MASP-2 Inhibitor and Method of Use

Abstract

The present disclosure provides, inter alia, compounds having MASP-2 inhibitory activity, compositions of such compounds, and methods of making and using such compounds.

Description

Technical Field

[0001] Description of the Sequence Listing The sequence listing related to this application is provided in text format instead of a hard copy and is hereby incorporated by reference into this specification. The text file name containing the sequence listing is 700128_424WO_SEQUENCE_LISTING.txt. The text file is 6.0 KB, was created on December 3, 2020, and was electronically submitted via EFS-Web.

[0002] Technical Field The present disclosure generally aims at compositions and methods useful in the medical field. More specifically, the disclosure provides synthetic inhibitors of MASP-2 comprising inhibitors that selectively inhibit mannan-binding lectin-associated serine protease-2 (MASP-2) compared to thrombin, compositions thereof, and methods for their manufacture and use.

Background Art

[0003] Background The complement system is involved in the inflammatory response and is activated by tissue damage or microbial infection. To ensure the selective targeting of invading microorganisms and avoid self-damage, the activation of complement must be tightly regulated (Ricklin et al., Nat. Immunol. 11:785-797, 2010 (Non-Patent Document 1)). Currently, it is widely recognized that the complement system can be activated by three distinct pathways: the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway is usually triggered by a complex composed of host antibodies bound to a foreign substance (i.e., antigen) and usually requires prior exposure to the antigen for the generation of a specific antibody response. Since the activation of the classical pathway depends on the host's prior adaptive immune response, the classical pathway is part of the acquired immune system. In contrast, both the lectin and alternative pathways are independent of adaptive immunity and are part of the innate immune system.

[0004] Mannan-binding lectin-associated serine protease-2 (MASP-2) has been shown to be required for the function of the lectin pathway, which is one of the major complement activation pathways (Vorup-Jensen et al., J. Immunol 165:2093-2100, 2000 (Non-Patent Document 2); Ambrus et al., J Immunol. 170: 1374-1382, 2003 (Non-Patent Document 3); Schwaeble et al., PNAS 108:7523-7528, 2011 (Non-Patent Document 4)). Importantly, inhibition of MASP-2 does not seem to interfere with the antibody-dependent classical complement activation pathway, which is an important element of the acquired immune response to infection. As described in U.S. Patent No. 9,011,860 (Patent Document 1) (assigned to Omeros Corporation), which is incorporated herein by reference, fully humanized monoclonal antibodies targeting human MASP-2 that bind to human MASP-2 with high affinity and block lectin pathway complement activity have been generated and are thus useful for treating diseases and disorders associated with various lectin complement pathways.

[0005] MASP-2-dependent complement activation has been implicated in the etiology of numerous acute and chronic pathologies. Accordingly, there is a need for compounds suitable for the administration / treatment of subjects suffering from MASP-2 complement pathway-related diseases and disorders, including diseases that are not appropriately or efficiently treated with macromolecular biological inhibitors.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

[0008] Summary One aspect provides a compound having the following structure (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, TIFF0007699389000001.tif44128wherein R 1 , R 2 , R 3 , R 4 , R 5a , and L 1 are as defined below.

[0009] Another aspect provides a compound having the following structure (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, TIFF0007699389000002.tif37128wherein R 6 , R 7 , R 8 and R 9 are as defined below.

[0010] Another aspect provides a compound having the following structure (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, TIFF0007699389000003.tif32128wherein R 11 , R 12 , R 13 , and n are as defined below.

[0011] Another aspect provides a compound having the following structure (IV) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, TIFF0007699389000004.tif37128wherein R 14 , R 15 , and L 2 are as defined below.

