s, 3H), 1.79-1.74 (m, 4H), 1.37 (s, 3H). LC-MS (ESI): m / z: [M + H] C 17 H 20 Calculation of Cl2N4S Value: 383.08; Measured value: 383.1.

[0385] [Example 3] Synthesis of 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-N,4-dimethylpiperidine-4-amine [ka]

[0386] Step 1. Synthesis of tert-butyl(1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-yl)(methyl)carbamate To a solution of tert-butyl(1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (150.00 mg, 310.27 μmol, 1.00 equivalent) in THF (5.00 mL), sodium hydride (12.41 mg, 310.27 μmol, 60% purity, 1 equivalent) was gradually added at 0°C under an inert atmosphere. The mixture was stirred at 0°C for 30 minutes, and then methyl iodide (44.04 mg, 310.27 μmol, 19.32 μL, 1 equivalent) was added dropwise at 0°C. The mixture was stirred at 0°C for 1.5 hours, and then the reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the methylation product as a yellow solid (110.00 mg, crude). LC-MS(ESI): m / z: C 23 H 30 Calculated [M+H] value of Cl2N4O2S: 497.15; Measured value: 497.1;RT=1.12 minutes.

[0387] Step 2. Synthesis of 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-N,4-dimethylpiperidine-4-amine 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-N,4-dimethylpiperidine-4-amine was synthesized in the same manner as in Example 1, except that N-((R)-8-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-yl)-2-methylpropane-2-sulfinamide was replaced with tert-butyl(1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-yl)(methyl)carbamate. 1¹H NMR (400 MHz, chloroform-d) δ ppm 8.38 (s, 1 H), 7.93 (s, 1 H), 3.87 - 3.84 (m, 1 H), 3.56 - 3.44 (m, 1 H), 2.40 (s, 3 H), 1.74 (br d, J = 4.15 Hz, 1 H), 1.35 - 1.29 (m, 1 H). LC-MS (ESI): m / z: [M + H]C 18 H 22 Calculated value of Cl2N4S: 397.09; Measured value: 396.9.

[0388] [Example 4] Synthesis of 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-aminomethyl-4-methylpiperidine [ka] 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-aminomethyl-4-methylpiperidine was synthesized in the same manner as in Example 1, except that 2-methyl-N-((R)-8-azaspiro[4.5]decane-1-yl)propan-2-sulfinamide was replaced with tert-butyl((4-methylpiperidine-4-yl)methyl)carbamate. After HPLC purification, 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-aminomethyl-4-methylpiperidine was isolated as its formate. 1 H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.22 (d, J = 0.7 Hz, 1H), 7.46 (dd, J = 8.0, 1.4 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.72 (dd, J = 8.0, 1.4 Hz, 1H), 3.89 (dt, J = 13.5, 5.0 Hz, 2H), 3.40 (ddd, J = 13.3, 9.6, 3.5 Hz, 2H), 2.57 (s, 2H), 2.38 (s, 3H), 1.49 (ddd, J = 13.7, 9.6, 4.1 Hz, 2H), 1.36 (dt, J = 13.5, 4.5 Hz, 2H), 1.00 (s, 3H). LC-MS (ESI): m / z: [M + H] C 18 H 22 Calculated value of Cl2N4S: 397.09; Measured value: 397.39.

[0389] [Example 5] Synthesis of (1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-(pyridine-3-yl)piperidine-4-yl)methanamine [ka]

[0390] Synthesis of 4-(pyridine-3-yl)piperidine-4-carbonitrile [ka] Synthesis of 4-(pyridine-3-yl)piperidine-4-carbonitrile To a mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (500 mg, 2.3 mmol, 1 equivalent) and 3-chloropyridine (405 mg, 3.5 mmol, 340 μL, 1.5 equivalents) in toluene (10 mL), LiHMDS (1 M, 7.1 mL, 3 equivalents) and Pd(t-Bu3P)2 (243 mg, 476 μmol, 0.2 equivalents) were added all at once under an inert atmosphere at 25°C. The mixture was stirred at 25°C for 2 hours, then heated to 90°C for 15 hours. The reaction mixture was then poured into H2O (5 mL), and the aqueous phase was converted to vinegar. Extraction was performed with ethyl acid (3 × 10 mL). The combined organic phase was washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain tert-butyl 4-cyano-4-(pyridine-3-yl) Peridine-1-carboxylate (180 mg, 626 μmol, yield 26%) was obtained as a yellow oily substance. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.64 (br s, 1H), 8.51 (br d, J = 3.53 Hz, 1H), 7.69 (br d, J = 7.94 Hz, 1H), 7.25 (dd, J = 7.94, 4.85 Hz, 1H), 7.14 (s, 1H), 4.32 - 4.11 (m, 2H), 3.09 (br s, 2H), 2.01 (br d, J = 12.8 Hz, 2H), 1.91 - 1.79 (m, 3H), 1.37 (s, 9H), 1.36 - 1.32 (m, 2H), 1.15 - 1.12 (m, 1H), 1.09 (s, 1H). Deprotection with HCl (4N, dioxane) results in 4-(pyridine-3). -yl)piperidine-4-carbonilicate hydrochloride was produced and used in the next step without further purification.

[0391] Step 1. Synthesis of 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-(pyridine-3-yl)piperidine-4-carbonitrile To a mixture of 4-(pyridine-3-yl)piperidine-4-carbonitride hydrochloride (108 mg, 356 μmol, 1 equivalent) in DIEA (4 mL), 5-chloro-2-((2,3-dichlorophenyl)thio)-3-methylpyrazine (80 mg, 427 μmol, 1.2 equivalents) was added under an inert atmosphere at 120°C. After stirring the mixture at 120°C for 15 hours, it was poured into H2O (5 mL), and the aqueous phase was then extracted with ethyl acetate (3 × 5 mL). The combined organic extracts were washed with brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-(pyridine-3-yl)piperidine-4-carbonitrile (60 mg, 131 μmol, yield 37%) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.80 (d, J = 2.19 Hz, 1H), 8.65 (d, J = 4.82 Hz, 1H), 8.07 (s, 1H), 7.85 (dd, J = 8.11, 1.53 Hz, 1H), 7.40 (dd, J = 7.89, 4.82 Hz, 1H), 7.30 (dd, J = 8.33, 1.32 Hz, 1H), 7.06 (t, J = 8.11 Hz, 1H), 6.83 - 6.78 (m, 1H), 5.31 (s, 1H), 4.62 (br d, J = 14.03 Hz, 2H), 3.44 (br t, J = 13.15 Hz, 2H), 2.53 (s, 3H), 2.31 (br d, J = 12.28 Hz, 2H), 2.19 - 2.09 (m, 2H).

[0392] Step 2. Synthesis of tert-butyl((1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-(pyridine-3-yl)piperidine-4-yl)methyl)carbamate To a solution of 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-(pyridine-3-yl)piperidine-4-carbonitrile (60 mg, 131 μmol, 1 equivalent) in THF (5 mL), lithium aluminum hydride (30 mg, 788 μmol, 6 equivalents) was added all at once at 0°C under an inert atmosphere. After stirring the mixture at 0°C for 2 hours, H2O (0.1 mL) was added dropwise to the reaction mixture to obtain a turbid liquid. Obtained. Next, this mixture was diluted with THF (10 mL), and then Boc2O (85 mg, 391 μmol (90 μL, 3 equivalents) was added under N2 conditions at 25°C. The mixture was then incubated at 25°C for 2 hours. After stirring for a period of time, the mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography to obtain tert-butyl((1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-(pyridine-3-yl)piperidine-4-yl)methyl)carbamate (27 mg, 51 μmol, yield 39%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.73 - 8.46 (m, 2H), 8.00 (s, 1H), 7.71 (br d, J = 6.58 Hz, 1H), 7.38 (br s, 1H), 7.25 (br d, J = 8.33 Hz, 1H), 7.01 (t, J = 7.89 Hz, 1H), 6.67 (d, J = 7.89 Hz, 1H), 4.31 (br s, 1H), 3.97 (br s, 2H), 3.41 (br d, J = 5.26 Hz, 3H), 2.47 (s, 3H), 2.25 (br s, 2H), 2.00 (br s, 2H), 1.40 (s, 9H), 1.31 - 1.23 (m, 1H).

[0393] Step 3. Synthesis of (1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-(pyridine-3-yl)piperidine-4-yl)methanamine (1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-(pyridine-3-yl)piperidine-4-yl)methanamine was synthesized in the same manner as in Example 1. 1 ¹H NMR (400 MHz, methanol-d4) δ 8.72 (s, 1 H), 8.56 (d, J = 4.63 Hz, 1H), 8.49 (br s, 1H), 8.08 (s, 1H), 8.03 (br d, J = 8.16 Hz, 1H), 7.56 (dd, J = 7.94, 4.85 Hz, 1H), 7.34 (d, J = 7.94 Hz, 1H), 7.11 (t, J = 8.05 Hz, 1H), 6.67 (d, J = 7.72 Hz, 1H), 4.16 (br d, J = 13.45 Hz, 2H), 3.35 - 3.33 (m, 1H), 3.28 (br s, 1H), 3.23 (s, 2H), 2.44 (s, 5H), 2.01 (br t, J = 10.14 Hz, 2H). LC-MS (ESI): m / z: [M + H] C 22 H 23 Calculated value for Cl2N5S: 460.11; Measured value: 459.9.