[0012] A further aspect of the disclosure provides a pharmaceutical composition comprising a compound of structure (I), (II), (III), or (IV) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0013] The compounds of structures (I), (II), (III), and (IV) are useful in the treatment of MASP-2 related diseases and disorders and in the manufacture of a medicament for treating MASP-2 related diseases and disorders. Accordingly, another aspect of the disclosure provides a method of treating MASP-2 related diseases and disorders comprising administering to a patient a therapeutically effective amount of a compound of structure (I), (II), (III), or (IV) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0014] [The present invention 1001] A compound having the following structure (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007699389000005.tif44128 In the formula, R 1 is a substituted or unsubstituted heteroaryl; R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 3 is hydrogen or alkyl; R 4 is alkyl, a substituted or unsubstituted arylalkyl, or a heterocyclyl substituted with a substituent selected from the group consisting of a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridinyl, or R 3 and R 4 together with the nitrogen to which they are attached form an optionally substituted 4- to 10-membered heterocyclyl; R 5ais hydrogen or halo; L 1 is a direct bond, -CH 2 -, -S(O) t -, NR 5b , -O-, -C=C-, or -C≡C-; t is 0, 1, or 2; and R 5b is hydrogen, alkyl, haloalkyl, (C=O)alkyl, (C=O)Oalkyl, (C=O)cycloalkyl, (C=O)Ocycloalkyl, (C=O)aryl, (C=O)Oaryl, (C=O)heteroaryl, (C=O)Oheteroaryl, (C=O)heterocyclyl, (C=O)Oheterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted cycloalkylalkyl, or a substituted or unsubstituted heterocyclylalkyl, provided that However, A) R 2 does not have one of the following structures: TIFF0007699389000006.tif23128 ; B) R 1 does not have one of the following structures: TIFF0007699389000007.tif23140 ; and C) When R 2 is unsubstituted phenyl, R 1 does not have one of the following structures: TIFF0007699389000008.tif40130 . [The present invention 1002] R 1 The compound of the present invention 1001, wherein is a substituted or unsubstituted 5- to 10-membered heteroaryl. R 1 [The present invention 1003] The compound of the present invention 1001 or 1002, wherein R 1 is a substituted or unsubstituted pyridinyl, a substituted or unsubstituted pyrrolopyridinyl, or a substituted or unsubstituted benzimidazolyl. 1a 、R 1b 、R 1c 、R 1d [The present invention 1004] 1e is substituted with one or more of R 1a 、R 1b 、R1c 、R 1d and R 1e , where R 1~6 , and R 1~6 are each independently C 2~6 alkyl, C 2~6 deuterated alkyl, C 1~6 alkenyl, C alkynyl, halo, C haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(=NR a )NR b R c , C(=NOR a )NR b R c , C(=NOC(O)R a )NR b R c , C(=NR a )N(R b )C(O)OR c, N(R a )C(=NR b )NR c R d , S(O)R a , S(O)NR a R b , S(O) 2 R a , N(R a )S(O) 2 R b , S(O) 2 NR a R b , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, selected from the group consisting of, , where R a 、R b 、R c , and R d are, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, selected from the group consisting of, a compound of any one of 1001-1003 of the present invention. [1005 of the present invention] R 1a 、R 1b 、R 1c 、R 1d , or R 1e is, substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, when R 1a 、R 1b 、R 1c 、R 1d , or R 1e is halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(=NR e )NR f R g , NR e C(=NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O)2 R e , NR e S(O) 2 R f , S(O) 2 NR e R f optionally substituted with one or more substituents selected from the group consisting of oxo, , where R e 、R f 、R g , and R h are, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, selected from the group consisting of, a compound of 1004 of the present invention. [1006 of the present invention] R 1 has one of the following structures: TIFF0007699389000009.tif217149TIFF0007699389000010.tif218148TIFF0007699389000011.tif181147 a compound of any one of 1001-1005 of the present invention having one of. [1007 of the present invention] R 1a or R 1b is independently C 1~6 The compound of the present invention 1006 which is alkyl, amino, or halo. [The present invention 1008] R 1a or R 1b The compound of the present invention 1007 in which is methyl. [The present invention 1009] R 1aor R 1b The compound of the present invention 1007 in which is F, Cl, or Br. [The present invention 1010] R bonded to nitrogen 1a or R 1b each is C 1~6 The compound of the present invention 1008 which is alkyl. [The present invention 1011] R 1a or R 1b The compound of the present invention 1010 in which is methyl or ethyl. [The present invention 1012] R 1 is one of the following structures: TIFF0007699389000012.tif166144 The compound of any one of the present inventions 1001 - 1011 having one of them. [The present invention 1013] R 1 is one of the following structures: TIFF0007699389000013.tif140147TIFF0007699389000014.tif213146TIFF0007699389000015.tif110145 The compound of any one of the present inventions 1001 - 1011 having one of them. [The present invention 1014] R 1 is one of the following structures: TIFF0007699389000016.tif67135 The compound of any one of the present inventions 1001 - 1011 having one of them. [The present invention 1015] R 2 The compound of any one of the present inventions 1001 - 1014 which is substituted or unsubstituted 6 - 10 membered aryl. [The present invention 1016] R 2 The compound of any one of the present inventions 1001 - 1015 which is substituted or unsubstituted phenyl. [The present invention 1017] R 1 The compound of any one of the present inventions 1001 - 1016 which is unsubstituted phenyl. [The present invention 1018] R 2 is R 2a 、R 2b 、R 2c 、R 2d , or R 2e substituted with one or more of them, where R 2a 、R 2b 、R 2c 、R 2d , and R 2e are each independently C 1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(=NR a )NR b R c, C(=NOR a )NR b R c , C(=NOC(O)R a )NR b R c , C(=NR a )N(R b )C(O)OR c , N(R a )C(=NR b )NR c R d , S(O)R a , S(O)NR a R b , S(O) 2 R a , N(R a )S(O) 2 R b , S(O) 2 NR a R b , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5 - 10 membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4 - 10 membered heterocyclyl selected from the group consisting of, where R a 、R b 、R c , and R d are, each time they appear, independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl selected from the group consisting of any compound of the present invention from 1001 to 1016. [the present invention 1019] R 2a 、R 2b 、R 2c 、R 2d , or R 2e is substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 2a 、R 2b 、R 2c 、R 2d , or R 2e is halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(=NR e )NRf R g , NR e C(=NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O) 2 R e , NR e S(O) 2 R f , S(O) 2 NR e R f and may be substituted with one or more substituents selected from the group consisting of oxo, wherein R e 、R f 、R g , and R h are each independently, at each occurrence, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl selected from the group consisting of the compound of the present invention 1018. [the present invention 1020] R 2 has the following structure: TIFF0007699389000017.tif170145 any compound of the present invention from 1001 to 1019 having one of [the present invention 1021] R 2 is substituted or unsubstituted 5- to 10-membered heteroaryl, any compound of the present invention from 1001 to 1014. [the present invention 1022] R 2 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolopyridinyl, or substituted or unsubstituted benzimidazolyl, any compound of the present invention from 1001 to 1014 or 1021. [the present invention 1023] R 2 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted isoquinolinyl, or substituted or unsubstituted pyrazolyl, any compound of the present invention from 1001 to 1014 or 1021 to 1022. [the present invention 1024] R 1 A compound of any one of the compounds of the present invention 1001 to 1014 or 1021 to 1023, which is unsubstituted pyridinyl, unsubstituted pyrrolyl, unsubstituted pyrimidinyl, or unsubstituted isoquinolinyl. [The present invention 1025] R 2 is R 2a 、R 2b 、R 2c 、R 2d , or R 2e and is substituted with one or more of them, where R 2a 、R 2b 、R 2c 、R 2d , and R 2e are each independently C 1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)Rb , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(=NR a )NR b R c , C(=NOR a )NR b R c , C(=NOC(O)R a )NR b R c , C(=NR a )N(R b )C(O)OR c , N(R a )C(=NR b )NR c R d , S(O)R a , S(O)NR a R b , S(O) 2 R a , N(R a )S(O) 2 R b , S(O) 2 NR a R b , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, and is selected from the group consisting of, where R a 、Rb 、R c , and R d are each independently, at each occurrence, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, and is selected from the group consisting of, A compound of any one of the compounds of the present invention 1001 to 1014 or 1021 to 1023. [The present invention 1026] R 2a 、R 2b 、R 2c 、R 2d , or R 2e is substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, then R 2a 、R 2b 、R 2c 、R 2d , or R 2e may be substituted with one or more substituents selected from the group consisting of halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f, NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(=NR e )NR f R g , NR e C(=NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O) 2 R e , NR e S(O) 2 R f , S(O) 2 NR e R f and oxo, where R e 、R f 、R g , and R h is, each time it appears, independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, selected from the group consisting of: The compound of the present invention 1025. [The present invention 1027] R 2 has the following structure: TIFF0007699389000018.tif116141 One of the compounds of the present invention 1001 to 1014 having one of the following: [The present invention 1028] R 3 The compound of any one of the present invention 1001 to 1027, wherein is hydrogen. [The present invention 1029] R 3 The compound of any one of the present invention 1001 to 1027, wherein is methyl. [The present invention 1030] R 3 and R 4 The compound of any one of the present invention 1001 to 1027, which together with the nitrogen to which they are attached form an optionally substituted 4- to 10-membered heterocyclyl. [The present invention 1031] R 3 and R 4 The compound of the present invention 1030, which together with the nitrogen to which they are attached form an unsubstituted 4- to 6-membered heterocyclyl. [The present invention 1032] R 3 and R 4 The compound of the present invention 1030 or 1031, which together with the nitrogen to which they are attached form an unsubstituted 5-membered ring. [The present invention 1033] R 3 and R 4 The compound of any one of the present invention 1030 to 1032, which together with the nitrogen to which they are attached form an unsubstituted pyrrolidinyl ring. [The present invention 1034] R 3 and R 4 The compound of the present invention 1030 or 1031, which together with the nitrogen to which they are attached form an unsubstituted 6-membered ring. [The present invention 1035] R 3 and R 4 The compound of any one of the present invention 1001 to 1013, which together with the nitrogen to which they are attached form one of the following structures: TIFF0007699389000019.tif51128 One of the following: [The present invention 1036] R 4is methyl or has one of the following structures: TIFF0007699389000020.tif29129 One of the compounds of the present invention 1001 to 1029 having one of the following: [The present invention 1037] R 4 The compound of any one of the present invention 1001 to 1029, which is a substituted or unsubstituted arylalkyl. [The present invention 1038] R 4 has the following structure: TIFF0007699389000021.tif218144TIFF0007699389000022.tif41141 One of the compounds of the present invention 1001 to 1029 having the following: [The present invention 1039] R 4 The compound of any one of the present invention 1001 to 1029, which is a heterocyclyl substituted with a substituent selected from the group consisting of substituted or unsubstituted phenyl or substituted or unsubstituted pyridinyl. [The present invention 1040] R 4 The compound of the present invention 1039, which is a 4- to 6-membered heterocyclyl ring. [The present invention 1041] R 4 A compound according to any one of the present inventions 1039 to 1040, which contains oxygen. [Present Invention 1042] R 4 has the following structure: TIFF0007699389000023.tif23128 A compound according to any one of the present inventions 1040 to 1041, which has one of the following: [Present Invention 1043] L 1 is a direct bond, -CH 2 -, or -C≡C-, a compound according to any one of the present inventions 1001 to 1042. [Present Invention 1044] L 1 is a direct bond, a compound according to any one of the present inventions 1001 to 1043. [Present Invention 1045] L 1 is -CH 2 ]-, a compound according to any one of the present inventions 1001 to 1043. [Present Invention 1046] L 1is -C≡C-, a compound according to any one of the present inventions 1001 to 1043. [Present Invention 1047] R 5a is hydrogen, a compound according to any one of the present inventions 1001 to 1046. [Present Invention 1048] R 5a is halo, a compound according to any one of the present inventions 1001 to 1046. [Present Invention 1049] R 5a is F, Br, or Cl, a compound according to any one of the present inventions 1001 to 1046. [Present Invention 1050] R 5a is Cl, a compound according to any one of the present inventions 1001 to 1046. [Present Invention 1051] A compound having the following structure (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007699389000024.tif37128 In the formula, R 6 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 7 is alkyl, -NR 10a R 10b , -SR 10c , a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R 8 is hydrogen, alkyl, haloalkyl, cycloalkyl, or a substituted or unsubstituted arylalkyl; R 9 is alkyl, a substituted or unsubstituted -S(O) 2 -arylalkyl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroarylalkyl, or R 8 and R 9 together with the nitrogen to which they are attached form an optionally substituted 4- to 10-membered heterocyclyl; R 10a 、R 10b , and R 10c are each independently hydrogen, alkyl, haloalkyl, or cycloalkyl, provided that however, A) R 7 is unsubstituted phenyl, 3-((methylsulfonyl)amino)phenyl, 2-methylphenyl, 3-(dimethylamino)phenyl, 3-(methylamino)phenyl, 3-methylphenyl, 3-aminomethylphenyl, 3-aminophenyl, unsubstituted pyridinyl, 3-(methylamino)-2-thienyl, 3,4-diamino-2-thienyl, 3-((methylsulfonyl)amino)-2-thienyl, 3-amino-2-thienyl, 3-amino-5-(aminocarbonyl)phenyl, or has one of the following structures: TIFF0007699389000025.tif139148 When having one of the following, R 6 has the following structure: TIFF0007699389000026.tif21128 not having; and B) When R 7 is unsubstituted phenyl, R 6 has the following structure: TIFF0007699389000027.tif21128 not having. [The present invention 1052] R 6 The compound of the present invention 1051, wherein is substituted or unsubstituted aryl. [The present invention 1053] R 6 The compound of the present invention 1051 or 1052, wherein is substituted or unsubstituted C 6 ~C 10 aryl. [The present invention 1054] R 6 The compound of any one of the present inventions 1051 to 1053, wherein is substituted or unsubstituted phenyl. [The present invention 1055] R 6 The compound of any one of the present inventions 1051 to 1054, wherein is substituted phenyl. [The present invention 1056] R 6 is phenyl substituted with one or more of R 6a 、R 6b 、R 6c 、R 6d , or R 6e , where R 6a 、R 6b 、R 6c 、R 6d , and R 6e are each independently C 1~6 alkyl, C 1~6 deuterated alkyl, C2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(=NR a )NR b R c , C(=NOR a )NR b R c , C(=NOC(O)R a )NR b R c , C(=NR a )N(R b )C(O)OR c , N(R a )C(=NR b )NR c R d , S(O)R a, S(O)NR a R b , S(O) 2 R a , N(R a )S(O) 2 R b , S(O) 2 NR a R b , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, selected from the group consisting of, where R a 、R b 、R c , and R d are each independently, at each occurrence, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, Any compound of the present invention Nos. 1051 to 1055. [The present invention 1057] R 6a 、R 6b 、R 6c 、R 6d , or R 6e is substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 6a 、R 6b 、R 6c 、R 6d , or R 6e is halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(=NR e )NR f R g , NR e C(=NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O) 2 R e , NR e S(O) 2 R f , S(O) 2 NRe R f and may be substituted with one or more substituents selected from the group consisting of oxo, wherein R e 、R f 、R g , and R h are each independently, at each occurrence, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, The compound of the present invention 1056. [The present invention 1058] R 6 is phenyl substituted with at least one substituent selected from the group consisting of halo, haloalkyl, C(=NR a )NR b R c , alkyl, and 5- to 10-membered heteroaryl, any compound of the present invention Nos. 1051 to 1057. [The present invention 1059] R 6 is -C(=NH)NH 2 , chloro, fluoro, methyl, and TIFF0007699389000028.tif14128 , the compound of the present invention 1058 substituted with at least one substituent selected from the group consisting of. [The present invention 1060] R 6 has one of the following structures: TIFF0007699389000029.tif174145 , any compound of the present invention Nos. 1057 to 1059. [The present invention 1061] R 6 has one of the following structures: TIFF0007699389000030.tif103143 , any compound of the present invention Nos. 1051 to 1060. [The present invention 1062] R 6 is unsubstituted phenyl, any compound of the present invention Nos. 1051 to 1053. [The present invention 1063] R 6 is substituted or unsubstituted heteroaryl, the compound of the present invention 1051. [The present invention 1064] R 6 is substituted or unsubstituted 5- to 10-membered heteroaryl, the compound of the present invention 1051 or 1063. [The present invention 1065] R 6 is a compound of any one of the present invention 1051 or 1063 - 1064, which is a substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolopyridinyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted thienopyridinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted isoindolinyl, or substituted or unsubstituted benzothiazolyl. [The present invention 1066] R 6 is a heteroaryl substituted by one or more of R 6a 、R 6b 、R 6c 、R 6d , or R 6e , where R 6a 、R 6b 、R 6c 、R 6d , and R 6e are each independently C 1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NRa R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(=NR a )NR b R c , C(=NOR a )NR b R c , C(=NOC(O)R a )NR b R c , C(=NR a )N(R b )C(O)OR c , N(R a )C(=NR b )NR c R d , S(O)R a , S(O)NR a R b , S(O) 2 R a , N(R a )S(O) 2 R b , S(O) 2 NR a R b , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5 - 10 - membered heteroaryl, substituted or unsubstituted C3~10 cycloalkyl, and substituted or unsubstituted 4 - 10 - membered heterocyclyl, selected from the group consisting of where R a 、R b 、R c , and R d are each independently, at each occurrence, selected from the group consisting of hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl. is a compound of any one of the present invention 1051 or 1063 - 1065. [The present invention 1067] R 6a 、R 6b 、R 6c 、R 6d , or when R 6e is substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5 - 10 - membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4 - 10 - membered heterocyclyl, R 6a 、R 6b 、R 6c 、R 6d , or R 6e is halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR eR f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(=NR e )NR f R g , NR e C(=NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O) 2 R e , NR e S(O) 2 R f , S(O) 2 NR e R f and may be substituted with one or more substituents selected from the group consisting of oxo, wherein R e 、R f 、R g , and R h are each independently, at each occurrence, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, a compound of the present invention 1066. [The present invention 1068] R 6 has one of the following structures: TIFF0007699389000031.tif185149TIFF0007699389000032.tif225146TIFF0007699389000033.tif223148 A compound of any one of the present invention 1051 or 1063 - 1066 having one of them. [The present invention 1069] R 6a or R 6b is independently C 1~6 alkyl, C 1~6 deuterated alkyl, amino, or halo, a compound of the present invention 1068. [The present invention 1070] R 6a or R 6b is methyl, a compound of the present invention 1069. [The present invention 1071] R 6a or R 6b is F, Cl, or Br, a compound of the present invention 1069. [The present invention 1072] R 6a or R 6b each bonded to nitrogen is C 1~6 alkyl, a compound of the present invention 1070. [The present invention 1073] R 6a or R 6b is methyl or ethyl, a compound of the present invention 1072. [The present invention 1074] R 6 has one of the following structures: TIFF0007699389000034.tif142144 A compound of any one of the present invention 1051 or 1053 - 1067 having one of them. [The present invention 1075] R 6 has one of the following structures: TIFF0007699389000035.tif139147TIFF0007699389000036.tif219147TIFF0007699389000037.tif86137 A compound of any one of the present invention 1051 or 1063 - 1065 having one of them. [The present invention 1076] R 6 has one of the following structures: TIFF0007699389000038.tif95146 A compound of any one of the present invention 1051 or 1063 - 1065 having one of them. [The present invention 1077] R 7 is C 1 ~C 6 alkyl, a compound of any one of the present invention 1051 - 1076. [The present invention 1078] R 7 is methyl, a compound of the present invention 1077. [The present invention 1079] R 7 is -NR 10a R 10b or -SR 10c , a compound of any one of the present invention 1051 - 1076. [The present invention 1080] R 7 has one of the following structures: TIFF0007699389000039.tif11128 A compound of the present invention 1079 having one of them. [The present invention 1081] R 7 is substituted or unsubstituted aryl, a compound of any one of the present invention 1051 - 1076. [The present invention 1082] R 7 is unsubstituted phenyl, a compound of the present invention 1081. [The present invention 1083] R 8is hydrogen, C 1 ~C 6 alkyl, unsubstituted -S(O) 2 -arylalkyl, or unsubstituted arylalkyl, a compound of any one of the present invention 1051 - 1082. [The present invention 1084] R 8 is hydrogen, -CH 3 or has one of the following structures: TIFF0007699389000040.tif20128 The compound of the present invention 1083 having one of them. [The present invention 1085] R 9 The compound of any one of the present inventions 1051 to 1084, wherein is a substituted or unsubstituted arylalkyl. R 9 [The present invention 1086] The compound of the present invention 1085, wherein R 9 is an unsubstituted arylalkyl. TIFF0007699389000041.tif14128 [The present invention 1087] The compound of the present invention 1085 or 1086 having the following structure: R 9 [The present invention 1088] R 9 The compound of any one of the present inventions 1051 to 1087, wherein is a substituted or unsubstituted heteroarylalkyl. R 9 [The present invention 1089] TIFF0007699389000042.tif16128 The compound of the present invention 1088, wherein is an unsubstituted heteroarylalkyl. R 8 [The present invention 1090] 9 The compound of any one of the present inventions 1051 to 1082, wherein and R R 8 together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocyclyl. 9 [The present invention 1091] The compound of the present invention 1090 or 1091, wherein R 8 and R 9 together with the nitrogen to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocyclyl. TIFF0007699389000043.tif13128 [The present invention 1092] The compound of the present invention 1090 or 1091, wherein and R TIFF0007699389000044.tif32128 together with the nitrogen to which they are attached form one of the following structures: R 11 TIFF0007699389000045.tif40132 In the formula, R 12 has one of the following structures: R 13 is methyl, alkoxy, or halo; is a substituted or unsubstituted aryl; and n is 1 or 2, provided that TIFF0007699389000046.tif32128 the compound of structure (III) does not have the following structure: [The present invention 1094] R 11 The compound of the present invention 1094 having the following structure: TIFF0007699389000047.tif16128 [The present invention 1095] R 11 The compound of the present invention 1094 having the following structure: TIFF0007699389000048.tif17128 [The present invention 1096] R 12 The compound of any one of the present inventions 1094 to 1096, wherein is methyl. R12 [The present invention 1097] The compound of any one of the present inventions 1094 to 1096, wherein R 12 is halo or butoxy. [The present invention 1098] The compound of the present invention 1097, wherein is Br. [The present invention 1099] The compound of any one of the present inventions 1094 to 1099, wherein n is 1. [The present invention 1100] The compound of any one of the present inventions 1094 to 1099, wherein n is 2. [The present invention 1101] [The present invention 1102] R 13 A compound according to any one of inventions 1094 to 1099, wherein the compound is a substituted or unsubstituted phenyl. [Invention 1103] R 13 A compound according to invention 1102, wherein the compound is an unsubstituted phenyl. [Invention 1104] A compound having the following structure (IV) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007699389000049.tif37128 In the formula, R 14 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 15 is a substituted or unsubstituted arylalkyl or a substituted or unsubstituted heteroarylalkyl; L 2 is a direct bond, -C(=O), or -S(=O) t -; and t is 0, 1, or 2. [Invention 1105] R 14 A compound according to invention 1104, wherein the compound is a substituted or unsubstituted aryl. [Invention 1106] R 14 is a substituted or unsubstituted C 6 ~C 10 aryl, a compound according to invention 1104 or 1105. [Invention 1107] R 14 A compound according to any one of inventions 1104 to 1106, wherein the compound is a substituted or unsubstituted phenyl. [Invention 1108] R14 A compound according to any one of inventions 1104 to 1107, wherein the compound is a substituted phenyl. [Invention 1109] R 14 is phenyl substituted with one or more of R 14a 、R 14b 、R 14c 、R 14d , or R 14e , wherein R 14a 、R 14b 、R 14c 、R 14d , and R 14e are each independently C 1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(=NR a)NR b R c , C(=NOR a )NR b R c , C(=NOC(O)R a )NR b R c , C(=NR a )N(R b )C(O)OR c , N(R a )C(=NR b )NR c R d , S(O)R a , S(O)NR a R b , S(O) 2 R a , N(R a )S(O) 2 R b , S(O) 2 NR a R b , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, selected from the group consisting of, wherein R a 、R b 、R c , and R d are each independently, at each occurrence, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 Selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, a compound of any one of Compounds 1104 to 1108 of the present invention. [Compound 1110 of the present invention] R 14a 、R 14b 、R 14c 、R 14d , or R 14e is a substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 14a 、R 14b 、R 14c 、R 14d , or R 14e is halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(=NR e )NR f R g , NR e C(=NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O) 2 R e , NR e S(O) 2 R f , S(O) 2 NR e R f and may be substituted with one or more substituents selected from the group consisting of oxo, wherein R e 、R f 、R g , and R h are each independently, at each occurrence, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, a compound of Compound 1109 of the present invention. [Compound 1111 of the present invention] R 14 is phenyl substituted with at least one substituent selected from the group consisting of halo, alkyl, hydroxy, amino, and C(=NR a )NR b R c , a compound of any one of Compounds 1104 to 1110 of the present invention. [Compound 1112 of the present invention] R14 has one of the following structures: TIFF0007699389000050.tif178148 a compound of any one of Compounds 1109 to 1111 of the present invention. [Compound 1113 of the present invention] R 14 has one of the following structures: TIFF0007699389000051.tif105155 a compound of any one of Compounds 1104 to 1111 of the present invention. [Compound 1114 of the present invention] R 14 has one of the following structures: TIFF0007699389000052.tif22128 a compound of Compound 1109 of the present invention. [Compound 1115 of the present invention] R 14 is unsubstituted phenyl, a compound of any one of Compounds 1104 to 1109 of the present invention. [Compound 1116 of the present invention] R 14 is substituted or unsubstituted heteroaryl, a compound of Compound 1104 of the present invention. [Compound 1117 of the present invention] R 14 is substituted or unsubstituted 5- to 10-membered heteroaryl, a compound of Compound 1104 or 1116 of the present invention. [Compound 1118 of the present invention] R 14 is a compound of any one of the present invention 1104 or 1116 - 1117, which is a substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolopyridinyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted thienopyridinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted isoindolinyl, or substituted or unsubstituted benzothiazolyl. [The present invention 1119] R 14 is a heteroaryl substituted by one or more of R 14a 、R 14b 、R 14c 、R 14d , or R 14e , where R 14a 、R 14b 、R 14c 、R 14d , and R 14e are each independently C1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(=NR a )NR b R c , C(=NOR a )NR b R c , C(=NOC(O)R a )NR b R c , C(=NR a )N(R b )C(O)OR c , N(R a )C(=NR b )NR cR d , S(O)R a , S(O)NR a R b , S(O) 2 R a , N(R a )S(O) 2 R b , S(O) 2 NR a R b , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5 - 10 membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4 - 10 membered heterocyclyl, selected from the group consisting of where R a 、R b 、R c , and R d are each independently, when they appear, selected from the group consisting of hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl. is a compound of any one of the present invention 1104 or 1116 - 1118. [The present invention 1120] R 14a 、R 14b 、R 14c 、R 14d , or when R 14e is a substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5 - 10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4 - 10 membered heterocyclyl, R 14a 、R 14b 、R 14c 、R 14d , or R 14e is halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(=NR e )NR f R g , NR e C(=NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O) 2 R e , NR e S(O) 2 Rf , S(O) 2 NR e R f and may be substituted with one or more substituents selected from the group consisting of oxo, wherein R e 、R f 、R g , and R h are, each occurrence, independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, a compound of the present invention 1119. [The present invention 1121] R 14 has one of the following structures: TIFF0007699389000053.tif154145TIFF0007699389000054.tif211145TIFF0007699389000055.tif212145TIFF0007699389000056.tif78129 A compound of any one of the present invention 1104 or 1116 - 1120 having one of them. [The present invention 1122] R 14a or R 14b is independently C 1~6 alkyl, amino, or halo, a compound of the present invention 1121. [The present invention 1123] R 14a or R 14b is methyl, a compound of the present invention 1122. [The present invention 1124] R 14a or R 14b is F, Cl, or Br, a compound of the present invention 1122. [The present invention 1125] R 14a or R 14b each bonded to nitrogen is C 1~6 alkyl, a compound of the present invention 1122. [The present invention 1126] R 14a or R 14b is methyl or ethyl, a compound of the present invention 1125. [The present invention 1127] R 14 has one of the following structures: TIFF0007699389000057.tif151139 A compound of any one of the present invention 1104 or 1116 - 1118 having one of them. [The present invention 1128] R 14 has one of the following structures: TIFF0007699389000058.tif49140TIFF0007699389000059.tif216147TIFF0007699389000060.tif179145 A compound of any one of the present invention 1104 or 1116 - 1118 having one of them. [The present invention 1129] R 14 has one of the following structures: TIFF0007699389000061.tif95146 A compound of any one of the present invention 1104 or 1116 - 1118 having one of them. [The present invention 1130] R 15 is substituted or unsubstituted arylalkyl, a compound of any one of the present invention 1104 - 1129. [The present invention 1131] R 15 is unsubstituted arylalkyl, a compound of any one of the present invention 1104 - 1130. [The present invention 1132] R 15 has one of the following structures: TIFF0007699389000062.tif15128 A compound of any one of the present invention 1104 - 1131 having one of them. [The present invention 1133] R 15 is substituted or unsubstituted heteroarylalkyl, a compound of any one of the present invention 1104 - 1129. [The present invention 1134] R 15 is unsubstituted heteroarylalkyl, a compound of any one of the present invention 1104 - 1129 or 1133. [The present invention 1135] R 15 has one of the following structures: TIFF0007699389000063.tif30144 A compound of any one of the present invention 1104 - 1129 or 1133 - 1134 having one of them. [The present invention 1136] L 2 A compound according to any one of the present inventions 1104 to 1135, wherein [the relevant group] is a direct bond. [The present invention 1137] L 2 A compound according to any one of the present inventions 1104 to 1135, wherein [the relevant group] is -C(=O)-. [The present invention 1138] L 2 A compound according to any one of the present inventions 1104 to 1135, wherein [the relevant group] is -S(=O) 2 -. [The present invention 1139] L 2 A compound according to any one of the present inventions 1104 to 1135, wherein [the relevant group] is -S-. [The present invention 1140] L 2 A compound according to any one of the present inventions 1104 to 1135, wherein [the relevant group] is -S(O)-. [The present invention 1141] A compound having the structure found in Table 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. [The present invention 1142] A pharmaceutical composition comprising a compound according to any one of the present inventions 1001 to 1141 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. [The present invention 1143] A method for treating a MASP-2 related disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of the present inventions 1001 to 1141 or the pharmaceutical composition of the present invention 1142. [The present invention 1144] The method of the present invention 1143, wherein the compound is administered in an amount sufficient to inhibit MASP-2 dependent complement activation in the subject. [The present invention 1145] The method of the present invention 1143, wherein the subject is diagnosed as in need of treatment for a lectin complement related disease or disorder. [The present invention 1146] The method of the present invention 1143, wherein the disease or disorder is thrombotic microangiopathy (TMA), kidney disease, inflammatory reaction due to tissue or organ transplantation, ischemia-reperfusion injury, complications related to diabetes, cardiovascular disease or disorder, inflammatory gastrointestinal disorder, lung disorder, eye disease or disorder, disseminated intravascular coagulation, graft-versus-host disease, venous occlusion, diffuse alveolar hemorrhage, idiopathic pulmonary inflammatory syndrome, capillary leak syndrome, engraftment syndrome, fluid overload, or a combination thereof. [The present invention 1147] The method of the present invention 1143, wherein the disease or disorder is thrombotic microangiopathy (TMA), thrombotic thrombocytopenic purpura (TTP), refractory TTP, Upshaw - Schulman syndrome (USS), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), factor H - independent atypical hemolytic uremic syndrome, aHUS secondary to infection, plasma - therapy - resistant aHUS, TMA secondary to cancer, TMA secondary to chemotherapy, TMA secondary to transplantation, TMA associated with hematopoietic stem cell transplantation, or a combination thereof. [The present invention 1148] The method of the present invention 1143, wherein the disease or disorder is graft - versus - host disease. [The present invention 1149] The method of the present invention 1143, wherein the disease or disorder is diffuse alveolar hemorrhage (DAH). [The present invention 1150] The method of the present invention 1143, wherein the disease or disorder is veno - occlusive disease (VOD). [The present invention 1151] The method of the present invention 1143, wherein the disease or disorder is a renal disease. [The present invention 1152] The method of the present invention 1143, wherein the renal disease is mesangial proliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), post - infectious acute glomerulonephritis (post - streptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, pauci - immune necrotizing crescentic glomerulonephritis, lupus nephritis, Henoch - Schönlein purpura nephritis, IgA nephropathy, or a combination thereof. [The present invention 1153] The method of the present invention 1143, wherein the disease or disorder is renal fibrosis, proteinuria, or a combination thereof. [The present invention 1154] The method of the present invention 1143, wherein the disease or disorder is an inflammatory reaction resulting from tissue or solid organ transplantation. [The present invention 1155] The method of the present invention 1143, wherein the disease or disorder is ischemia - reperfusion injury (I / R). [The present invention 1156] The method of the present invention 1143, wherein the disease or disorder is a complication associated with non - obese diabetes, type 1 diabetes, a complication associated with type 2 (adult - onset) diabetes, or a combination thereof. [The present invention 1157] The method of the present invention 1143, wherein the disease or disorder is a cardiovascular disease or disorder. [The present invention 1158] The method of the present invention 1143, wherein the disease or disorder is an inflammatory gastrointestinal disorder. [The present invention 1159] The method of the present invention 1143, wherein the disease or disorder is a lung disorder. [The present invention 1160] The method of the present invention 1143, wherein the disease or disorder is an in vitro exposure - induced inflammatory reaction. [The present invention 1161] The method of the present invention 1160, further comprising the step of treating a subject undergoing extracorporeal circulation technique. [The present invention 1162] The method of the present invention 1143, wherein the disease or disorder is inflammatory arthritis, non-inflammatory arthritis, musculoskeletal disorder, or a combination thereof. [The present invention 1163] The method of the present invention 1143, wherein the disease or disorder is a skin disorder. [The present invention 1164] The method of the present invention 1143, wherein the disease or disorder is a peripheral nervous system (PNS) disorder or injury, a central nervous system (CNS) disorder or injury, or a combination thereof. [The present invention 1165] The method of the present invention 1143, wherein the disease or disorder is sepsis or a condition resulting from sepsis. [The present invention 1166] The method of the present invention 1143, wherein the disease or disorder is a urogenital disorder. [The present invention 1167] The method of the present invention 1143, wherein the disease or disorder is an inflammatory response in a subject being treated with a chemotherapeutic agent, radiation therapy, or a combination thereof. [The present invention 1168] The method of the present invention 1143, wherein the disease or disorder is an angiogenesis-dependent cancer. [The present invention 1169] The method of the present invention 1143, wherein the disease or disorder is an angiogenesis-dependent benign tumor. [The present invention 1170] The method of the present invention 1143, wherein the disease or disorder is an endocrine disorder. [The present invention 1171] The method of the present invention 1143, wherein the disease or disorder is an eye disease or disorder. [The present invention 1172] The method of the present invention 1143, wherein the disease or disorder is an ocular angiogenesis disease or condition. [The present invention 1173] The method of the present invention 1143, wherein the disease or disorder is disseminated intravascular coagulation (DIC), complement-mediated coagulation disorder, or a combination thereof. [The present invention 1174] The method of the present invention 1143, wherein the disease or disorder is acute radiation syndrome, dense deposit disease, Degos disease, catastrophic antiphospholipid antibody syndrome (CAPS), Behçet's disease, cryoglobulinemia; paroxysmal nocturnal hemoglobinuria ("PNH"), cold agglutinin disease, or a combination thereof. [The present invention 1175] The method of the present invention 1143, wherein the disease or disorder is atypical hemolytic uremic syndrome (aHUS). [The present invention 1176] The method of the present invention 1143, wherein the disease or disorder is hematopoietic stem cell transplantation-related TMA. [The present invention 1177] The method of the present invention 1143, wherein the disease or disorder is immunoglobulin A nephropathy (IgAN). [The present invention 1178] The method of the present invention 1143, wherein the disease or disorder is lupus nephritis (LN). These and other aspects, objects, and embodiments will become more apparent upon reading the following detailed description and drawings. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description I. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the subject matter of this disclosure, the preferred methods and materials are described below. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0016] In certain aspects herein, reference is made to features and aspects of the disclosure that include steps of a method. All possible combinations of such features and aspects within an aspect of the disclosure are included, at least to the extent that such combinations are not inconsistent. For example, if an aspect shows aspects A, B, and C, this is understood to also disclose aspects that include both aspects A and B, both aspects B and C, and both aspects A and C, as well as an aspect having aspects A, B, and C.