[0394] [Example 6] Synthesis of (R)-8-(5-((2-amino-3-chloropyridine-4-yl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-amine [ka]

[0395] Step 1. Synthesis of 4-bromo-3-chloropyridine-2-amine Three separate batches of 4-bromo-3-chloro-2-fluoropyridine (3 × 8.00 g, 3 × 38.02 mmol, 3 × 1 equivalent) and NH3·H2O (3 × 60 mL) were stirred at 120°C for 2 hours. The three batches were then combined and concentrated to reduce the volume of the solution. The aqueous phase was then extracted with dichloromethane (3 × 50 mL), the combined organic extract was washed with brine (2 × 50 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated to obtain 4-bromo-3-chloropyridine-2-amine (22.06 g, 106.33 mmol, 93% yield) as a white solid. 1¹H NMR (400 MHz, chloroform-d) δ 7.76 (d, J) = 5.26 Hz, 1H), 6.91 (d, J = 5.26 Hz, 1H), 5.06 (br, 2H).

[0396] Step 2. Synthesis of 2-ethylhexyl 3-((2-amino-3-chloropyridine-4-yl)thio)propanoate To a solution of 4-bromo-3-chloropyridine-2-amine (5 g, 24.1 mmol, 1 equivalent) in dioxane (50 mL), 2-ethylhexyl 3-sulfanylpropanoate (5.2 g, 24.1 mmol, 1 equivalent), xanthophos (1.3 g, 2.4 mmol, 0.1 equivalent), Pd2(dba)3 (831 mg, 1.4 mmol, 0.06 equivalents), and DIPEA (8.4 mL, 48.2 mmol, 2 equivalents) were added at 20°C. The mixture was then heated to 110°C and stirred under an inert atmosphere for 5 hours. After this, the reaction product was diluted with H2O. The mixture was separated, and the aqueous phase was extracted with dichloromethane (3 × 50 mL). The combined organic extracts were washed with brine (2 × 50 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated. The reaction mixture was stirred and then filtered to obtain 2-ethylhexyl 3-((2-amino-3-chloropyridine-4-yl)thio)propanoate (5 g, 14.7 mmol, yield 61%) as a pale green solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.85 (d, J = 5.51 Hz, 1H), 6.50 (d, J = 5.51 Hz, 1H), 4.84 (br s, 1H), 4.03 (dd, J = 5.84, 1.21 Hz, 2H), 3.20 (t, J = 7.50 Hz, 2H), 2.71 (t, J = 7.39 Hz, 2H), 1.66 - 1.51 (m, 3H), 1.45-1.31 (m, 2H), 1.27 (br s, 5H), 0.87 (t, J = 7.39 Hz, 6H).

[0397] Step 3. Synthesis of 2-amino-3-chloropyridine-4-thiol Under an inert atmosphere, at -78°C, potassium tert-butoxide (1M in THF, 29 mL, 29 mmol, 2 equivalents) was added to a solution of 2-ethylhexyl 3-((2-amino-3-chloropyridine-4-yl)thio)propanoate (5 g, 14.5 mmol, 1 equivalent) in THF (50 mL). The reaction mixture was stirred at -78°C for 1 hour, and then the reaction mixture was filtered and concentrated. The crude residue was purified by silica gel column chromatography to obtain 2-amino-3-chloropyridine-4-thiol (1.9 g, 11.8 mmol, yield 81%) as a yellow solid.

[0398] Step 4. Synthesis of 3-chloro-4-((5-chloro-3-methylpyrazine-2-yl)thio)pyridine-2-amine Under an inert atmosphere, DIEA (8.08 mL, 46.2 mmol, 2 equivalents), 2-bromo-5-chloro-3-methylpyrazine (4.80 g, 23.1 mmol, 1 equivalent), xanthophos (1.34 g, 2.31 mmol, 0.1 equivalent), and Pd2(dba)3 (1.69 g, 1.85 mmol, 0.08 equivalents) were added to a solution of 2-amino-3-chloropyridine-4-thiol (4.09 g, 25.4 mmol, 1.1 equivalent) in dioxane (25 mL). The reaction mixture was stirred at 80°C for 1 hour, and then concentrated. The residue was purified by silica gel column chromatography to obtain 3-chloro-4-((5-chloro-3-methylpyrazine-2-yl)thio)pyridine-2-amine (3.20 g, 11.1 mmol, yield 48%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.23 ​​(s, 1H), 7.82 (d, J = 5.29 Hz, 1H), 6.44 (d, J = 5.29 Hz, 1H), 4.93 (br s, 2H), 2.56 (s, 3H).