[0017] The terms "a," "an," or "the" include aspects having one element as well as aspects having a plurality of elements. By way of example, the singular forms "a," "an," and "the" include a plurality of referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a cell" includes a plurality of such cells, and a reference to "the agent" includes a reference to one or more agents known to those of ordinary skill in the art.

[0018] The terms "about" and "approximately" refer to the degree of acceptable error for each measured quantity, taking into account the nature or accuracy of the measurement. A typical and illustrative degree of error is within ±20 percent (%) of a given value or range of values; preferably within ±10%; more preferably within ±5%. Any reference to "about X" specifically indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to teach and provide support for a claim limitation such as "0.98X", for example. Alternatively, in biological systems, the terms "about" and "approximately" may mean a value within one order of magnitude of a given value, preferably within five-fold, more preferably within two-fold. Quantities given herein are approximate unless otherwise specified, which means that the terms "about" or "approximately" are inferable when not explicitly stated. When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "about 5-20%" is equivalent to "about 5% to about 20%". When "about" is applied to the first value of a set of values, it applies to all values in that set. Thus, "about 7, 9, or 11 mg / kg" is equivalent to "about 7, about 9, or about 11 mg / kg".

[0019] The term "MASP-2" refers to mannan-binding lectin-associated serine protease-2. It is a human MASP-2 protein having the UniProt accession code O00187 (SEQ ID NO:1). The serine protease domain ('B chain' = mannan-binding lectin serine protease 2 B chain, based on UniProtKB - O00187 (MASP-2_HUMAN)) comprises (or consists of) residues 445-686.

[0020] The term "MASP-2-dependent complement activation" refers to the MASP-2-dependent activation of the lectin pathway, which leads to the formation of the lectin pathway C3 convertase C4b2a and, upon accumulation of the C3 cleavage product C3b, subsequently the C5 convertase C4b2a(C3b)n under physiological conditions (i.e., in the presence of Ca ++ ).

[0021] The term "MASP-2-dependent complement-related disease or disorder" refers to a disease or disorder associated with MASP-2-dependent complement activation.

[0022] The term "MASP-2-related disease or disorder" refers to a disease or disorder associated with the activation of MASP-2 or its activity, including MASP-2-dependent complement-related diseases or disorders, for which inhibition of MASP-2 is therapeutically beneficial or expected to be beneficial.

[0023] The term "lectin pathway" refers to complement activation that occurs via the specific binding of serum and non-serum carbohydrate-binding proteins, including mannose-binding lectin (MBL), CL-11, and ficolin (H-ficolin, M-ficolin, or L-ficolin).

[0024] The term "classical pathway" refers to complement activation that is triggered by an antibody bound to a foreign substance and requires the binding of the recognition molecule Clq.

[0025] Amino acid residues are omitted as follows: alanine (Ala; A), asparagine (Asn; N), aspartic acid (Asp; D), arginine (Arg; R), cysteine (Cys; C), glutamic acid (Glu; E), glutamine (Gln; Q), glycine (Gly; G), histidine (His; H), isoleucine (Ile), leucine (Leu), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0026] In the broadest sense, naturally occurring amino acids can be grouped based on the chemical properties of the side chains of the individual amino acids. By "hydrophobic" amino acids is meant any of His, Leu, Met, Phe, Trp, Tyr, Val, Ala, Cys or Pro. By "hydrophilic" amino acids is meant any of Gly, Asn, Gln, Ser, Thr, Asp, Glu, Lys, Arg or His. This grouping of amino acids can be further classified as follows: By "uncharged hydrophilic" amino acids is meant any of Ser, Thr, Asn or Gln. By "acidic" amino acids is meant any of Glu or Asp. By "basic" amino acids is meant any of Lys, Arg or His.

[0027] The term "conservative amino acid substitution" is illustrated by substitutions between amino acids within each of the following groups: (1) Glycine, alanine, valine, leucine, and isoleucine; (2) Phenylalanine, tyrosine, and tryptophan; (3) Serine and threonine; (4) Aspartate and glutamate; (5) Glutamine and asparagine; and (6) Lysine, arginine and histidine.

[0028] The term "subject" includes all mammals, including but not limited to humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs, and rodents.

[0029] "Mammals" includes both humans and domestic animals such as laboratory and pet animals (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and non-domestic animals such as wild animals.

[0030] The terms "small molecule" and "small organic molecule" refer to small carbon-containing molecules having a molecular weight of about 2500 Daltons or less. In some embodiments, the small molecule has a molecular weight of about 2000 Daltons or less. In some embodiments, the small molecule has a molecular weight of about 1500 Daltons or less. In some embodiments, the small molecule has a molecular weight of about 1000 Daltons or less. In some embodiments, the small molecule has a molecular weight of about 750 Daltons or less. In some embodiments, the small molecule has a molecular weight of about 500 Daltons or less. In some embodiments, the small molecule has a molecular weight of about 50 Daltons or more. In some embodiments, the small molecule has a molecular weight of about 75 Daltons or more. In some embodiments, the small molecule has a molecular weight of about 100 Daltons or more. In some embodiments, the small molecule has a molecular weight of about 150 Daltons or more. In some embodiments, the small molecule has a molecular weight of about 250 Daltons or more. In some embodiments, the small molecule may have a molecular weight in the range of about 50 Daltons to about 500 Daltons, about 50 Daltons to about 750 Daltons, about 50 Daltons to about 1000 Daltons, about 50 Daltons to about 1500 Daltons, about 50 Daltons to about 2000 Daltons, or about 50 Daltons to about 2500 Daltons. When the term "compound" is used herein, it is expressly intended to include small molecule compounds as defined herein (including any of its embodiments).

[0031] As used herein, the terms "disease" and "condition" may be used interchangeably, or may differ in that a particular malady or condition may not have a known causative agent (and thus the etiology has not yet been elucidated) and is therefore still only recognized as an undesirable condition or syndrome (characterized by a more or less specific set of symptoms identified by a clinician). In some embodiments, a disease is a pathological condition of an organ, body part, or system resulting from various causes such as an infection, genetic defect, or environmental stress, characterized by a distinguishable group of symptoms.

[0032] "Therapeutically effective amount", "effective amount", or "effective dosage" refers to the amount of the disclosed compound sufficient to effect the treatment, as hereinafter defined, of a disease or condition in a mammal (e.g., a human) when administered to the mammal, preferably a human. The amount of the disclosed compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the mode of administration, and the age of the mammal being treated, but can be routinely determined by one of ordinary skill in the art in view of their knowledge and the present disclosure.

[0033] The term "subcutaneous administration" refers to the administration of a formulation beneath all layers of the skin of a subject.

[0034] The term "histidine" includes, unless otherwise specified, L-histidine in particular.

[0035] The term "isotonic" refers to a formulation having essentially the same osmotic pressure as human blood. Isotonic formulations generally have an osmotic pressure of about 250 to about 350 mOsmol / L. Isotonicity can be measured, for example, using a vapor pressure or freezing point depression osmometer.

[0036] The term "hypertonic" refers to a formulation having an osmotic pressure higher than that of human osmotic pressure (i.e., greater than 350 mOsm / L).

[0037] The term "hydrogen bond" refers to a partial electrostatic attraction between a hydrogen (H) bonded to a more electronegative atom such as nitrogen (N) or oxygen (O), and another adjacent atom with a lone pair of electrons. For example, when nitrogen is described as acting as a "hydrogen bond donor", this means that as the hydrogen (H) bonded to the nitrogen (N) is electrostatically attracted or accepted by an adjacent atom with a lone pair such as oxygen, it is donated by the nitrogen. Similarly, when oxygen is described as acting as a "hydrogen bond acceptor", this means that a hydrogen (H) bonded to a more electronegative atom such as nitrogen (N) is electrostatically attracted or "accepted" by an adjacent atom such as oxygen with a lone pair of electrons. There may be cases where hydrogen-bonded atoms are described without explicitly stating the origin and presence of the intervening hydrogen atom. The term "hydrogen bond" is used when the LigPlot+ software predicts hydrogen bond interactions using its algorithm and a parameter of 3.35 Å applied to the maximum distance between the hydrogen bond donor and acceptor. Not all hydrogen bonds actually exist simultaneously; this is evident from the fact that there are atoms that are shown to potentially form four hydrogen bonds by estimation, but in a given case, only three hydrogen bonds may be chemically possible. Generally, crystal structures such as the co-crystal structure information in this specification do not directly show or detect hydrogen bonds, but the software used to explain the co-crystal predicts the existence of such H-bonds. Thus, throughout the disclosure, when an H-bond is stated to exist and is described, it can be said that it is "predicted" to exist by the software.

[0038] The term "ionic bond" includes a type of chemical bond that is a primary interaction occurring in ionic compounds, involving an electrostatic attraction between ions with opposite charges.

[0039] The term "van der Waals" interaction includes weak, short-range electrostatic attractions between uncharged molecules that result from the interaction of permanent or transient electric dipole moments. As determined by LigPlot+ software using a model derived from the corresponding crystallographic MASP-2 compound co-structure, such interactions include all contacts calculated using non-bonded contact parameters between hydrophobic contacts and any contacts for interactions with a maximum contact distance of 3.90 Å.

[0040] The term "π-π interaction" or "π-π stacking" interaction includes attractive non-covalent interactions (such as "edge-face" interactions) between aromatic rings that are oriented approximately parallel or approximately perpendicular to each other because the aromatic rings contain π bonds.

[0041] Typically, the active site of a serine protease such as MASP-2 has a cleft-like shape to which a polypeptide substrate or inhibitor binds. Schechter and Berger labeled the amino acid residues from the N- to the C-terminus of a polypeptide substrate as follows: Pi, ..., P3, P2, P1, P1', P2', P3', ..., Pj) and their respective binding subsites Si, ..., S3, S2, S1, S1', S2', S3', ..., Sj. Cleavage is catalyzed between P1 and P1' (Schechter, I. & Berger, A. On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun. 27 (1967)).

[0042] The term "binding site" is a region on a protein, such as a region on the surface of MASP-2, where a small molecule can interact. The binding site or region may or may not overlap with the active site, or may only partially overlap, yet still be able to lower or inactivate the activity of the MASP-2 molecule.

[0043] The term "or" refers to alternatives and should generally be construed as non-exclusive. For example, a reference to "a composition comprising A or B" will typically contemplate a situation having a composition that includes both A and B. However, "or" should be construed to exclude indicated alternatives that cannot be combined without contradiction (e.g., a composition pH of 9-10 or 7-8).

[0044] The group "A or B" is equivalent to a group "selected from the group consisting of A and B".

[0045] The connective "comprising" or "comprise" is not exclusive. For example, a "composition comprising A" must include at least the component A, but may also include one or more other components (e.g., B; B and C; B, C, and D; etc.). Thus, the term "comprising" should generally be construed not to exclude additional components. For example, a claim to "a composition comprising A" will encompass compositions that include A and B; A, B, and C; A, B, C, and D; A, B, C, D, and E; etc.

[0046] The term "hypertonic" refers to a formulation having an osmotic pressure higher than that of human osmotic pressure (i.e., greater than 350 mOsm / Kg lHhO).

[0047] The term "agent" refers to a compound or mixture of compounds that, when added to a composition, tend to affect the properties of the composition. For example, a composition containing a thickening agent will tend to be more viscous than the same comparative composition except for not containing the thickening agent.

[0048] A "synthetic" compound means a compound that does not occur naturally and is synthesized by a human. References to compounds herein may be understood to include references to synthetic compounds, unless the context indicates otherwise.

[0049] As used herein, the terms "ambient temperature" and "room temperature" are understood in the art and generally refer to a reaction temperature that is approximately the same as the temperature of the room in which the reaction is carried out, for example, a temperature of about 20 °C to about 30 °C.

[0050] At various places in this specification, certain features of compounds are disclosed in groups or ranges. This is specifically intended to include every individual sub - combination of the members of such groups and ranges. For example, the terms "C 1~6 alkyl" and "C1 - C6 alkyl" are specifically intended to disclose (non - limitingly) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl independently.

[0051] The term "substituted" means that an atom or group of atoms is formally replaced by a "substituent" in place of hydrogen when attached to another group. The term "substituted", unless otherwise indicated, refers to any level of substitution, such as mono - substitution, di - substitution, tri - substitution, tetra - substitution, penta - substitution, or higher degrees of substitution, where such substitution is tolerated (e.g., results in a stable compound). Substituents are independently selected and the substitution may be at any chemically accessible position. It should be understood that substitution at a given atom is limited by valence. The phrase "optionally substituted" means substitution or non - substitution. The term "substituted" means that at least one hydrogen atom is replaced by a substituent. A single divalent substituent, such as oxo, can replace two hydrogen atoms.

[0052] The terms "C n~m " and "C n ~C m ", where n and m are integers, denote a group containing n to m carbon atoms. Examples include C 1~4 , C 1~6 , etc. The term includes all members within the range, i.e., C n , C n+1 , C n+2 ... C m-2 Cm-1 and C m is intended to be explicitly disclosed. For example, C 1~6 is intended to disclose C1, C2, C3, C4, C5, and C6. As used herein, "C n~m " has the same meaning as "C n ~C m ".

[0053] The term "n-membered" where n is an integer (e.g., 6-membered) typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. The term "n~m-membered" where n and m are integers (e.g., 6~10-membered) describes a range where the number of ring-forming atoms is from n to m. For example, piperidinyl is an example of a 6-membered heterocyclic ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0054] "Alkyl" consists of only carbon and hydrogen atoms, contains no unsaturation, has 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and is bonded to the remainder of the molecule by a single bond, and refers to a straight-chain or branched hydrocarbon chain radical such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. In certain specific embodiments, the alkyl group may be substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, -OR 100 , -OC(O)R 100 , -N(R 100 )2, -C(O)R 100 , -C(O)OR 100 , -C(O)N(R 100 )2, -N(R 20 )C(O)OR 102 , -N(R 100 )C(O)R 102, -N(R 102 )S(O) p R 102 (where p is from 1 to 2), -S(O) p OR 102 (where p is from 1 to 2), -S(O) t R 102 (where t is from 0 to 2), and -S(O) p N(R 100 )2(where p is from 1 to 2), where each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 102 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0055] "Alkenyl" consists of only carbon and hydrogen atoms, contains at least one double bond, has 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, and is bonded to the rest of the molecule by a single bond, and refers to a linear or branched hydrocarbon chain radical group such as ethenyl, prop - 1 - enyl, but - 1 - enyl, pent - 1 - enyl, penta - 1,4 - dienyl, etc. In certain embodiments, the alkyl group may be substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, -OR 100 , -OC(O)R 100 , -N(R 100 )2, -C(O)R 100 , -C(O)OR 100 , -C(O)N(R 100 )2, -N(R 20 )C(O)OR 102 , -N(R 100 )C(O)R 102 , -N(R 102 )S(O) p R 102(where p is from 1 to 2), -S(O) p OR 102 (where p is from 1 to 2), -S(O) t R 102 (where t is from 0 to 2), and -S(O) p N(R 100 )2(where p is from 1 to 2), where each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 102 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0056] "Alkynyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group as defined above having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne in which one C-H bond has been replaced by the point of attachment of the alkyl group to the remainder of the compound. "C n~m alkynyl" and "C n ~C m alkynyl" refer to an alkynyl group having from n to m carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains from 2 to 6, from 2 to 4, or from 2 to 3 carbon atoms. Unless otherwise indicated, the alkynyl group may be substituted.

[0057] "Alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain consisting of only carbon and hydrogen, having 1 to 12 carbon atoms, containing no unsaturation, and connecting the remaining part of the molecule to a radical group or connecting two parts of the molecule, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain may optionally contain one or more heteroatoms, where the carbon of the alkylene chain is replaced by a heteroatom selected from oxygen, nitrogen, or sulfur. The alkylene chain is bonded to the remaining part of the molecule through a single bond and to the radical group through a single bond, or is bonded to two parts of the molecule through a single bond at each bonding point. In some embodiments, the alkyl group may be substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, -OR 100 , -OC(O)R 100 , -N(R 100 )2, -C(O)R 100 , -C(O)OR 100 , -C(O)N(R 100 )2, -N(R 20 )C(O)OR 102 , -N(R 100 )C(O)R 102 , -N(R 102 )S(O) p R 102 (where p is 1 to 2), -S(O) p OR 102 (where p is 1 to 2), -S(O) t R 102 (where t is 0 to 2), and -S(O) p N(R 100 )2(where p is 1 to 2), where each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 102is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0058] The term "hydroxyalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by a hydroxy group (i.e., -OH). "C n~m The term "hydroxyalkyl" refers to a C n~m alkyl group having from n to m carbon atoms and at least one hydroxy group. In some embodiments, the hydroxyalkyl group contains one hydroxy group. In certain aspects, the hydroxyalkyl group contains two or more hydroxy groups, each on the same or different carbon atoms (e.g., "dihydroxyalkyl"). In certain aspects, the hydroxyalkyl group has 1, 2, 3, 4, 5, 6, or more hydroxy groups. Examples can include, without limitation, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.

[0059] "Aminylalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by an aminyl group (i.e., -NR 100 R 101 where R 100 and R 101 are each independently hydrogen, alkyl, alkenyl, or alkynyl as defined herein). In some embodiments, aminylalkyl contains one aminyl group. In some embodiments, the aminyl group is -NH2.

[0060] "Carboxyalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by a carboxy group (i.e., -C(O)OH). In some embodiments, carboxyalkyl contains one carboxy group.

[0061] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For the purposes of this disclosure, the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may include a fused or bridged ring system. The aryl radical non-limitingly includes aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, perylene, pyrene, and triphenylene. In some embodiments, the aryl group is alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 101 -OR 100 、-R 101 OC(O)R 100 、-R 101 -N(R 100 )2、-R 101 -N(R 100 )-R 103 -OR 100 、-R 101 -C(O)R 100 、-R 101 -C(O)OR 100 、-R 101 -C(O)N(R 100 )2、-R 101 -N(R 100 )C(O)OR 102 、-R 101 -N(R 100 )C(O)R 102 、-R 101 -N(R 100 )S(O) p R 102 (where p is 1 to 2), -R 101 -N=C(OR 100 )R 100 、-R 101 -S(O) p OR 102 (where p is 1 to 2), -R 101 -S(O)t R 102 (where t is from 0 to 2), and -R 101 -S(O) p N(R 100 )2(where p is from 1 to 2), and may be substituted by one or more substituents independently selected from the group consisting of; here, each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 101 is independently a direct bond or a straight or branched alkylene chain; each R 102 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 103 is a direct bond or a straight or branched alkylene chain. In some embodiments, the aryl group has the following structure. TIFF0007699389000064.tif23128

[0062] "Arylalkyl" or "aralkyl" refers to a group of the formula -alkylene-aryl, where the alkylene group and the aryl group are as defined herein. In some embodiments, arylalkyl is C 6~10 aryl-C 1~3 alkyl. In some embodiments, arylalkyl is C 6~10 aryl-C 1~4 alkyl. In some embodiments, arylalkyl is C 6~10 aryl-C 1~3 alkyl. In some embodiments, arylalkyl is phenyl-C 1~3 alkyl. Examples include, but are not limited to, benzyl, 1-phenylethyl, 4-methylbenzyl, and 1,1-dimethyl-1-phenylmethyl. In some embodiments, arylalkyl is optionally substituted benzyl.

[0063] "Aryloxy" refers to a group having the formula -O-aryl, where aryl is a group as defined above. In some embodiments, the aryloxy group is -O-C 6~10 aryl. In some embodiments, aryloxy is substituted or unsubstituted phenyloxy (i.e., -O-C6 aryl).

[0064] "Arylalkoxy" refers to a group having the formula -alkoxy-aryl, where alkoxy and aryl are each a group as defined above. In some embodiments, arylalkoxy is C 6~10 aryl-C 1~3 alkoxy. In some embodiments, arylalkoxy is C 6~10 aryl-C 1~4 alkoxy. In some embodiments, arylalkoxy is C 6~10 aryl-C 1~3 alkoxy. In some embodiments, arylalkoxy is phenyl-C 1~3 alkoxy (e.g., methoxy).

[0065] "Cycloalkyl" consists of only carbon and hydrogen atoms, may include a fused or bridged ring system, has 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, is saturated or unsaturated, and is a stable non-aromatic monocyclic or polycyclic hydrocarbon radical bonded to the remainder of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, etc. In some embodiments, the cycloalkyl group is alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 101 -OR 100 -R 101 -OC(O)-R 100 -R101 -N(R 100 )-R 103 -OR 100 、-R 101 -N(R 100 )2、-R 101 -C(O)R 100 、-R 101 -C(O)OR 100 、-R 101 -C(O)N(R 100 )2、-R 101 -N(R 100 )C(O)OR 102 、-R 101 -N(R 100 )C(O)R 102 、-R 101 -N(R 100 )S(O) p R 102 (where p is from 1 to 2), -R 101 -N=C(OR 100 )R 100 、-R 101 -S(O) p OR 102 (where p is from 1 to 2), -R 101 -S(O) t R 102 (where t is from 0 to 2), and -R 101 -S(O) p N(R 100 )2(where p is from 1 to 2), and may be substituted by one or more substituents independently selected from the group consisting of; here, each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 101 is independently a direct bond or a straight or branched alkylene chain; each R 102 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 103 is a direct bond or a straight or branched alkylene chain.

[0066] "Cycloalkylalkyl" refers to a radical of the formula -R 100 R 101 wherein R 100 is an alkylene chain as defined above, and R 101 is a cycloalkyl radical as defined above. When specifically described in the specification, the alkylene chain and / or cycloalkyl radical may be substituted as defined above for optionally substituted alkylene chains and optionally substituted cycloalkyls.

[0067] "Alkoxy" refers to a radical group having the following formula "-O-alkyl", wherein the alkyl group is as defined above in this specification. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Unless otherwise indicated, the alkoxy group may be substituted.

[0068] "Alkoxyalkyl" refers to a radical having the following formula "-alkylene-O-alkyl", wherein the alkylene and alkyl groups are each as defined above in this specification. In some embodiments, the alkoxyalkyl group contains one -O-alkyl group. In some embodiments, the alkoxyalkyl group contains two or more alkoxy groups. Examples can include, without limitation, methoxymethyl, ethoxymethyl, 3-ethoxyethyl, and 1-methoxyethyl. Unless otherwise indicated, the alkoxyalkyl group may be substituted.

[0069] "Oxo" refers to the =O group. For example, oxo bonded to a carbon atom forms a carbonyl group (i.e., C=O). Alternatively, when an oxo group is bonded to a heteroatom, for example, a sulfoxide, sulfone group, N-oxide group is formed.

[0070] "Sulfide" refers to the =S group.

[0071] "Amino" refers to the -NH2 group.

[0072] "Carbamyl" refers to the -C(O)NH2 group.

[0073] "Carboxy" refers to the -C(O)OH group.

[0074] "Carbonyl" refers to the C(=O) group, which may also be described as C(O).

[0075] "Cyano" or "Nitrile" refers to the -C≡N group, which may also be described as -CN.

[0076] "Nitro" refers to the -NO2 group.

[0077] "Hydroxy" or "Hydroxyl" refers to the -OH group.

[0078] "Halo" or "Halogen" refers to bromo, chloro, fluoro, or iodo.

[0079] "Haloalkyl" refers to an alkyl radical as defined above that is substituted by one or more of the halo radicals defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, etc. The alkyl portion of the haloalkyl radical may be substituted as defined above for an alkyl group.

[0080] The term "haloalkoxy", employed alone or in combination with other terms, refers to a group of the formula -O-haloalkyl, where the haloalkyl group is as defined above. Exemplary haloalkoxy groups include trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, etc.

[0081] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless specifically described in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may include fused, bridged, and spiro ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be oxidized, and the nitrogen atom may be quaternized; the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, without limitation, azetidinyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1-azaspiro[3.3]heptan-1-yl, 5-azaspiro[2.3]hexan-5-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 1-oxa-6-azaspiro[3.4]octan-6-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 2,6-diazaspiro[3.3]heptan-2-yl, dioxolanyl, dioxinyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, 1,2,4-thiadiazol-5(4H)-ylidene, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.In certain embodiments, the heterocyclic group is alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclicalkyl, heteroaryl, heteroarylalkyl, -R. 101 -OR 100 、-R 101 -OC(O)-R 100 、-R 101 -N(R 100 )-R 103 -OR 100 、-R 101 -N(R 100 )2、-R 101 -C(O)R 100 、-R 101 -C(O)OR 100 、-R 101 -C(O)N(R 100 )2、-R 101 -N(R 100 )C(O)OR 102 、-R 101 -N(R 100 )C(O)R 102 、-R 101 -N(R 100 )S(O) p R 102 (where p is from 1 to 2), -R 101 -N=C(OR 100 )R 102 、-R 101 -S(O) p OR 102 (where p is from 1 to 2), -R 101 -S(O) t R 102 (where t is from 0 to 2), and -R 101 -S(O) p N(R 100 )2(where p is from 1 to 2) and may be substituted by one or more substituents selected from the group consisting of, where each R 100is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 101 is independently a direct bond or a straight or branched alkylene chain; each R 102 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R 103 is a direct bond or a straight or branched alkylene chain.

[0082] "Heterocyclylalkyl" refers to a radical of the formula -R 100 R 101 wherein R 100 is an alkylene chain as defined above, and R 101 is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be bonded to the alkyl radical at the nitrogen atom. In some embodiments, the alkylene chain of the heterocyclylalkyl radical may be optionally substituted as defined above for optionally substituted alkylene chains. In some embodiments, the heterocyclyl moiety of the heterocyclylalkyl radical may be optionally substituted as defined above for optionally substituted heterocyclyl groups.

[0083] "Heteroaryl" refers to a 4- to 14-membered ring system radical that includes a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For the purposes of the present disclosure, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may include a fused or bridged ring system; the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be oxidized; and the nitrogen atom may be quaternized.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl, benzimidazolothionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, purimidinonyl, pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl, quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). In certain embodiments, the heteroaryl group is alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, thioxo, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R. 101 -OR 100 , -R 101-OC(O)-R 100 、 -R 101 -N(R 100 )-R 103 -OR 100 、 -R 101 -N(R 100 )2、 -R 101 -C(O)R 100 、 -R 101 -C(O)OR 100 、 -R 101 -C(O)N(R 100 )2、 -R 101 -N(R 100 )C(O)OR 102 、 -R 101 -N(R 100 )C(O)R 100 )C(O)R 102 、 -R 101 -N(R 100 )S(O) p R 102 (where p is 1 - 2), -R 101 -N=C(OR 100 )R 100 、 -R 101 -S(O) p OR 102 (where p is 1 - 2), -R 101 -S(O) t R 102 (where t is 0 - 2), and -R 101 -S(O) p N(R 100 )2(where p is 1 - 2) and may be substituted by one or more substituents selected from the group consisting of, where each R 100 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 101 is independently a direct bond or a straight or branched alkylene chain; each R 102 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, each R103 is a direct bond or a straight or branched alkylene chain. Preferably, R in the present specification 1 Any optional substituent on the optionally substituted bicyclic heteroaryl group for is halo. Preferably, R in the present specification 1 Any optional substituent on the optionally substituted monocyclic heteroaryl group for is alkyl. The term "heteroaryl" includes, for example, the following structures. TIFF0007699389000065.tif23128

[0084] "N-heteroaryl" refers to a heteroaryl radical as defined above that contains at least one nitrogen. The point of attachment of the N-heteroaryl to the remainder of the molecule may be through a nitrogen atom or a carbon atom in the N-heteroaryl. When specifically described herein, the N-heteroaryl radical may be optionally substituted as described above for the optionally substituted heteroaryl radical.

[0085] "Heteroarylalkyl" refers to a radical of the formula -R 100 R 101 wherein R 100 is an alkylene chain as defined above and R 101 is a heteroaryl radical as defined above. When specifically described herein, the heteroaryl portion of the heteroarylalkyl radical may be optionally substituted as described above for the optionally substituted heteroaryl group. In some specific embodiments, the alkylene chain portion of the heteroarylalkyl radical may be optionally substituted as described above for the optionally substituted alkylene chain.

[0086] The compounds and methods of the present disclosure also mean to include all pharmaceutically acceptable compounds of structures (I), (II), (III) and (IV) that are isotopically labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers.

[0087] Examples of isotopes that can be incorporated into the disclosed compounds are, respectively 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, 125 I and the like, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. These radiolabeled compounds may be useful, for example, in determining or measuring the effectiveness of a compound by characterizing the site or mechanism of action or binding affinity. Certain isotope-labeled compounds of structure (I), (II), (III), or (IV), for example, compounds incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose from the viewpoint of ease of incorporation and simplicity of detection means.

[0088] Substitution with heavier isotopes such as deuterium, i.e., 2 H, may result in certain therapeutic advantages due to higher metabolic stability, e.g., an increase in in vivo half-life or a reduction in the required dose, and may therefore be preferred in certain situations. In one aspect, the compounds of structure (I), (II), (III), or (IV) are enriched in deuterium. Such deuterated compounds can be achieved by methods known to those skilled in the art such as exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials.

[0089] 11 C, 18 F, 15 O, and13 Substitution with a positron-emitting isotope such as N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotope-labeled compounds of structure (I), (II), (III) or (IV) can generally be prepared by conventional techniques known to those skilled in the art or by a process similar to that described in the examples and preparations below using appropriate isotope-labeled reagents in place of the unlabeled reagents previously employed.

[0090] The present disclosure also means including the in vivo metabolites of the disclosed compounds. Such products can result, for example, mainly from enzymatic processes such as oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound. Accordingly, the present disclosure includes compounds produced by a process that includes contacting a compound of the present disclosure with a mammal for a period sufficient to produce its metabolites. Such products are typically identified by administering a radiolabeled compound to an animal such as a rat, mouse, guinea pig, monkey, etc. or to a human at a detectable dose, allowing sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological samples.

[0091] By "stable compound" and "stable structure" is meant a compound that is robust enough to withstand isolation to useful purity from a reaction mixture and formulation into an effective therapeutic agent.

[0092] "Optional" or "optionally" means that the subsequently described event or situation may or may not occur, and that the description includes the case where the event or situation occurs or does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and that the description includes both substituted aryl radicals and unsubstituted ( "non-substituted") aryl radicals. When a functional group is described as "optionally substituted", and conversely, the substituent on the functional group is also described as "optionally substituted", etc., for the purposes of the present disclosure, such repetition is limited to 5 times at most, preferably such repetition is limited to 2 times at most.

[0093] "Pharmaceutically acceptable carrier, diluent or excipient" includes, without limitation, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the US Food and Drug Administration as acceptable for use in humans or livestock.

[0094] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0095] "Pharmaceutically acceptable acid addition salts" refer to salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as 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, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hypuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic 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, undecylenic acid, etc., which retain the biological effectiveness and properties of the free base, are not undesirable in a biological or other manner, and are salts formed thereby.

[0096] "Pharmaceutically acceptable basic addition salts" refers to salts that retain the biological effectiveness and properties of the free acid and are not undesirable in a biological or other manner. These salts are prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, without limitation, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0097] Crystallization often results in the formation of solvates of the disclosed compounds (e.g., compounds of Structures (I), (II), (III), or (IV)). As used herein, the term "solvate" refers to an aggregate that includes one or more molecules of a solvent together with one or more molecules of the disclosed compound. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present disclosure may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvated forms. The disclosed compounds may be true solvates, but in other cases, the disclosed compounds may simply retain adventitious water or be a mixture of adventitious water and some adventitious solvent.

[0098] A "pharmaceutical composition" refers to a formulation of a disclosed compound with a medium generally acceptable in the art for the delivery of a biologically active compound to a mammal, such as a human. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0099] As used herein, "treating" or "treatment" includes treating a mammalian, preferably a human, having a target disease or condition, and: (a) preventing a disease or condition from occurring in a mammal, particularly when such a mammal is predisposed to the condition but has not yet been diagnosed as having it; (b) inhibiting a disease or condition, i.e., arresting the progression of the disease or condition; (c) alleviating (or ameliorating) a disease or condition, i.e., causing regression of the disease or condition; or (d) alleviating (or ameliorating) the symptoms caused by a disease or condition, e.g., without addressing the underlying disease or condition and includes.

[0100] As used herein, the terms "disease" and "condition" may be used interchangeably, or may differ in that a particular adverse effect or condition may not have a known causative agent (and thus the etiology has not yet been elucidated) and is thus only recognized as an undesirable condition or syndrome (with a more or less specific set of symptoms identified by a clinician) that is not yet recognized as a disease.