[0399] Step 5. Synthesis of (R)-N-((R)-8-(5-((2-amino-3-chloropyridine-4-yl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-yl)-2-methylpropane-2-sulfinamide (R)-2-methyl-N-((R)-8-azaspiro[4.5]decane-1-yl)propan-2-sulfinamide (1.01 g, 3.92 mmol, 1.5 equivalents) was added to a solution of 3-chloro-4-((5-chloro-3-methylpyrazine-2-yl)thiopyridine-2-amine (750 mg, 2.61 mmol, 1 equivalent) in DIEA (9.00 mL) and NMP (3.00 mL). The reaction mixture was stirred at 100°C for 2 hours, and then the reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain (R)-N-((R)-8-(5-((2-amino-3-chloropyridine-4-yl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-yl)-2-methylpropane-2-sulfinamide (750 mg, 1.47 mmol, yield 56%) as a solid.

[0400] Step 6. Synthesis of (R)-8-(5-((2-amino-3-chloropyridine-4-yl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-amine A mixture of (R)-N-((R)-8-(5-((2-amino-3-chloropyridine-4-yl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-yl)-2-methylpropane-2-sulfinamide (1.00 g, 1.96 mmol, 1 equivalent) in HCl / MeOH (10 mL) was stirred at 20°C for 1 hour, and the reaction mixture was then concentrated under reduced pressure. The residue was purified by HPLC to obtain (R)-8-(5-((2-amino-3-chloropyridine-4-yl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-amine (350 mg, 864 μmol, yield 44%) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.03 (s, 1H), 7.62 (d, J = 5.51 Hz, 1H), 5.88 (d, J = 5.51 Hz, 1H), 5.14 (br s, 2H), 4.24 (br t, J = 14.33 Hz, 2H), 3.13 (br s, 2H), 2.98 (br s, 1H), 2.44 (s, 3H), 1.26 - 1.92 (m, 10H). LC-MS (ESI): m / z: [M + H] C 19 H 25 Calculated value for Cl2N6S: 405.15; Measured value: 405.0.

[0401] [Example 7] Synthesis of 4-((5-(4-amino-4-methylpiperidine-1-yl)-3-methylpyrazine-2-yl)thio)-3-chloropyridine-2-amine [ka] 4-((5-(4-amino-4-methylpiperidine-1-yl)-3-methylpyrazine-2-yl)thio)-3-chloropyridine-2-amine was synthesized in the same manner as in Example 6, except that (R)-2-methyl-N-((R)-8-azaspiro[4.5]decane-1-yl)propan-2-sulfinamide was replaced with 4-methylpiperidine-4-amine. 1 H NMR (400 MHz, methanol-d4) δ 8.52 (s, 1H), 8.18 (s, 1H), 7.57 (d, J = 5.70 Hz, 1H), 5.78 (d, J = 5.70 Hz, 1H), 4.31 - 4.15 (m, 2H), 3.60 - 3.40 (m, 2H), 2.46 (s, 3H), 1.97 - 1.79 (m, 4H), 1.49 (s, 3H). LC-MS (ESI): m / z: [M + H] C 16 H 21 Calculated value for ClN6S: 365.1; Measured value: 365.1.

[0402] N-(3-bromo-2-chlorophenyl)-2,2,2-trifluoroacetamide [ka] Under an inert atmosphere, at 0°C, a solution of 3-bromo-2-chloroaniline (8 g, 39 mmol, 1 equivalent) in DCM (80 mL) was mixed with triethylamine (16.11 mL, 116 mmol, 3 equivalents), followed by trifluoroacetic anhydride (8.1 mL, 58 mmol, 1.5 equivalents). The resulting mixture was then heated to 20°C and stirred for 2 hours. Afterward, the reaction mixture was quenched with H2O (100 mL) and extracted with DCM (3 × 150 mL). The combined organic extracts were washed with brine (140 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to obtain N-(3-bromo-2-chlorophenyl)-2,2,2-trifluoroacetamide (10 g, 33 mmol, yield 85%) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.48 (s, 1H) 8.34 - 8.31 (m, 1H) 7.53 - 7.51 (m, 1H) 7.26 - 7.21 (m, 1H).

[0403] [Example 8] Synthesis of (R)-8-(5-((3-amino-2-chlorophenyl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-amine [ka] (R)-8-(5-((3-amino-2-chlorophenyl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-amine was synthesized in the same manner as in Example 6, except that 4-bromo-3-chloropyridine-2-amine was replaced with N-(3-bromo-2-chlorophenyl)-2,2,2-trifluoroacetamide. 1 ¹H NMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 8.65 - 8.47 (m, 1H), 8.02 (s, 1H), 6.85 (t, J = 7.94 Hz, 1H), 6.64 (dd, J = 8.05, 1.43 Hz, 1H), 5.99 (dd, J = 7.72, 1.32 Hz, 1H), 4.42 - 4.19 (m, 2H), 3.20 - 3.04 (m, 2H), 2.41 (s, 2H), 2.22 - 2.13 (m, 1H), 2.04 - 2.34 (m, 8H). LC-MS (ESI): m / z: [M + H] C 20 H 26 Calculated value for ClN5S: 404.16; Measured value: 404.1.

[0404] [Example 9] Synthesis of 4-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)-3-methylpyrazine-2-yl)thio)-3-chloropyridine-2-amine [ka]

[0405] Step 1. Synthesis of tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate Under an inert atmosphere, at -78°C, LDA (2M in THF, 7.85mL, 1.1 equivalents) was added dropwise over 15 minutes to a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (3.00g, 14.2 mmol, 1 equivalent) in THF (60mL). The resulting yellow solution was stirred at -78°C for 30 minutes, after which iodomethane (1.33mL, 21.4 mmol, 1.5 equivalents) was added dropwise. The reaction mixture was stirred at -78°C for 30 minutes, then warmed to 25°C and stirred for 1 hour. After this, the reaction mixture was carefully poured into 100mL of ice water, and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (3 × 100mL). The combined organic extracts were washed with brine (5mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to obtain tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate (1.82 g, 8.11 mmol, yield 56%) as a white solid. 11H NMR (400 MHz, chloroform-d) δ 4.22 - 3.93 (m, 2H), 3.00 (br s, 2H), 1.85 (br d, J = 13.23 Hz, 2H), 1.47 - 1 0.31 (m, 14H).

[0406] Step 2. Synthesis of 4-methylpiperidine-4-carbonitride Under an inert atmosphere, tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate (1.82 g, 8.11 mmol, 1 equivalent) was added to a solution of HCl / siRNA (4 M, 20 mL) at 25°C. The mixture was stirred at 25°C for 3 hours, and then the reaction mixture was filtered and concentrated under reduced pressure to obtain 4-methylpiperidine-4-carbonitride (1.46 g, crude, HCl salt) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 3.45 (br d, J = 13.67 Hz, 2H), 3.16 (td, J = 13.34, 2.65 Hz, 2H), 2.19 (br d, J = 14.11 Hz, 2H), 1.74 - 1.86 (m, 2H), 1.46 (s, 3H).

[0407] Step 3. Synthesis of 1-(5-((2-amino-3-chloropyridine-4-yl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-carbonitrile A mixture of 4-methylpiperidine-4-carbonitride (200 mg, 696 μmol, 1 equivalent) and 3-chloro-4-((5-chloro-3-methylpyrazine-2-yl)thio)pyridine-2-amine (112 mg, 696 μmol, 1 equivalent) in DIPEA (2.00 mL) was stirred at 120°C for 2 hours under an inert atmosphere. The reaction mixture was then heated to H2 The mixture was poured into 5 mL of O and the aqueous phase was extracted with 3 × 5 mL of toluene. The combined organic extract was washed with brine (1 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The crude residue was then purified by column chromatography to obtain 1-(5-((2-amino-3-chloropyridine-4-yl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-carbonitrile (100 mg, 266 μmol, yield 38%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.05 (s, 1H), 7.67 (d, J = 5.29 Hz, 1H), 5.87 (d, J = 5.51 Hz, 1 H), 4.84 (br s, 2H), 4.43 (br d, J = 13.01 Hz, 2H), 3.26 (br t, J = 12.24 Hz, 2H), 2.47 (s, 3H), 2.07 (br s, 1H), 1.41 - 1.47 (m, 4H).

[0408] Step 4. Synthesis of 4-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)-3-methylpyrazine-2-yl)thio)-3-chloropyridine-2-amine Under an inert atmosphere, at -78°C, LAH (60.7 mg, 1.60 mmol, 6 equivalents) was added all at once to a mixture of 1-(5-((2-amino-3-chloropyridine-4-yl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-carbonitrile (100 mg, 266 μmol, 1.00 equivalent) in THF (2.60 mL). The mixture was stirred at 25°C for 2 hours. After this, H2O (0.1 mL) was added dropwise to the reaction mixture. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by HPLC to obtain 4-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)-3-methylpyrazine-2-yl)thio)-3-chloropyridine-2-amine (500 ug, 1.32 μmol, yield 0.49%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 8.11 (s, 1H), 7.56 (d, J = 5.51 Hz, 1H), 5.77 (d, J = 5.73 Hz, 1H), 4.58 (s, 2H), 4.09 (s, 2H), 3.47 (br s, 3H), 2.87 (s, 2H), 2.43 (s, 3H), 1.57 (br s, 4H), 1.27 (s, 1H), 1.17 (s, 3H).LC-MS (ESI): m / z: [M + H] C 17 H 24 Calculated value for ClN6S: 379.1; Measured value: 379.2.