[0101] The disclosed compounds or their pharmaceutically acceptable salts may contain one or more stereocenters and thus may exist in the form of enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- from the perspective of absolute stereochemistry or (D)- or (L)- for amino acids. This disclosure is meant to include all such possible isomers as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using a chiral synthon or chiral reagent or may be separated using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemate (or a racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). Where the compounds described herein contain olefinic double bonds or other centers that give rise to geometric asymmetry, unless otherwise specified, the compounds are intended to include both the E and Z geometric isomers. Similarly, all tautomeric forms are intended to be included.

[0102] "Stereoisomers" refer to compounds composed of the same atoms linked by the same bonds, but having non-superimposable different three-dimensional structures. This disclosure contemplates various stereoisomers and mixtures thereof, including enantiomers, which refer to two stereoisomers that are mirror images and cannot be superimposed on each other. For a detailed description of the structures and properties of enantiomers and stereoisomers, see, for example, Smith, M. B. and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007).

[0103] "Tautomers" refer to a proton shift from one atom in a molecule to another atom in the same molecule. This disclosure includes tautomers of any of the foregoing compounds.

[0104] The use of parentheses and brackets in substituents is employed herein for space saving. Thus, the use of parentheses in a substituent indicates that the group enclosed by the parentheses is directly bonded to the atom preceding the parentheses. The use of brackets in a substituent indicates that the group enclosed by the brackets is also directly bonded to the atom preceding the parentheses.

[0105] The chemical nomenclature protocol and structural diagrams used herein are a variation of the I.U.P.A.C. nomenclature using the ChemBioDraw Ultra Version 14.0 software program. For complex chemical names adopted herein, the substituent is named before the group to which it is attached. For example, cyclopropylethyl contains an ethyl backbone with a cyclopropyl substituent. In chemical structural diagrams, all bonds are specified except for some carbon atoms that are assumed to be bonded to sufficient hydrogen atoms to satisfy their valences.

[0106] At a particular position, a definition or aspect may refer to a specific ring (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member as long as the valence of the atoms is not exceeded.

[0107] When any two groups or two instances of the same substituent are "independently selected" from a list of options, the groups may be the same or different. For example, if R a and R b are independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, the two R a groups and the two R b groups in the molecule may all be alkyl groups (e.g., four different alkyl groups). Alternatively, the first R a may be alkyl, the second R a may be fluoro, the first R b may be hydroxyalkyl, and the second R b may be amino (or any other substituent selected from the group). Alternatively, both R a and the first R b may be fluoro, while the second R b may be alkyl (i.e., some pairs of substituents may be the same and others may be different). Unless otherwise indicated, there are two or more groups with the same definition, and when the definition provides options, each occurrence of the same group should be understood to be independently selected from the possible options. For example, if there are two or more R a groups in a compound and the definition of R a is such that R a may be A, B, or C, each R a group present in the compound is independently selected from A, B, and C, so it should be understood that the R a groups present in the compound may be the same or different.

[0108] The compounds and salts thereof, including pharmaceutically acceptable salts, can be found together with other substances such as water and solvents (e.g., hydrates and solvates), or can be isolated. When in the solid state, the compounds and salts thereof described herein may exist in various forms, for example, in the form of solvates including hydrates. Since the compound may be in any solid form such as a polymorph or a solvate, unless otherwise expressly stated, references to the compound and its salts should be understood to encompass any solid form of the compound.

[0109] In some embodiments, the compounds or salts thereof described herein are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition in which the compound of the present disclosure is concentrated. Substantial separation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% of the disclosed compound or its salt.

[0110] The following abbreviations may be used herein and, unless otherwise specified, have the meanings shown below: μ (micro); °C (degrees Celsius); Ac (acetyl); ACN (acetonitrile); anhyd (anhydrous); aq (aqueous); atm (atmosphere); Bn (benzyl); Boc (tert-butoxycarbonyl); Bu (butyl); calcd (calculated); Cbz (benzyloxycarbonyl); chrom.(Chromatography); CPME (Cyclopentyl Methyl Ether); CH2Cl2 (Dichloromethane); concd (Concentrated); conc (Concentration); DCC (N,N'-Dicyclohexylcarbodiimide); DIAD (Diisopropyl Azodicarboxylate); DIEA (N,N-Diisopropylethylamine); DMAP (4-(N,N-Dimethylamino)pyridine); DMF (Dimethylformamide); DMSO (Dimethyl Sulfoxide); EDC (N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide Hydrochloride); equiv (Equivalent); ES (Electrospray); Et (Ethyl); Et2O (Diethyl Ether); g (Gram); h (Hour); HATU (N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium Hexafluorophosphate N-Oxide); HBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium Hexafluorophosphate); HPLC (High Performance Liquid Chromatography); HOBt (1-Hydroxybenzotriazole Hydrate); L (Liter); m (Milli); m- (Meta); M (Molarity); MeCN (Acetonitrile); min (Minute); mL (Milliliter); mol (Mole; molecule (as in mol wt)); Ms (Methanesulfonyl); MS (Mass Spectrometry); MW (Molecular Weight); NBS (N-Bromosuccinimide); NCS (N-Chlorosuccinimide); NIS (N-Iodosuccinimide); NHS (N-Hydroxysuccinimide); NMM (4-Methylmorpholine); NMR (Nuclear Magnetic Resonance); o- (Ortho); obsd (Observed); p- (Para); Ph (Phenyl); Phth (Phthalimide); ppt (Precipitate); Pr (Propyl); psi (Pounds per Square Inch); temp (Temperature); TFA (Trifluoroacetic Acid); THF (Tetrahydrofuran); TPP (Triphenylphosphine); and Tr (Trityl). Other abbreviations may also be used and have meanings understood by those skilled in the art.

[0111] II. Compounds In certain aspects, the present disclosure provides a compound of structure (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, TIFF0007699389000066.tif44128wherein, R 1 is a substituted or unsubstituted heteroaryl; R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 3 is hydrogen or alkyl; R 4 is alkyl, a substituted or unsubstituted arylalkyl, or a heterocyclyl substituted with a substituent selected from the group consisting of a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridinyl, or R 3 and R 4 together with the nitrogen and carbon to which they are respectively attached form an optionally substituted 4- to 10-membered heterocyclyl; R 5a is hydrogen or halo; L 1 is a direct bond, -CH2-, -S(O) t -, NR 5b -, -O-, -C=C-, or -C≡C-; t is 0, 1, or 2; and R 5b is hydrogen, alkyl, haloalkyl, (C=O)alkyl, (C=O)Oalkyl, (C=O)cycloalkyl, (C=O)Ocycloalkyl, (C=O)aryl, (C=O)Oaryl, (C=O)heteroaryl, (C=O)Oheteroaryl, (C=O)heterocyclyl, (C=O)Oheterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted cycloalkylalkyl, or a substituted or unsubstituted heterocyclylalkyl, provided that however, A) R 2has the following structure: does not have one of TIFF0007699389000067.tif23128; B) R 1 has the following structure: does not have one of TIFF0007699389000068.tif23140; and C) R 2 when is unsubstituted phenyl, R 1 has the following structure: does not have one of TIFF0007699389000069.tif40130.

[0112] In some embodiments, R 1 is substituted or unsubstituted 5- to 10-membered heteroaryl. In certain embodiments, R 1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolopyridinyl, or substituted or unsubstituted benzimidazolyl.

[0113] In some specific embodiments, R 1 is R 1a R 1b R 1c R 1d R 1e one or more of and R 1a R 1b R 1c R 1d R 1e wherein each of and R 1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a SR a C(O)R a C(O)NR a R b C(O)OR a OC(O)R a OC(O)OR a OC(O)NR aR b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(=NR a )NR b R c , C(=NOR a )NR b R c , C(=NOC(O)R a )NR b R c , C(=NR a )N(R b )C(O)OR c , N(R a )C(=NR b )NR c R d , S(O)R a , S(O)NR a R b , S(O)2R a , N(R a )S(O)2R b , S(O)2NR a R b , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, selected from the group consisting of, wherein R a , R b , R c , and R d are, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6Haloalkyl, C 1~6 Haloalkoxy, C 1~6 is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0114] In certain specific embodiments, R 1a , R 1b , R 1c , R 1d , or R 1e is substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, then R 1a , R 1b , R 1c , R 1d , or R 1e is halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(=NR e )NR f R g , NR e C(=NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O)2R e , NR e S(O)2R f , S(O)2NRe R f and may be substituted with one or more substituents selected from the group consisting of oxo, where R e , R f , R g , and R h is, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0115] In some embodiments, R 1 has the following structure: TIFF0007699389000070.tif78128TIFF0007699389000071.tif227149TIFF0007699389000072.tif215148TIFF0007699389000073.tif94147.

[0116] In some more specific embodiments, R 1a or R 1b is independently C 1~6 alkyl, amino, or halo. In certain embodiments, R 1a or R 1b is methyl. In some embodiments, R 1a or R 1b is F, Cl, or Br. In certain specific embodiments, R 1a or R 1b each bonded to nitrogen is C 1~6 alkyl. In some more specific embodiments, R 1a or R 1b is methyl or ethyl.

[0117] In some embodiments, R 1has the following structure: has one of TIFF0007699389000074.tif167144.

[0118] In certain embodiments, R 1 has the following structure: has one of TIFF0007699389000075.tif114147, TIFF0007699389000076.tif213146, TIFF0007699389000077.tif138145.

[0119] In certain embodiments, R 1 has the following structure: has one of TIFF0007699389000078.tif67134.

[0120] In some embodiments, R 2 is a substituted or unsubstituted 6- to 10-membered aryl. In certain embodiments, R 2 is a substituted or unsubstituted phenyl. In some specific embodiments, R 1 is unsubstituted phenyl. In certain specific embodiments, R 2 is R 2a R 2b R 2c R 2d or R 2e is substituted with one or more of, where R 2a R 2b R 2c R 2d and R 2e are each independently C 1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, phosphate, phosphonalkyl, phosphoalkyl, cyano, nitro, OR a SR a C(O)R a C(O)NR a R b C(O)ORa , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(=NR a )NR b R c , C(=NOR a )NR b R c , C(=NOC(O)R a )NR b R c , C(=NR a )N(R b )C(O)OR c , N(R a )C(=NR b )NR c R d , S(O)R a , S(O)NR a R b , S(O)2R a , N(R a )S(O)2R b , S(O)2NR a R b , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, wherein R a , R b , R c , and R d are, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C2~6 Alkynyl, hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0121] In certain embodiments, R 2a , R 2b , R 2c , R 2d , or R 2e is substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, then R 2a , R 2b , R 2c , R 2d , or R 2e is halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(=NR e )NR f R g , NR e C(=NR f )NR g R h , S(O)R e , S(O)NR e Rf 、 S(O)2R e 、 NR e S(O)2R f 、 S(O)2NR e R f and may be substituted with one or more substituents selected from the group consisting of oxo, where R e 、 R f 、 R g 、 and R h are, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0122] In some specific embodiments, R 2 has one of the following structures: TIFF0007699389000079.tif169145.

[0123] In some embodiments, R 2 has one of the following structures: TIFF0007699389000080.tif116143.

[0124] In some embodiments, R 2 has one of the following structures TIFF0007699389000081.tif29128 wherein n is 1, 2, 3, 4, 5, or 6.

[0125] In some embodiments, R 2is a substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolopyridinyl, or substituted or unsubstituted benzimidazolyl. In certain embodiments, R 2 is a substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted isoquinolinyl, or substituted or unsubstituted pyrazolyl. In certain embodiments, R 1 is an unsubstituted pyridinyl, unsubstituted pyrrolyl, unsubstituted pyrimidinyl, or unsubstituted isoquinolinyl.

[0126] In some embodiments, R 2 is R 2a , R 2b , R 2c , R 2d , or R 2e substituted with one or more of, wherein R 2a , R 2b , R 2c , R 2d , and R 2e are each independently C 1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a)C(O)OR b 、C(=NR a )NR b R c 、C(=NOR a )NR b R c 、C(=NOC(O)R a )NR b R c 、C(=NR a )N(R b )C(O)OR c 、N(R a )C(=NR b )NR c R d 、S(O)R a 、S(O)NR a R b 、S(O)2R a 、N(R a )S(O)2R b 、S(O)2NR a R b 、 oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, and is selected from the group consisting of, where R a 、R b 、R c 、 and R d is, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0127] In certain embodiments, R 2a, R 2b , R 2c , R 2d , or R 2e is a substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 2a , R 2b , R 2c , R 2d , or R 2e is substituted with one or more substituents selected from the group consisting of halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(=NR e )NR f R g , NR e C(=NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O)2R e , NR e S(O)2R f , S(O)2NR e R f and may be substituted with one or more substituents selected from the group consisting of oxo, where R e , R f , R g , and R h is, each occurrence independently, hydrogen, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0128] In some specific embodiments, R 2 has the following structure: TIFF0007699389000082.tif110149.

[0129] In some embodiments, R 3 is hydrogen. In certain embodiments, R 3 is methyl.

[0130] In some specific embodiments, R 3 and R 4 together with the nitrogen to which they are attached form an optionally substituted 4- to 10-membered heterocyclyl. In some more specific embodiments, R 3 and R 4 together with the nitrogen to which they are attached form an unsubstituted 4- to 6-membered heterocyclyl. In certain more specific embodiments, R 3 and R 4 together with the nitrogen to which they are attached form an unsubstituted 5-membered ring. In some embodiments, R 3 and R 4 together with the nitrogen to which they are attached form an unsubstituted 6-membered ring. In certain specific embodiments, R 3 and R 4 together with the nitrogen to which they are attached form an unsubstituted pyrrolidinyl ring. In some embodiments, R 3 and R 4 together with the nitrogen to which they are attached form one of the following structures: TIFF0007699389000083.tif51128.

[0131] In a more specific embodiment, R 4 is methyl or has one of the following structures: TIFF0007699389000084.tif29129.

[0132] In certain specific embodiments, R 4 is a substituted or unsubstituted arylalkyl. In some embodiments, R 4 is substituted. In some embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl, cycloalkyl, heterocyclyl, hydroxyl, carboxy, and combinations thereof. In some more specific embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl, methoxy, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, hydroxyl, carboxy, and combinations thereof. In some embodiments, R 4 is unsubstituted. In some more specific embodiments, R 4 is benzyl or phenethyl. In some embodiments, R 4 is benzyl. In certain specific embodiments, R 4 is phenethyl.

[0133] In some embodiments, R 4 has the following structure: TIFF0007699389000085.tif40144TIFF0007699389000086.tif219141.

[0134] In some embodiments, R 4 has the following structure: TIFF0007699389000087.tif23128.

[0135] In some embodiments, R 4is a heterocyclyl substituted with a substituent selected from the group consisting of substituted or unsubstituted phenyl or substituted or unsubstituted pyridinyl. In some more specific embodiments, R 4 is a 4- to 6-membered heterocyclic ring. In some embodiments, R 4 contains oxygen. In certain embodiments, R 4 has one of the following structures: TIFF0007699389000088.tif23128.

[0136] In some embodiments, L 1 is a direct bond, -CH2-, or -C≡C-. In some embodiments, L 1 is a direct bond. In certain embodiments, L 1 is -CH2-. In some specific embodiments, L 1 is -C≡C-.

[0137] In certain embodiments, R 5a is hydrogen. In some embodiments, R 5a is halo. In some specific embodiments, R 5a is F, Br, or Cl. In a more specific embodiment, R 5a is Cl.

[0138] Another embodiment provides a compound having the following structure (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, TIFF0007699389000089.tif37128 wherein, R 6 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 7 is alkyl, -NR 10a R 10b -, -SR 10c -, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8 is hydrogen, alkyl, haloalkyl, cycloalkyl, or substituted or unsubstituted arylalkyl; R 9 is alkyl, substituted or unsubstituted -S(O)2-arylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or R 8 and R 9 together with the nitrogen to which they are attached form an optionally substituted 4- to 10-membered heterocyclyl; R 10a 、R 10b 、and R 10c are each independently hydrogen, alkyl, haloalkyl, or cycloalkyl, provided that however, A) R 7 is unsubstituted phenyl, 3-((methylsulfonyl)amino)phenyl, 2-methylphenyl, 3-(dimethylamino)phenyl, 3-(methylamino)phenyl, 3-methylphenyl, 3-aminomethylphenyl, 3-aminophenyl, unsubstituted pyridinyl, 3-(methylamino)-2-thienyl, 3,4-diamino-2-thienyl, 3-((methylsulfonyl)amino)-2-thienyl, 3-amino-2-thienyl, 3-amino-5-5(aminocarbonyl)phenyl, or has one of the following structures: TIFF0007699389000090.tif139148, then R 6 has the following structure: TIFF0007699389000091.tif21128 and; B) If R 7 is unsubstituted phenyl, then R 6 has the following structure: TIFF0007699389000092.tif21128.

[0139] In some embodiments, R 6 is substituted or unsubstituted aryl. In certain embodiments, R 6 is substituted or unsubstituted C6-C 10 aryl. In some more specific embodiments, R 6 is substituted or unsubstituted phenyl. In some embodiments, R 6is a substituted phenyl.

[0140] In some embodiments, R 6 is R 6a , R 6b , R 6c , R 6d , or R 6e substituted phenyl, where R 6a , R 6b , R 6c , R 6d , and R 6e are each independently C 1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(=NR a )NR b R c , C(=NOR a )NR b R c , C(=NOC(O)R a )NR b R c , C(=NR a )N(R b )C(O)OR c , N(R a )C(=NR b )NR c Rd , S(O)R a , S(O)NR a R b , S(O)2R a , N(R a )S(O)2R b , S(O)2NR a R b , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and selected from the group consisting of substituted or unsubstituted 4- to 10-membered heterocyclyl, where R a , R b , R c , and R d is, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0141] In certain embodiments, R 6a , R 6b , R 6c , R 6d , or R 6e is a substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, where R 6a , R 6b , R 6c , R 6dor R 6e is halo, CN, OR e SR e C(O)R e C(O)NR e R f C(O)OR e OC(O)R e OC(O)NR e R f NR e R f NR e C(O)R f NR e C(O)NR f R g NR e C(O)OR f C(=NR e )NR f R g NR e C(=NR f )NR g R h S(O)R e S(O)NR e R f S(O)2R e NR e S(O)2R f S(O)2NR e R f and may be substituted with one or more substituents selected from the group consisting of oxo, where R e R f R g and R h is, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0142] In some embodiments, R 6 is halo, haloalkyl, C(=NRa )NR b R c is phenyl substituted with at least one substituent selected from the group consisting of alkyl and 5- to 10-membered heteroaryl. In some more specific embodiments, R 6 is -C(=NH)NH2, chloro, fluoro, methyl, and substituted with at least one substituent selected from the group consisting of TIFF0007699389000093.tif14128.

[0143] In some embodiments, R 6 has one of the following structures: TIFF0007699389000094.tif176144.

[0144] In some embodiments, R 6 has one of the following structures: TIFF0007699389000095.tif105143.

[0145] In certain embodiments, R 6 is unsubstituted phenyl.

[0146] In some other embodiments, R 6 is substituted or unsubstituted heteroaryl. In some more specific embodiments, R 6 is substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R 6 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolopyridinyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted thienopyridinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted isoindolinyl, or substituted or unsubstituted benzothiazolyl.

[0147] In more specific embodiments, R 6 is R 6a 、R 6b 、R 6c 、R 6d 、or R 6ea heteroaryl substituted by one or more of, wherein R 6a R 6b R 6c R 6d and R 6e are each independently C 1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a SR a C(O)R a C(O)NR a R b C(O)OR a OC(O)R a OC(O)OR a OC(O)NR a R b NR a R b N(R a )C(O)R b N(R a )C(O)NR b R c N(R a )C(O)OR b C(=NR a )NR b R c C(=NOR a )NR b R c C(=NOC(O)R a )NR b R c C(=NR a )N(R b )C(O)OR c N(R a )C(=NR b )NR c R d S(O)R a S(O)NR a R b S(O)2R a N(R a )S(O)2R b S(O)2NR a Rb , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and selected from the group consisting of substituted or unsubstituted 4- to 10-membered heterocyclyl, wherein R a , R b , R c , and R d are, each time they appear, independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0148] In some specific embodiments, R 6a , R 6b , R 6c , R 6d , or R 6e is substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, then R 6a , R 6b , R 6c , R 6d , or R 6e is halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)Re 、 OC(O)NR e R f 、 NR e R f 、 NR e C(O)R f 、 NR e C(O)NR f R g 、 NR e C(O)OR f 、 C(=NR e )NR f R g 、 NR e C(=NR f )NR g R h 、 S(O)R e 、 S(O)NR e R f 、 S(O)2R e 、 NR e S(O)2R f 、 S(O)2NR e R f and may be substituted with one or more substituents selected from the group consisting of oxo, where R e 、 R f 、 R g 、 and R h is, independently at each occurrence, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0149] In some embodiments, R 6 has the following structure: TIFF0007699389000096.tif217149TIFF0007699389000097.tif215146TIFF0007699389000098.tif202148.

[0150] In some embodiments, R 6a or R 6b is independently C 1~6 alkyl, deuterated alkyl, amino, or halo. In certain embodiments, R 1~6 or R 6a or R 6b is methyl. In some specific embodiments, R 6a or R 6b is F, Cl, or Br. In some embodiments, each of R 6a or R 6b bonded to nitrogen is C 1~6 alkyl. In more specific embodiments, R 6a or R 6b is methyl or ethyl.

[0151] In some embodiments, R 6 has one of the following structures: TIFF0007699389000099.tif140144.

[0152] In certain embodiments, R 6 has one of the following structures: TIFF0007699389000100.tif49140TIFF0007699389000101.tif216147TIFF0007699389000102.tif179145.

[0153] In some more specific embodiments, R 6 has one of the following structures: TIFF0007699389000103.tif95146.

[0154] In some embodiments, R 7 is C1-C6 alkyl. In more specific embodiments, R 7 is methyl. In more embodiments, R 7 is -NR 10a R 10b or -SR 10c In certain embodiments, R 7 has the following structure: It has one of TIFF0007699389000104.tif11128.

[0155] In some embodiments, R 7 is a substituted or unsubstituted aryl. In certain embodiments, R 7 is unsubstituted phenyl.

[0156] In some embodiments, R 8 is hydrogen, unsubstituted arylalkyl, or C1-C6 alkyl. In more specific embodiments, R 8 is hydrogen, -CH3, or has one of the following structures: It has one of TIFF0007699389000105.tif20128.

[0157] In certain embodiments, R 9 is a substituted or unsubstituted arylalkyl. In some specific embodiments, R 9 is unsubstituted arylalkyl. In certain specific embodiments, R 9 has the following structure: It has TIFF0007699389000106.tif14128.

[0158] In certain embodiments, R 9 is a substituted or unsubstituted heteroarylalkyl. In more specific embodiments, R 9 is unsubstituted heteroarylalkyl. In even more specific embodiments, R 9 has the following structure: It has one of TIFF0007699389000107.tif16128.

[0159] In certain embodiments, R 8 and R 9 together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocyclyl. In certain embodiments, R 8 and R 9Together with the nitrogen to which they are attached, they form an optionally substituted 4-, 5-, or 6-membered heterocyclyl. In some embodiments, R 8 and R 9 together with the nitrogen to which they are attached form one of the following structures: TIFF0007699389000108.tif13128.

[0160] Another embodiment provides a compound having the following structure (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, TIFF0007699389000109.tif32128 wherein, R 11 has one of the following structures: TIFF0007699389000110.tif40133; R 12 is methyl, alkoxy, or halo; R 13 is substituted or unsubstituted aryl; and n is 1 or 2, provided that however, the compound of structure (III) does not have the following structure: TIFF0007699389000111.tif32128.

[0161] In some embodiments, R 11 has the following structure: TIFF0007699389000112.tif16128.

[0162] In certain embodiments, R 11 has the following structure: TIFF0007699389000113.tif17128.

[0163] In some embodiments, R 12 is methyl. In certain embodiments, R 12 is halo or butoxy. In more specific embodiments, R 12 is Br.

[0164] In some embodiments, n is 1. In certain embodiments, n is 2.

[0165] In some embodiments, R 13 is substituted or unsubstituted phenyl. In certain embodiments, R 13 is unsubstituted phenyl.

[0166] Yet another embodiment provides a compound having the following structure (IV) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, TIFF0007699389000114.tif37128wherein, R 14 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 15 is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl; L 2 is a direct bond, -C(=O), or -S(=O) t -; and t is 0, 1, or 2.

[0167] In some embodiments, R 14 is substituted or unsubstituted aryl. In certain embodiments, R 14 is substituted or unsubstituted C6-C 10 aryl. In some specific embodiments, R 14 is substituted or unsubstituted phenyl. In certain specific embodiments, R 14 is substituted phenyl.

[0168] In some embodiments, R 14 is phenyl substituted with one or more of R 14a R 14b R 14c R 14d or R 14e , wherein R 14a R 14b R 14c, R 14d , and R 14e are each independently, C 1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(=NR a )NR b R c , C(=NOR a )NR b R c , C(=NOC(O)R a )NR b R c , C(=NR a )N(R b )C(O)OR c , N(R a )C(=NR b )NR c R d , S(O)R a , S(O)NR a R b , S(O)2R a , N(R a )S(O)2R b , S(O)2NR a R b , oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10Arylalkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3~10 Selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, wherein R a , R b , R c , and R d are, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0169] In certain embodiments, R 14a , R 14b , R 14c , R 14d , or R 14e is substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, then R 14a , R 14b , R 14c , R 14d , or R 14e is halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f, NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(=NR e )NR f R g , NR e , C(=NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O)2R e , NR e S(O)2R f , S(O)2NR e R f and may be substituted with one or more substituents selected from the group consisting of oxo, where R e , R f , R g , and R h is, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0170] In some specific embodiments, R 14 is phenyl substituted with at least one substituent selected from the group consisting of halo, alkyl, hydroxyl, amino, and C(=NR a )NR b R c . In a more specific embodiment, R 14 has one of the following structures: TIFF0007699389000115.tif179148.

[0171] In some embodiments, R 14 has the following structure: has one of TIFF0007699389000116.tif105143.

[0172] In some embodiments, R 14 has the following structure: has one of TIFF0007699389000117.tif22128.

[0173] In some embodiments, R 14 is unsubstituted phenyl.

[0174] In certain embodiments, R 14 is substituted or unsubstituted heteroaryl. In some more specific embodiments, R 14 is substituted or unsubstituted 5- to 10-membered heteroaryl. In certain embodiments, R 14 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolopyridinyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted thienopyridinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted isoindolinyl, or substituted or unsubstituted benzothiazolyl.

[0175] In some embodiments, R 14 is heteroaryl substituted with one or more of R 14a , R 14b , R 14c , R 14d , or R 14e , wherein R 14a , R 14b , R 14c , R 14d , or R 14e are each independently C 1~6 alkyl, C 1~6 deuterated alkyl, C 2~6 alkenyl, C 2~6 alkynyl, halo, C 1~6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SRa 、 C(O)R a 、 C(O)NR a R b 、 C(O)OR a 、 OC(O)R a 、 OC(O)OR a 、 OC(O)NR a R b 、 NR a R b 、 N(R a )C(O)R b 、 N(R a )C(O)NR b R c 、 N(R a )C(O)OR b 、 C(=NR a )NR b R c 、 C(=NOR a )NR b R c 、 C(=NOC(O)R a )NR b R c 、 C(=NR a )N(R b )C(O)OR c 、 N(R a )C(=NR b )NR c R d 、 S(O)R a 、 S(O)NR a R b 、 S(O)2R a 、 N(R a )S(O)2R b 、 S(O)2NR a R b 、 Oxo, substituted or unsubstituted C 6~10 aryl, substituted or unsubstituted C 6~10 arylalkyl, substituted or unsubstituted C 6~10 aryloxy, substituted or unsubstituted C 6~10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, selected from the group consisting of, where R a 、 R b 、 R c 、 and Rd is, independently at each occurrence, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, and is selected from the group consisting of

[0176] In some specific embodiments, R 14a , R 14b , R 14c , R 14d , or R 14e is substituted C 6~10 aryl, substituted C 6~10 arylalkyl, substituted C 6~10 aryloxy, substituted C 6~10 arylalkoxy, substituted 5- to 10-membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, then R 14a , R 14b , R 14c , R 14d , or R 14e is halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e , C(O)OR f , C(=NR e )NR f R g , NR e , C(=NR f )NRg R h 、 S(O)R e 、 S(O)NR e R f 、 S(O)2R e 、 NR e S(O)2R f 、 S(O)2NR e R f and may be substituted with one or more substituents selected from the group consisting of oxo, wherein R e 、 R f 、 R g 、 and R h is, each occurrence independently, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, hydroxyl, C 1~6 alkoxy, aryl, arylalkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0177] In some embodiments, R 14 has the following structure: TIFF0007699389000118.tif217146TIFF0007699389000119.tif220138TIFF0007699389000120.tif219145.

[0178] In more specific embodiments, R 14a or R 14b is independently C 1~6 alkyl, amino, or halo. In some embodiments, R 14a or R 14b is methyl. In certain embodiments, R 14a or R 14b is F, Cl, or Br. In some embodiments, each of R 14a or R 14b bonded to nitrogen is C 1~6 alkyl. In some embodiments, R14a or R 14b is methyl or ethyl.

[0179] In some embodiments, R 14 has one of the following structures: TIFF0007699389000121.tif140144.

[0180] In more specific embodiments, R 14 has one of the following structures: TIFF0007699389000122.tif218147TIFF0007699389000123.tif226145.

[0181] In some embodiments, R 14 has one of the following structures: TIFF0007699389000124.tif95146.

[0182] In some embodiments, R 15 is substituted or unsubstituted arylalkyl. In certain embodiments, R 15 is unsubstituted arylalkyl. In some more specific embodiments, R 15 has one of the following structures: TIFF0007699389000125.tif15128.

[0183] In some more specific embodiments, R 15 is substituted or unsubstituted heteroarylalkyl.

[0184] In certain embodiments, R 15 is unsubstituted heteroarylalkyl. In some embodiments, R 15 has one of the following structures: TIFF0007699389000126.tif30144.

[0185] In certain embodiments, L 2is a direct bond. In some embodiments, L 2 is -C(=O)-. In certain embodiments, L 2 is -S(=O)2-. In some embodiments, L 2 is -S-. In yet another embodiment, L 2 is -S(O)-.

[0186] In some embodiments, the compounds of structures (I), (II), (III) or (IV) and their embodiments may be in the form of salts such as pharmaceutically acceptable salts.

[0187] The compounds of structures (I), (II), (III) or (IV) and their embodiments are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of structures (I), (II), (III) or (IV) and their embodiments are useful in the treatment of MASP-2 related diseases and disorders and in the manufacture of medicaments for treating MASP-2 related diseases and disorders. The present disclosure also provides a method of treating MASP-2 related diseases and disorders comprising administering to a patient a therapeutically effective amount of a compound of structure (I), (II), (III) or (IV) or an embodiment thereof, optionally in the form of a salt.

[0188] In some embodiments, the structure of structures (I), (II), (III) or (IV) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising a compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

[0189] In certain aspects, the compound is one or more selected from compounds of structures (I), (II), (III) or (IV) described in the examples including the compounds listed in Table 1 (e.g., compounds having selectivity for MASP-2 compared to thrombin). In certain aspects, one or more of the variables defining the compounds of structures (I), (II), (III) or (IV) are selected from the corresponding substituents in the compounds of structures (I), (II), (III) or (IV) in the examples including the compounds listed in Table 1, preferably those of compounds having selectivity for MASP-2 compared to thrombin.

[0190] In certain aspects, the disclosure describes stereochemically pure enantiomers or diastereomers (e.g., optically active compounds having one or more stereocenters). Where not specifically indicated, any compound having one or more stereocenters is intended to include and describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures enriched in enantiomers or diastereomers (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and racemic mixtures of enantiomers or diastereomers.

[0191] Certain embodiments provide pharmaceutically acceptable salts of the disclosed chemical structures (e.g., hydrogen halides such as hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are described, for example, in Burge, S. M. et al., J. Pharm. Sci 1977, 66, 1-19. They include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, arylsulfonates, alkylsulfonates, fatty acid salts, etc. The salts can be prepared by various methods known to those skilled in the art including precipitation with a conjugate acid or base (e.g., treatment with HCl gas or HCl solution).

[0192] In certain embodiments, prodrugs are provided. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., from an ester to an acid form, from a carbamate to an amino or hydroxy group; from a hydroxyamidine to an amidine). Exemplary prodrugs are described, for example, in Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191 - 222; Peterlin - Masic et al. Curr. Pharma. Design 2006, 12, 73 - 91. Prodrugs for amidine groups include amidoxime, O - alkylamidoxime, acyl amidine, carbamate, 1,2,4 - oxadiazolin - 4 - one, and the like.

[0193] In certain aspects, the compounds are useful for selectively inhibiting MASP - 2 as compared to thrombin, and the method includes the step of administering a compound described herein. In certain aspects, the selectivity ratio of MASP - 2:thrombin is at least 1.1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1. In certain aspects, the selectivity ratio of MASP - 2:thrombin is at least 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 125:1, 150:1, 175:1, 200:1, 250:1, 300:1, 350:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, 1000:1, 2000:1, 3000:1, 4000:1, 5000:1, 7500:1, 10,000:1, 25,000:1, or 50,000:1, or greater than that.

[0194] III. Synthesis The compounds described herein that contain the salt can be prepared using known organic synthesis techniques and can be synthesized by any of a number of possible synthetic routes, such as those shown in the examples below.

[0195] The reactions for preparing the compounds described herein can be carried out in a suitable solvent that can be readily selected by one of ordinary skill in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, in the range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for the particular reaction step can be selected by one of ordinary skill in the art.

[0196] The preparation of the disclosed compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one of ordinary skill in the art. The chemical nature of protecting groups is described, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0197] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, etc., or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0198] The specific synthetic methods used in the examples provide general guidance related to preparing the disclosed compounds. One of ordinary skill in the art will understand that the preparation methods can be modified or optimized using general knowledge of organic chemistry to prepare various compounds within the scope of this disclosure.

[0199] Starting materials, reagents, and intermediates not described herein as being synthesized are either commercially available or known in the literature, or can be prepared by methods known to one of ordinary skill in the art.

[0200] It will be recognized by those skilled in the art that the described process is not the only means by which the disclosed compounds can be synthesized, and that a wide repertoire of synthetic organic reactions that may be employed in synthesizing the disclosed compounds is available. Those skilled in the art will know how to select and implement an appropriate synthetic route.Suitable synthetic methods for starting materials, intermediates, and products can be identified by referring to the literature including references such as Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry, Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010 / 1-4; 2011 / 1-4; 2012 / 1-2 (Thieme, 2001-2012); Katritzky, et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2nd Edition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

[0201] IV. Treatment Method In another aspect, the present disclosure provides a method of treating a patient who has or is at risk of developing a MASP-2 related disease or disorder, such as a MASP-2 dependent complement related disease or disorder, comprising administering a small molecule inhibitor of MASP-2.

[0202] The compound may be any small molecule inhibitor of MASP-2. In some embodiments, the compound may be a small molecule inhibitor of MASP-2 that binds to the serine protease domain of MASP-2. In some embodiments, the compound may be a small molecule inhibitor, such as a synthetic small molecule inhibitor of MASP-2. In some embodiments, the compound may be a small molecule inhibitor of MASP-2 that binds to the catalytic substrate binding region of MASP-2. In some embodiments, the compound selectively inhibits MASP-2 as compared to thrombin. For example, in some embodiments, the compound is a compound of structure (I), (II), (III) or (IV) described in any of the foregoing embodiments.

[0203] U.S. Patent No. 7,919,094; U.S. Patent No. 8,840,893; U.S. Patent No. 8,652,477; U.S. Patent No. 8,951,522, U.S. Patent No. 9,011,860, U.S. Patent No. 9,475,885, U.S. Patent No. 9,644,035, U.S. Patent Application Publication No. 2013 / 0344073, 2013 / 0266560, 2015 / 0166675, 2017 / 0137537, 2017 / 0166660, 2017 / 0189525, 2017 / 0267781, 2017 / 0283508, 2017 / 0253667, 2018 / 0105604, and International Publication Nos. 2018 / 045054, 2019 / 036460 and co-pending U.S. Patent Application No. 62 / 688,611 (each of which has been assigned to Omeros Corporation, the assignee of the present application, and each of which is hereby incorporated by reference herein), MASP-2-dependent complement activation has been implicated in the etiology of a number of acute and chronic pathologies. For example, as described in U.S. Patent No. 8,951,522, the principal function of the complement system, which is part of the innate immune system, is to protect the host from infectious agents, but inappropriate or excessive activation of the complement system can lead to serious diseases such as endothelial damage and thrombotic microangiopathies (TMAs including aHUS, TTP, and HUS) where fibrin- and platelet-rich thrombi in the microvasculature lead to organ damage. The lectin pathway plays a major role in activating complement and interfering with the activation of MASP-2 under conditions of endothelial stress or injury, and the lectin pathway halts a series of enzymatic reactions that lead to the formation of the membrane attack complex, platelet activation, and leukocyte recruitment. As described in U.S. Patent No. 8,652,477, in addition to initiating the lectin pathway, MASP-2 can also activate the coagulation system and is capable of cleaving prothrombin to thrombin.