[0409] [Example 10] Synthesis of (R)-8-(5-((2,3-difluorophenyl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-amine [ka] (R)-8-(5-((2,3-difluorophenyl)thio)-6-methylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-amine was synthesized in the same manner as in Example 1, except that 2,3-dichlorobenzenethiol was replaced with 2,3-difluorobenzenethiol. 1 ¹H NMR (400 MHz, methanol-d4) δ 8.52 - 8.50 (m, 2H), 7.98 (s, 2H), 7.19 - 7.17 (m, 1H), 7.15 - 7.13 (m, 1H), 7.07 - 7.04 (m, 1H), 4.32 - 4.24 (m, 2H), 3.19 - 3.14 (m, 2H), 2.46 (s, 3H), 2.32 - 2.23 (m, 1H), 1.88 - 1.32 (m, 10 H). LC-MS (ESI): m / z: [M + H] C 20 H 24 Calculated value for F2N4S: 391.17; Measured value: 391.0.

[0410] [Example 11] Synthesis of 1-(5-((2,3-difluorophenyl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-amine [ka] 1-(5-((2,3-difluorophenyl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-amine was synthesized in the same manner as in Example 1, except that 2,3-dichlorobenzenethiol and (R)-2-methyl-N-((R)-8-azaspiro[4.5]decane-1-yl)propane-2-sulfinamide were replaced with 2,3-difluorobenzenethiol and 4-methylpiperidine-4-amine, respectively. 1 H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 8.01 (s, 1H), 7.18 - 7.17 (m, 1H), 7.16 - 7.08 (m, 1H), 6.95 - 6.91 (m, 1H), 4.12 - 4.09 (m, 2H), 3.43 - 3.41 (m, 2H), 2.47 (s, 3H), 1.83 - 1.81 (m, 4H), 1.45 (s, 3H). LC-MS (ESI): m / z: [M + H] C 17 H 20 Calculated value for F2N4S: 351.14; Measured value: 351.2.

[0411] [Example 12] Synthesis of 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-amine [ka] 1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-amine is 4-bromo-3-chloropyridine-2-amine The compound was synthesized in the same manner as in Example 6, except that it was replaced with 2,3-dichloro-4-iodopyridine. 1¹H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 8.17 (s, 1H), 7.98 (d, J = 5.26 Hz, 1H), 6.54 (d, J = 5.26 Hz, 1H), 4.46 - 4.31 (m, 2H), 3.23 - 3.14 (m, 2H), 2.44 (s, 3H), 2.24 - 2.14 (m, 1H), 1.91 - 1.53 (m, 9H), LC-MS (ESI): m / z: [M + H]C 19 H 24 Calculated value for Cl2N5S: 424.11; Measured value: 424.1.

[0412] [Example 13] Synthesis of 5-(4-amino-4-methylpiperidine-1-yl)-N-(2,3-dichlorophenyl)-3-methylpyrazine-2-amine [ka]

[0413] Step 1. Synthesis of tert-butyl(1-(5-bromo-6-methylpyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate Under an inert atmosphere, a mixture of 2-bromo-5-chloro-3-methylpyrazine (300 mg, 1.5 mmol, 1 equivalent) and tert-butyl(4-methylpiperidine-4-yl)carbamate (373 mg, 1.7 mmol, 1.1 equivalents) in DMA (4 mL) was mixed with Cs2CO3 (945 mg, 2.9 mmol, 1.9 equivalents). The resulting mixture was heated to 70°C and stirred for 3 hours. The reaction mixture was then cooled and concentrated under reduced pressure. The crude residue was purified by preparative TLC to obtain tert-butyl(1-(5-bromo-6-methylpyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (90 mg, 234 μmol, yield 16%). 1¹H NMR (400 MHz, chloroform-d) δ values: 7.68 (s, 1H), 4.39 (br, s, 1H), 3.83 - 3.78 (m, 2H), 3.31 - 3.25 (m, 2H), 2.48 (s, 3H), 2.10 - 2.07 (m, 2H), 1.66 - 1.61 (m, 2H), 1.43 (s, 9H), 1.38 (s, 3H).