[0204] Accordingly, in some embodiments, the method comprises administering to a patient suffering from or at risk of developing a MASP-2-dependent complement-related disease or disorder an amount of the disclosed compound sufficient to inhibit MASP-2-dependent complement activation in a mammalian subject, thereby treating the disease or disorder. In some embodiments, the method may further comprise determining that the patient is suffering from a lectin complement-related disease or disorder prior to administering the disclosed compound to the patient.

[0205] In some embodiments, the MASP-2-dependent complement-related disease or disorder is selected from the group consisting of thrombotic microangiopathy (TMA), kidney disease, inflammatory reactions due to tissue or organ transplantation, ischemia-reperfusion injury, complications associated with diabetes, cardiovascular disease or disorder, inflammatory gastrointestinal disorder, lung disorder, eye disease or disorder, disseminated intravascular coagulation, graft-versus-host disease, veno-occlusive disease, diffuse alveolar hemorrhage, and combinations thereof.

[0206] In some embodiments, the MASP-2-dependent complement-related disease or disorder is thrombotic microangiopathy (TMA) including thrombotic thrombocytopenic purpura (TTP), refractory TTP, Upshaw-Schulman syndrome (USS), hemolytic uremic syndrome (HUS), atypical hemolytic syndrome (aHUS), factor H-independent atypical hemolytic syndrome, aHUS secondary to infection, plasma therapy-resistant aHUS, TMA secondary to cancer, TMA secondary to chemotherapy, TMA secondary to transplantation, or TMA associated with hematopoietic stem cell transplantation.

[0207] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing graft-versus-host disease (GVHD) including acute GVHD, chronic GVHD, or steroid-resistant GVHD an amount of the disclosed compound sufficient to inhibit MASP-2-dependent complement activation in a mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing GVHD has previously undergone, is undergoing, or is about to undergo a hematopoietic stem cell transplantation.

[0208] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing diffuse alveolar hemorrhage (DAH) an amount of the disclosed compound sufficient to inhibit MASP-2-dependent complement activation in a mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing DAH has previously undergone, is undergoing, or is about to undergo a hematopoietic stem cell transplant.

[0209] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing veno-occlusive disease (VOD) an amount of the disclosed compound sufficient to inhibit MASP-2-dependent complement activation in a mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing VOD has previously undergone, is undergoing, or is about to undergo a hematopoietic stem cell transplant.

[0210] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing idiopathic pulmonary syndrome (IPS) an amount of the disclosed compound sufficient to inhibit MASP-2-dependent complement activation in a mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing IPS has previously undergone, is undergoing, or is about to undergo a hematopoietic stem cell transplant.

[0211] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing capillary leak syndrome (CLS) an amount of the disclosed compound sufficient to inhibit MASP-2-dependent complement activation in a mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing CLS has previously undergone, is undergoing, or is about to undergo a hematopoietic stem cell transplant.

[0212] In some embodiments, the method comprises administering to a patient having or at risk of developing engraftment syndrome (ES) an amount of the disclosed compound sufficient to inhibit MASP-2-dependent complement activation in a mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject having or at risk of developing ES has previously undergone, is undergoing, or is to undergo a hematopoietic stem cell transplant.

[0213] In some embodiments, the method comprises administering to a patient having or at risk of developing fluid overload (FO) an amount of the disclosed compound sufficient to inhibit MASP-2-dependent complement activation in a mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject having or at risk of developing FO has previously undergone, is undergoing, or is to undergo a hematopoietic stem cell transplant.

[0214] In some embodiments, the method comprises administering to a patient suffering from any of the diseases or conditions referenced above an amount of a compound disclosed in International Application No. PCT / US19 / 34225, which is hereby incorporated by reference in its entirety.

[0215] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a kidney disease including, but not limited to, mesangial proliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), acute post-infectious glomerulonephritis (post-streptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, pauci-immune necrotizing crescentic glomerulonephritis, lupus nephritis, Henoch-Schönlein purpura nephritis, IgA nephropathy, and combinations thereof.

[0216] In some embodiments, the MASP-2-dependent complement-related disease or disorder is chronic kidney disease, chronic renal failure, glomerular disease (e.g., focal segmental glomerulosclerosis), immune complex disorder (e.g., IgA nephropathy, membranous nephropathy), lupus nephritis, nephrotic syndrome, diabetic nephropathy, tubulointerstitial injury and glomerulonephritis (e.g., C3 glomerulopathy), or nephrotic syndrome, preeclampsia, eclampsia, toxic nephropathy, amyloidosis, collagen vascular disease (e.g., systemic lupus erythematosus), dehydration, glomerular disease (e.g., membranous glomerulonephritis, focal segmental glomerulonephritis, C3 glomerular disorder, minimal change disease, lipoid nephrosis), strenuous exercise, stress, benign orthostatic (postural) proteinuria, focal segmental glomerulosclerosis, IgA nephropathy (i.e., Berger's disease), IgM nephropathy, membranoproliferative glomerulonephritis, membranous nephropathy, minimal change disease, sarcoidosis, Alport syndrome, diabetes (diabetic nephropathy), drug-induced toxicity (e.g., NSAIDs, nicotine, penicillamine, lithium carbonate, gold and other heavy metals, ACE inhibitors, antibiotics (e.g., Adriamycin), opioids (e.g., heroin), or other nephrotoxins); Fabry disease, infectious diseases (e.g., HIV, syphilis, hepatitis A, B or C, post-streptococcal infection, urinary schistosomiasis); aminoaciduria, Fanconi syndrome, hypertensive nephrosclerosis, interstitial nephritis, sickle cell disease, hemoglobinuria, multiple myeloma, myoglobinuria, organ rejection (e.g., kidney transplant rejection), Ebola hemorrhagic fever, nail-patella syndrome, familial Mediterranean fever, HELLP syndrome, systemic lupus erythematosus, Wegener granulomatosis, rheumatoid arthritis, type 1 glycogenosis, Goodpasture syndrome, Henoch-Schönlein purpura, urinary tract infection spreading to the kidney, Sjögren syndrome and post-infectious glomerulonephritis, including but not limited to, fibrosis (e.g., tubulointerstitial fibrosis) and / or proteinuria in a subject having or at risk of developing a disease or condition associated with proteinuria.

[0217] In some embodiments, the MASP-2-dependent complement-related disease or disorder is an inflammatory reaction resulting from tissue or solid organ transplantation, including allograft or xenograft of an organ (e.g., kidney, heart, liver, pancreas, lung, cornea, etc.) as a whole or tissue transplantation (e.g., valve, tendon, bone marrow, etc.).

[0218] In some embodiments, MASP-2-dependent complement-related disorders are ischemia-reperfusion injury (I / R) including myocardial I / R, gastrointestinal I / R, renal I / R, and I / R after aortic aneurysm repair, I / R associated with cardiopulmonary bypass, cerebral I / R, stroke, organ transplantation, or reattachment of severed or traumatized limbs or digits; revascularization of grafts and / or replants, and shock, hemodynamic resuscitation after surgical procedures, etc., and combinations thereof.

[0219] In some embodiments, MASP-2-dependent complement-related diseases or disorders are complications associated with non-obese diabetes (type 1 diabetes or insulin-dependent diabetes) and / or complications associated with type 1 or type 2 (adult-onset) diabetes, including diabetic angiopathy, diabetic neuropathy, diabetic retinopathy, diabetic macular edema, etc., and combinations thereof.

[0220] In some embodiments, MASP-2-dependent complement-related diseases or disorders are cardiovascular diseases or disorders including Henoch-Schönlein purpura nephritis, systemic lupus erythematosus-related vasculitis, vasculitis associated with rheumatoid arthritis (also called malignant rheumatoid arthritis), immune complex vasculitis, and Takayasu disease; dilated cardiomyopathy; diabetic angiopathy; Kawasaki disease (arteritis); venous gas embolism (VGE); and inhibition of restenosis after stent placement, rotational atherectomy, percutaneous transluminal coronary angioplasty (PTCA), etc., and combinations thereof.

[0221] In some embodiments, MASP-2-dependent complement-related diseases or disorders are inflammatory gastrointestinal disorders including pancreatitis, diverticulitis, and bowel disorders including Crohn's disease, ulcerative colitis, irritable bowel syndrome, inflammatory bowel disease (IBD), etc., and combinations thereof.

[0222] In some embodiments, MASP-2-dependent complement-related diseases or disorders are lung disorders including, for example, acute respiratory distress syndrome, transfusion-related acute lung injury, ischemia / reperfusion acute lung injury, chronic obstructive pulmonary disease, asthma, Wegener's granulomatosis, anti-glomerular basement membrane disease (Goodpasture's disease), meconium aspiration syndrome, aspiration pneumonia, bronchiolitis obliterans syndrome, idiopathic pulmonary fibrosis, acute lung injury secondary to burns, non-cardiogenic pulmonary edema, transfusion-related respiratory depression, pulmonary emphysema, and combinations thereof.

[0223] In some embodiments, MASP-2-dependent complement-related diseases or disorders are inflammatory reactions caused by extracorporeal exposure, and the method includes the step of treating a subject undergoing an extracorporeal circulation procedure. In some embodiments, extracorporeal circulation procedures include hemodialysis, plasmapheresis, leukapheresis, extracorporeal membrane oxygenation (ECMO), heparin-induced extracorporeal membrane oxygenation LDL precipitation (HELP), cardiopulmonary bypass (CPB), and the like.

[0224] In some embodiments, MASP-2-dependent complement-related diseases or disorders are selected from inflammatory or non-inflammatory arthritis and other musculoskeletal disorders, such as osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, gout, neuropathic arthritis, psoriatic arthritis, ankylosing spondylitis or other spondyloarthropathies and crystalline arthritis, muscular dystrophy, systemic lupus erythematosus (SLE), and combinations thereof.

[0225] In some embodiments, MASP-2-dependent complement-related diseases or disorders are skin disorders; for example, psoriasis, autoimmune bullous dermatosis, eosinophilic spongiosis, bullous pemphigoid, acquired epidermolysis bullosa, atopic dermatitis, herpes gestationis, and other skin disorders. In some embodiments, MASP-2-dependent complement-related diseases or disorders are burns, chemical burns, or combinations thereof, including capillary leakage caused thereby.

[0226] In some embodiments, MASP-2-dependent complement-related diseases or disorders are peripheral nervous system (PNS) and / or central nervous system (CNS) disorders or injuries, including, but not limited to, multiple sclerosis (MS), myasthenia gravis (MG), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Guillain-Barré syndrome, reperfusion after stroke, intervertebral disc degeneration, traumatic brain injury, Parkinson's disease (PD), Alzheimer's disease (AD), Miller Fisher syndrome, trauma and / or bleeding in the brain, traumatic brain injury, demyelination, meningitis, and combinations thereof.

[0227] In some embodiments, MASP-2-dependent complement-related diseases or disorders are sepsis or conditions resulting from sepsis, including, but not limited to, severe sepsis, septic shock, acute respiratory distress syndrome resulting from sepsis, hemolytic anemia, systemic inflammatory response syndrome, hemorrhagic shock, and combinations thereof.

[0228] In some embodiments, MASP-2-dependent complement-related diseases or disorders are genitourinary disorders, including, but not limited to, painful bladder disorders, sensory bladder disorders, chronic aseptic cystitis and interstitial cystitis, male and female infertility, placental insufficiency and miscarriage, preeclampsia, and combinations thereof.

[0229] In some embodiments, MASP-2-dependent complement-related diseases or disorders are inflammatory responses in subjects being treated with chemotherapy and / or radiotherapy, including, but not limited to, the treatment of cancerous diseases.

[0230] In some embodiments, MASP-2-dependent complement-related diseases or disorders are angiogenesis-dependent cancers, including, but not limited to, solid tumors, blood-borne tumors, high-risk carcinoid tumors, tumor metastasis, and combinations thereof.

[0231] In some embodiments, MASP-2-dependent complement-related diseases or disorders are angiogenesis-dependent benign tumors, including, but not limited to, hemangiomas, acoustic neuromas, neurofibromas, trachomas, carcinoid tumors, pyogenic granulomas, and combinations thereof.

[0232] In some aspects, the MASP-2-dependent complement-related disease or disorder is an endocrine disorder, including prolactin, growth or insulin-like growth factor from the pituitary gland, Hashimoto's thyroiditis with controlled release of adrenocorticotropic hormone, stress, anxiety, other potential hormonal disorders, and combinations thereof.

[0233] In some aspects, the MASP-2-dependent complement-related disease or disorder is an eye disease or disorder, including age-related macular degeneration, glaucoma, endophthalmitis, and combinations thereof.

[0234] In some aspects, the MASP-2-dependent complement-related disease or disorder is an ocular neovascular disease or condition, including age-related macular degeneration, uveitis, ocular melanoma, corneal neovascularization, primary pterygium, HSV stromal keratitis, HSV-1-induced corneal lymphangiogenesis, proliferative diabetic retinopathy, diabetic macular edema, retinopathy of prematurity, retinal vein occlusion, corneal graft rejection, neovascular glaucoma, vitreous hemorrhage secondary to proliferative diabetic retinopathy, neuromyelitis optica, rubeosis, and combinations thereof.

[0235] In some aspects, the MASP-2-dependent complement-related disease or disorder is disseminated intravascular coagulation (DIC) or other complement-mediated coagulation disorders, including DIC secondary to sepsis, severe trauma (e.g., acute head trauma; see Kumura et al, Acta Neurochirurgica 55:23-28 (1987)), infectious diseases (e.g., bacterial, viral, fungal, parasitic), cancer, childbirth complications, liver disease, severe toxic reactions (e.g., snake bites, insect stings, transfusion reactions), shock, heat stroke, transplant rejection, hemangioma, liver failure, cancer treatment by chemotherapy or radiotherapy, burns, or accidental radiation exposure.

[0236] In some embodiments, the MASP-2-dependent complement-related disease or disorder is selected from the group consisting of acute radiation syndrome, dense deposit disease, Degos disease, catastrophic antiphospholipid syndrome (CAPS), Behçet's disease, cryoglobulinemia, paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease, and combinations thereof.

[0237] In some embodiments, the MASP-2-dependent complement-related disease or disorder is selected from the group consisting of aHUS, HSCT-TMA, IgAN, lupus nephritis (LN), and combinations thereof.

[0238] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing a disease, disorder or condition associated with fibrin-induced activation of the complement system and associated activation of the coagulation and / or contact systems, an amount of a compound according to any one of the above-described embodiments (e.g., a compound of structure (I), (II), (III) or (IV)) in an amount sufficient to inhibit MASP-2-dependent complement activation in a mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffers from or is at risk of developing a complement-related inflammation, excessive coagulation or contact system activation initiated by fibrin or activated platelets. In some embodiments, the subject suffers from a disease or disorder selected from the group consisting of arterial thrombosis, venous thrombosis, deep vein thrombosis, postoperative thrombosis, restenosis after coronary artery bypass grafting and / or interventional cardiovascular procedures (e.g., angioplasty or stent placement), atherosclerosis, plaque rupture, plaque instability, restenosis, hypotension, acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), disseminated intravascular coagulation (DIC), veno-occlusive disease (VOD), thrombotic microangiopathy, lupus nephritis, superficial thrombophlebitis, factor V Leiden mutation, ischemic / reperfusion injury, human immunodeficiency virus (HIV) infection, being on hormone replacement therapy (HRT), Alzheimer's disease and / or suffers from a hypercoagulable state.

[0239] In some embodiments, the subject has or is at risk of developing an acquired hypercoagulable state due to at least one or more of the following: being under a treatment regimen with a drug selected from the group consisting of 5-FU, GM-CSF, cisplatin, heparin, a COX-2 inhibitor, a contrast agent, a corticosteroid, and an antipsychotic; venous stasis (constraint, surgery, etc.), antiphospholipid antibody syndrome, cancer (promyelocytic leukemia, lung, breast, prostate, pancreas, stomach, and colon tumors), tissue injury by trauma or surgery, the presence of a catheter in a central vein, an acquired deficiency of a protein involved in blood clot formation (e.g., protein C), paroxysmal nocturnal hemoglobinuria (PNH), elevated homocysteine levels, heart failure, the presence of a mechanical valve, pulmonary hypertension with in situ thrombosis, atrial fibrillation, heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia and thrombosis (HITT), Kawasaki disease with in situ thrombosis, Takayasu arteritis with in situ thrombosis, thrombotic predisposition of metastatic cancer, elevated factor VIII levels, pregnancy, inflammatory bowel disease (IBD), or a genetic abnormality that causes or increases the risk of developing a hypercoagulable state, such as a genetic abnormality selected from the group consisting of a prothrombin 20210 gene mutation, an MTHFR mutation, a deficiency of protein C, a deficiency of protein S, a deficiency of protein A, a deficiency of protein Z, an antithrombin deficiency, and a genetic disorder that results in a thrombotic predisposition.

[0240] In some embodiments, the subject has or is at risk of developing a disease or disorder amenable to treatment with a kallikrein inhibitor. In some embodiments, the subject has or is at risk of developing a disease or disorder amenable to treatment with a kallikrein inhibitor selected from the group consisting of hereditary angioedema, diabetic macular edema, and bleeding during cardiopulmonary bypass. In some embodiments, the subject has or is at risk of developing a disease or disorder amenable to treatment with a thrombin inhibitor, such as arterial thrombosis, venous thrombosis, pulmonary embolism, atrial fibrillation, heparin-induced thrombocytopenia, conversion from one anticoagulant to another, or off-label use for maintenance of extracorporeal circuit patency (maintenance) of continuous renal replacement therapy (CRRT) in critically ill patients with HIT.