[0414] Step 2. Synthesis of tert-butyl(1-(5-((2,3-dichlorophenyl)amino)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate Under an inert atmosphere, at 20°C, tert-butyl (1-(5-bromo-6-methylpyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (45 mg, 117 μmol, 1 equivalent) was dissolved in toluene (1.5 mL) to which 2,3-dichloroaniline (21 μL, 175 μmol, 1.5 equivalents), sodium tert-butoxide (22.5 mg, 234 μmol, 2 equivalents), Pd2(dba)3 (10.7 mg, 11.7 μmol, 0.1 equivalent), and BINAP (14.5 mg, 23.4 μmol, 0.2 equivalents) were sequentially added. The resulting mixture was heated to 125°C by microwave for 1.5 hours. After this, the mixture was cooled, concentrated under reduced pressure, and the crude residue was purified by preparative TLC to obtain tert-butyl ( 1-(5-((2,3-dichlorophenyl)amino)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (50 mg, 107 μmol, yield 46%) was obtained as a yellow oily substance. LC-MS(ESI): m / z:C 22 H 29 Cl2N5O2 [M+H] Calculated value: 466.17; Measured value: 466.2.

[0415] Step 3. Synthesis of 5-(4-amino-4-methylpiperidine-1-yl)-N-(2,3-dichlorophenyl)-3-methylpyrazine-2-amine A solution of tert-butyl(1-(5-((2,3-dichlorophenyl)amino)-6-methylpyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (50 mg, 107 μmol, 1 equivalent) in TFA (1 mL) and DCM (1 mL) was stirred at 20°C for 2 hours. Afterward, the pH of the mixture was adjusted to pH=8 with saturated NaHCO3. The mixture was extracted with DCM (3 × 5 mL). The organic extract was washed with brine (5 mL), dehydrated with Na₂SO₄, filtered, and concentrated. The resulting crude residue was purified by preparative HPLC to obtain 5-(4-amino-4-methylpiperidine-1-yl)-N-(2,3-dichlorophenyl)-3-methylpyrazine-2-amine (6.5 mg, 15.8 μmol, yield 15%) as its formate. 1 H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H, HCOOH), 7.82 (s, 1H), 7.19 - 7.17 (m, 1H), 7.11 - 7.07 (m, 1H), 7.00 - 6.98 (m, 1H), 4.03 - 3.99 (m, 2H), 3.34 - 3.30 (m, 2H), 2.39 (s, 3H), 1.91 - 1.84 (m, 4H), 1.46 (s, 3H). LC-MS (ESI): m / z: [M + H] C 17 H 21 Calculated value of Cl2N5: 366.12; Measured value: 366.0.

[0416] [Example 14] Synthesis of (R)-8-(5-((2,3-dichlorophenyl)thio)-6-ethylpyrazine-2-yl)-8-azaspiro[4.5]decane-1-amine [ka]

[0417] Step 1. Synthesis of 6-chloro-3-((2,3-dichlorophenyl)thio)pyrazine-2-amine Under an inert atmosphere, at 20°C, a solution of 2,3-dichlorobenzenethiol (1.3 g, 7.2 mmol, 1.5 equivalents) and 3-bromo-6-chloropyrazine-2-amine (1 g, 4.8 mmol, 1 equivalent) in dioxane (10 mL) was prepared. K3PO4 (1.0 g, 4.8 mmol, 1 equivalent), 1,10-phenanthroline (86 mg, 480 μmol, 0.1 equivalent), and CuI (91 mg, 480 μmol, 0.1 equivalent) were added. The resulting mixture was heated to 130°C for 1.5 hours using microwave radiation, and then the reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to obtain 6-chloro-3-((2,3-dichlorophenyl)thio)pyrazine-2-amine (400 mg, 1.3 mmol, yield 27%) as a yellow solid.

[0418] Step 2. Synthesis of 5-chloro-2-((2,3-dichlorophenyl)thio)-3-iodopyrazine At 20°C, a solution of 6-chloro-3-((2,3-dichlorophenyl)thio)pyrazine-2-amine (800 mg, 2.6 mmol, 1 equivalent) in CH2I2 (15 mL) is prepared by adding I2( 795 mg (3.1 mmol, 1.2 equivalents) was added, followed by t-BuONO (1.2 mL, 10.4 mmol, 4 equivalents). The resulting mixture was stirred at 20°C for 3 hours. After this, the reaction product was quenched with saturated Na2SO3 aqueous solution (15 mL)...

Claims

1. Formula I-W7: 【Chemistry 1】 (In the formula: A is a monocyclic or polycyclic heteroaryl with 5 to 12 members; Y 1 It is a direct bond; Y 2 -NR a - and; here, Y 2 The bond on the left side is pyrazine, as depicted. It is bonded to the ring, Y 2 The joint on the right side of the section is R, as depicted. 3 It is coupled to; R 3 is combined with R a to form a monocyclic or polycyclic heterocyclic ring of 3 to 12 members or a spiro heterocyclic ring of 5 to 12 members, where each heterocyclic ring or spiro heterocyclic ring has one or more -C 1 ~C 6 alkyl, -OH, -NH 2 heteroaryl, heterocyclic Lil, - (CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COO R b ,-NHCOOR b , -CF 3 ,-CHF 2 or -CH 2 F may be replaced depending on the case. the law of nature; R 1 These are independent, and in each occurrence, -H and -C. 1 ~C 6 Alkyl, -OH, halogen, -NO 2 -CN, -NR 5 R 6 , -SR 5 , -C(O)R 5 or -CO 2 R 5 And; R 2 is, -C 1 ~C 6 It is alkyl; R b These are independent, and in each occurrence, -H or -C 1 ~C 6 It is alkyl; R 4 is -H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -C 1 ~C 6 hydroxy Alkyl, -CF 2 OH, -CHFOH, -C(O)NH(CH 2 ) n OH, -C(O)N H(CH) 2 ) n R b , -C(O)R b , -C(O)NR 5 R 6 Or -OH, where a Lukil is one or more -OH, -NH 2 , halogen or oxo, depending on the case It has been replaced; or R 5 and R 6 Each of these is independent, and in each occurrence, -H or -C 1 ~C 6 It is alkyl; n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 in each occurrence. However, the following compounds are excluded: 【Chemistry 2】 ) compounds, or pharmaceutically acceptable salts, solvates, hydrates, or stereoisomers thereof.

2. A is pyridinyl, the compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

3. R 1 These are independent, and in each occurrence, -C 1 ~C 6 Alkyl, halogen, or -NR 5 R 6 That is, A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

4. R 2 The compound according to any one of claims 1 to 3, or its pharmaceutically acceptable form, is -OH. A salt, solvate, hydrate, or stereoisomer that is permissible.

5. R 2 The compound according to any one of claims 1 to 3, or its pharmaceutically acceptable form, is methyl. A salt, solvate, hydrate, or stereoisomer that is permissible.

6. R 2 The compound according to any one of claims 1 to 3, or its pharmaceutically acceptable form, is -CN. A salt, solvate, hydrate, or stereoisomer that is permissible.

7. R 2 Ha-C 1 ~C 6 A compound according to any one of claims 1 to 3, which is alkyl, This refers to its pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer.

8. R 2 Ha-C 2 ~C 6 The compound according to any one of claims 1 to 3, which is an alkenyl, or its pharmaceutically acceptable salts, solvates, hydrates, or stereoisomers.

9. R 2 Ha-C 2 ~C 6 The compound according to any one of claims 1 to 3, which is an alkynyl, or its pharmaceutically acceptable salts, solvates, hydrates, or stereoisomers.

10. R 4 is one or more -OH, -NH 2 -C which may be substituted with halogen or oxo. 1 ~C 6 A compound according to any one of claims 1 to 9, which is alkyl, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

11. R 4 is -H, the compound according to any one of claims 1 to 9, or the pharmaceutically Acceptable salts, solvates, hydrates, or stereoisomers.

12. R 4 Ha-CF 2 A compound according to any one of claims 1 to 9, wherein the compound is OH or -CHFOH, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.

13. R 3 and R a They combine with the atoms to which they are attached, resulting in -C 1 ~C 6 Alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ), n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ), n COOR b , -NHCOOR b , -CF 3 , -CHF 2 or -CH 2 F, optionally substituted by a 3- to 12-membered monocyclic hetero A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, which forms a ring.

14. R 3 and R a They combine with the atoms to which they are attached, resulting in -C 1 ~C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b ,-NHCOOR b , -CF 3 ,-CHF 2 or -CH 2 Polycyclic complexes of 3 to 12 members that are sometimes substituted by F A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, which forms a ring.

15. R 3 and R a They combine with the atoms to which they are attached, resulting in -C 1 ~C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b ,-NHCOOR b , -CF 3 ,-CHF 2 or -CH 2 Five- to twelve-member spirocomplexes that are sometimes substituted with F A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, which forms a ring. 【Request Item 16】 【Chemistry 3】 A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, selected from the group consisting of the above. 【Request Item 17】 【Table 11】 Table 15 Table 16 Table 18 Table 19 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 28 A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, selected from the group consisting of the above. 【Request Item 18】 【Table 30】 Table 31 Table 32 Table 33 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 56 Table 57 A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, selected from the group consisting of the above.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition according to claim 19 for treating or preventing diseases related to SHP2 modulation.

21. The pharmaceutical composition according to claim 20, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung, and colon.

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