[0241] In some embodiments, the subject has previously experienced, currently has, or is at risk of developing atrial fibrillation, and the MASP-2 inhibitor compound (e.g., a compound of structure (I), (II), (III), or (IV)) is administered in an amount sufficient to reduce the risk of stroke in the subject. In some embodiments, the subject has, or is at risk of developing, a disease or disorder suitable for treatment with a factor XII inhibitor, such as deep vein thrombosis (both primary prevention and long-term treatment), pulmonary embolism, non-valvular atrial fibrillation, prevention of recurrent ischemia after acute coronary syndrome in subjects with or without atrial fibrillation, end-stage renal disease, cerebral ischemia, angina, or reduction or prevention of coagulation associated with medical devices (e.g., valves, small diameter grafts, etc.) and / or extracorporeal circuits.

[0242] In some embodiments, the subject has previously experienced, currently has, or is at risk of developing non-valvular atrial fibrillation, and the MASP-2 inhibitor compound (e.g., a compound of structure (I), (II), (III), or (IV)) is administered in an amount sufficient to reduce the risk of stroke and / or embolism in the subject. In some embodiments, the subject has an acquired disease or disorder that increases the tendency to thromboembolism, such as atherosclerosis, antiphospholipid antibodies, cancer (e.g., promyelocytic leukemia, lung, breast, prostate, pancreas, stomach, and colon), hyperhomocysteinemia, infectious diseases, tissue damage, venous stasis (such as due to surgery, orthopedic or paralytic restraint, heart failure, pregnancy, or obesity), and the subject taking an oral contraceptive containing estrogen.

[0243] In some embodiments, the subject requires anticoagulation therapy and the MASP-2 inhibitory compound (e.g., a compound of structure (I), (II), (III) or (IV)) is used as an alternative to standard anticoagulation therapy (e.g., warfarin). In some embodiments, the subject has a condition in which standard anticoagulation therapy is usually contraindicated, such as CNS amyloid angiopathy. In some embodiments of the method, the MASP-2 inhibitory compound is administered as a bridging agent perioperatively to a subject receiving standard anticoagulation therapy. In some embodiments, the subject has sickle cell disease, which is a vascular occlusive disorder associated with platelet activation.

[0244] Atypical hemolytic uremic syndrome (aHUS) is part of a spectrum of conditions called "thrombotic microangiopathies." In the atypical form of HUS (aHUS), the disease is associated with abnormal regulation of the complement and can be either sporadic or familial. Familial cases of aHUS are associated with mutations in genes encoding complement activation or complement regulatory proteins, including complement factor H, factor I, factor B, CD46 membrane cofactor, and complement factor H-related protein 1 (CFHR1) and complement factor H-related protein 3 (CFHR3). (Zipfel, P.F., et al., PloS Genetics 3(3):e41 (2007)). The unifying feature of this diverse set of gene mutations associated with aHUS is a predisposition to enhanced complement activation at the cell or tissue surface. A subject is at risk of developing aHUS upon the occurrence of at least one or more symptoms indicative of aHUS (e.g., the presence of anemia, thrombocytopenia, and / or renal insufficiency) and / or upon the presence of thrombotic microangiopathy in a biopsy obtained from the subject. In determining whether a subject is at risk of developing aHUS, Determining whether a subject has a genetic predisposition to develop aHUS, by evaluating genetic information (e.g., from a database containing the genotype of the subject), or by performing at least one genetic screening test on the subject via either genome sequencing or gene-specific analysis (e.g., PCR analysis) to determine the presence or absence of gene markers associated with aHUS (i.e., complement factor H (CFH), factor I (CFI), factor B (CFB), membrane complement factor CD46, C3, complement factor H-related protein 1 (CFHR1), or THBD (encoding the anticoagulant protein thrombomodulin) or complement factor H-related protein 3 (CFHR3), or complement factor H-related protein 4 (CFHR4)), and / or Determining whether the subject has a family history of aHUS is included. Methods for genetic screening for the presence or absence of mutations in genes associated with aHUS are well established; see, for example, Noris M et al. "Atypical Hemolytic-Uremic Syndrome," 2007 Nov 16 [Updated 2011 Mar 10]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews(tm), Seattle (WA): University of Washington, Seattle

[0245] Hematopoietic stem cell transplantation-related thrombotic microangiopathy (HSCT-TMA) is a life-threatening complication caused by endothelial injury. The kidney is the most commonly affected organ, but HSCT-TMA can be a multi-system disease involving the lung, intestine, heart, and brain. Even the occurrence of mild TMA is associated with long-term renal dysfunction. The incidence of post-allogeneic HSCT-related TMA varies based on various diagnostic criteria and conditions as well as prophylaxis regimens for graft-versus-host disease, with calcineurin inhibitors being the most frequently implicated agents (Ho VT et al., Biol Blood Marrow Transplant, 11(8):571-5, 2005).

[0246] Immunoglobulin A nephropathy (IgAN) is an autoimmune kidney disease that causes inflammation and damage in the kidneys. IgAN is the most common primary glomerular disease worldwide. In the United States, the annual incidence is approximately 2.5 per 100,000 people, and it is estimated that 1 in 1,400 people develop IgAN. As many as 40% of IgAN patients will develop end-stage renal disease (ESRD). Patients typically present with microscopic hematuria with mild to moderate proteinuria and varying levels of renal insufficiency (Wyatt R.J., et al., NEnglJ Med 36S(25):2402-4, 2013). Clinical markers such as kidney dysfunction, persistent hypertension, and severe proteinuria (more than 1 g per day) are associated with a poor prognosis (Goto M et al., Nephrol Dial Transplant 24(10):3068-74, 2009; Berthoux F. et al., J Am Soc Nephrol 22(4):752-61, 2011). Proteinuria is the most powerful prognostic factor independent of other risk factors in multiple large observational studies and prospective trials (Coppo R. et al., J Nephrol 18(5):503-12, 2005; Reich H. N., et al., J Am Soc Nephrol 18(12):3177-83, 2007). If left untreated, it is estimated that 15-20% of patients will reach ESRD within 10 years of onset (D'Amico G., Am J Kidney Dis 36(2):227-37, 2000). The diagnostic feature of IgAN is the predominance of IgA deposits alone or together with IgG, IgM, or both in the glomerular interstitium.

[0247] The main complication of systemic lupus erythematosus (SLE) is nephritis, also known as lupus nephritis, which is classified as a secondary form of glomerulonephritis. Kidney involvement in some form occurs in up to 60% of adults with SLE in the latter half of the disease process (Koda-Kimble et al., Koda-Kimble and Young's Applied Therapeutics: the clinical use of drugs, 10th Ed, Lippincott Williams & Wilkins: pages 792-9, 2012), with a prevalence of 20-70 per 100,000 in the United States. Lupus nephritis is often seen in patients along with other symptoms of active SLE, including malaise, fever, rash, arthritis, serositis, or central nervous system disease (Pisetsky D.S. et al., Med Clin North Am 81(1): 113-28, 1997). Some patients have asymptomatic lupus nephritis; however, an increase in serum creatinine levels, a decrease in albumin levels, or abnormal test findings such as urinary protein or sediment during regular follow-up suggest active lupus nephritis.

[0248] V. Compositions, Dosages, and Administrations The compounds described herein (e.g., compounds of structures (I), (II), (III), or (IV)) can be administered in a manner compatible with the dosage form and in an amount effective or suitable for treatment. The amount administered will vary depending on various factors including, for example, the age, weight, physical activity, and diet of the individual, as well as the desired effect. In certain embodiments, the magnitude of the dosage can also be determined by the presence, nature, and extent of any adverse side effects associated with the administration of the compound in a particular individual.

[0249] However, the specific dosage levels and frequency of administration for any given patient may vary depending on the physician and will be understood to vary depending on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, age, body weight, genetic characteristics, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host being treated.

[0250] In certain embodiments, the dosage may be in the form of a solid, semi-solid, or liquid, preferably in the form of a unit dosage form suitable for easy administration of an exact dosage.

[0251] As used herein, the term "unit dosage form" refers to physically discrete units suitable as a single dosage for humans and other mammals, each unit containing a predetermined quantity of the active agent calculated to produce the desired manifestation of activity, tolerance, and / or effective action in association with a suitable pharmaceutical excipient (e.g., an ampoule). Further, more concentrated dosage forms may be prepared from which more dilute unit dosage forms may then be produced.

[0252] The compounds described herein (e.g., compounds of structures (I), (II), (III), or (IV)) can be administered to a subject in need of treatment using methods known in the art, such as by oral administration or by injection. The injection can be, for example, subcutaneous, intravenous, intraperitoneal, or intramuscular. As described herein, parenteral formulations can be prepared in unit dosage form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to physically discrete units suitable as a single dosage form for each subject to be treated; each unit contains a predetermined quantity of the active compound calculated to produce the desired therapeutic effect.

[0253] The pharmaceutical composition of the present application comprises a therapeutically effective amount of the compound of the present disclosure (e.g., a compound of structure (I), (II), (III), or (IV)) formulated with one or more pharmaceutically acceptable carriers or excipients. As used herein, the term "pharmaceutically acceptable carrier" means any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. The pharmaceutical compositions for this use can be administered orally, rectally, parenterally, intracapsularly, intravaginally, intraperitoneally, topically (by powder, ointment, or droplet), buccally, or as an oral or nasal spray to humans and other animals.

[0254] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0255] Injectable formulations include, for example, sterile aqueous or oily suspensions formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable formulations may also be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that may be employed include water, U.S. Pharmacopeia Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils have conventionally been employed as solvents or suspending media. For this purpose, any low-irritant fixed oil containing synthetic mono- or diglycerides can be employed. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0256] To prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved using a liquid suspension of a crystalline or amorphous material with low water solubility. And the absorption rate of the drug varies according to its dissolution rate, which in turn can vary according to crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered dosage form is achieved by dissolving or suspending the drug in an oily vehicle.

[0257] Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose, i.e., milk sugar, and high molecular weight polyethylene glycol.

[0258] The active compound can also be in microencapsulated form containing one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also contain additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose, in the usual customary manner. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0259] Dosage forms for topical or transdermal administration of the compounds disclosed in the foregoing aspects (e.g., compounds of structures (I), (II), (III) or (IV)) include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. For example, the active ingredient may be mixed under aseptic conditions with a pharmaceutically acceptable carrier or excipient and, optionally, any necessary preservative or buffering agent.

[0260] Transdermal patches have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0261] According to the treatment methods of the present disclosure, a disorder is treated or prevented in a subject such as a human or other animal by administering to the subject a therapeutically effective amount of a compound according to any one of the foregoing aspects in an amount and for a time necessary to achieve the desired result. As is well understood in the medical field, a therapeutically effective amount of a compound will be present at a reasonable benefit / risk ratio applicable to any medical treatment.

[0262] Generally, the compounds (e.g., compounds of structures (I), (II), (III) or (IV)) are administered in a therapeutically effective amount, either alone or in combination with one or more other therapeutic agents, via any of the conventional and acceptable modes known in the art. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors.

[0263] Generally, satisfactory results have been shown to be obtained systemically at a daily dose of about 0.03 - 2.5 mg / kg body weight. The daily doses presented for larger mammals, such as humans, are in the range of about 0.5 mg to about 250 mg, about 5 mg to about 150 mg, about 5 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, e.g., 10, 20, 30, 40, or about 50 mg, and are conveniently administered, for example, in divided doses up to a maximum of 4 times a day or in a delayed form. Suitable unit dosage forms for oral administration contain about 1 - 60 mg of the active ingredient.

[0264] In certain embodiments, the therapeutic amount or dose of the compound (e.g., a compound of structures (I), (II), (III) or (IV)) is about 0.1 mg / kg ~ about 500 mg / kg or about 1 mg / kg ~ about 50 mg / kg and may be in the range. Generally, the treatment regimens according to the present application involve the administration of about 10 mg to about 1000 mg of the compound per day, in single or multiple doses, to patients in need of such treatment. The therapeutic amount or dose will also vary depending on the route of administration and the possibility of combination with other agents.

[0265] Once the condition of the subject has improved, the maintenance amount of the compound, composition, or combination of the present application may be administered as needed. Thereafter, depending on the symptoms, the dosage or dosing frequency, or both, may be reduced to a level at which the improved condition is maintained, and treatment should be discontinued when the symptoms have been alleviated to a desirable level. However, upon recurrence of the disease symptoms, the subject may require intermittent treatment over a long period of time.

[0266] However, it will be understood that the total daily usage amount of the compound (e.g., the compound of formula (I), (II), (III) or (IV)) and its composition is determined by the attending physician within the scope of sound medical judgment. The specific inhibitory amount for any particular patient will vary depending on the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration, and excretion rate of the specific compound employed; the duration of treatment; the drugs to be combined with or used concomitantly with the specific compound employed; and various factors including similar factors well known in the medical arts.

[0267] The present application also provides a) a first agent that is a compound of the present application disclosed herein in free form or in pharmaceutically acceptable salt form, and b) at least one adjuvant in a pharmaceutical combination, such as a kit. The kit may include instructions for its administration.

[0268] Methods for preparing such dosage forms are known to those skilled in the art (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ED., Mack Publishing Co., Easton, PA (1990)). Dosage forms typically include conventional pharmaceutical carriers or excipients and may further include other drugs, carriers, adjuvants, diluents, tissue penetration enhancers, solubilizing agents, etc. Suitable excipients can be tailored for a particular dosage form and route of administration by methods well known in the art (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ED., Mack Publishing Co., Easton, PA (1990)).

Examples

[0269] The following examples are provided only by way of illustration and not limitation. Those skilled in the art will readily recognize various minor parameters that can be changed or modified to obtain essentially the same results.

[0270] Basic method Unless otherwise specified, chromatography refers to flash chromatography performed on silica gel. "Amine column" refers to flash chromatography performed on a Redisep Rf Gold high-performance amine column.

[0271] HPLC purification was performed by one of two methods. Method 1: On a Gilson preparative reverse-phase HPLC system combined with a UV / ELS detector (254 nm and 280 nm) and a ThermoFisher Hypersil GOLD Agilent (21.2×250 mm) 5 μm C 18 column. The eluent was a mixture of water and acetonitrile (containing 0.05% trifluoroacetic acid). The flow rate was typically 20 mL / 分and the water in acetonitrile had a linear gradient that changed from 2 to 90% over 45 minutes. The injection volume was 1 - 3 mL, with a maximum of 20 mg per injection. Method 2: On a Waters preparative reverse-phase HPLC system combined with a UV / MS detector (254 nm and 280 nm) and an XBridge Prep (19×50 mm) C 18 10 μM OBD column. The eluent was a mixture of water and acetonitrile (containing 0.05% trifluoroacetic acid). The flow rate was typically 50 mL / 分 and the water in acetonitrile had a linear gradient that changed from 5 to 95% over 8 minutes. The injection volume was 0.2 - 1 mL, with a maximum of 20 mg per injection.

[0272] Abbreviations μ micro ℃ degree Celsius Ac acetyl anhyd anhydrous aq aqueous atm atmosphere Bn benzyl Boc tert-butoxycarbonyl Bu butyl calcd calculated value Cbz benzyloxycarbonyl CPME cyclopentylmethyl ether concd concentrated conc concentration DCC N,N'-dicyclohexylcarbodiimide DIEA N,N-diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DMF dimethylformamide DMSO dimethyl sulfoxide EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride equiv equivalent ES electrospray Et ethyl Et2O diethyl ether g gram h hour HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HPLC High Performance Liquid Chromatography / High Performance Liquid Chromatography HOBt 1-hydroxybenzotriazole hydrate iPrOH Isopropanol L liter LiOH Lithium hydroxide m milli M Molar concentration MeCN Acetonitrile min minute mL Milliliter mol mole; molecule (in the case of mol wt, etc.) MS Mass spectrometry MW Molecular weight NBS N-bromosuccinimide NCS N-chlorosuccinimide NHS N-hydroxysuccinimide NMM 4-methylmorpholine NMR Nuclear magnetic resonance o ortho obsd Observed value p para Pd-RuPhos-G2 chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) Pd-XPhos-G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) Ph Phenyl ppt Precipitate Pr Propyl psi pounds per square inch RT room temperature (e.g., about 20 - 23 °C) temp temperature TFA trifluoroacetic acid THF tetrahydrofuran

[0273] Example 1 Preparation of N-((6-amino-2-methylpyridin-3-yl)methyl)-2-(2-methyl-6-oxo-5-((phenylmethyl)sulfonamido)pyrimidin-1(6H)-yl)acetamide, trifluoroacetate (Compound 1) TIFF0007699389000127.tif24128 Step 1 : 440 mg (11 mmol) of NaH (60% in oil) was charged into a 100 mL RBF and washed three times with hexane under Ar. Then 5-amino-2-methylpyrimidin-4(3H)-one (1.25 g, 10 mmol), THF (10 mL) and DMF (5 mL) were added to the flask and the mixture was stirred at room temperature for 1.5 h. Then ethyl bromoacetate (1.33 mL, 12 mmol) was added undiluted and the reaction was stirred at room temperature for 1.5 h. Then the reaction was diluted with ethyl acetate, quenched with H2O and partitioned. The organic layer was washed with 5% aqueous LiCl solution and brine, dried over Na2SO4, filtered through a silica gel plug using ethyl acetate and concentrated to give a 4:1 mixture of N- vs O-alkylation products (965 mg, 46% yield).

[0274] TIFF0007699389000128.tif25128 Step 2: Ethyl 2-(5-amino-2-methyl-6-oxopyrimidin-1(6H)-yl)acetate (110 mg, 0.52 mmol) was dissolved in THF (5 mL), cooled to 0 °C, and treated with NMM (114 μL, 1.04 mmol). Sulfonyl chloride (109 mg, 0.57 mmol) in THF (5 mL) was slowly added via syringe, and the resulting mixture was then stirred at room temperature for 12 h. The reaction was then diluted with ethyl acetate, washed with 1 N HCl, brine, saturated NaHCO3, dried over Na2SO4, and concentrated. The residue was then purified by chromatography (6 - 8% MeOH / DCM) to afford ethyl 2-(2-methyl-6-oxo-5-((phenylmethyl)sulfonamido)pyrimidin-1(6H)-yl)acetate as a pale yellow solid (190 mg, quantitative).

[0275] TIFF0007699389000129.tif19138 Step 3 : Ethyl 2-(2-methyl-6-oxo-5-((phenylmethyl)sulfonamido)pyrimidin-1(6H)-yl)acetate (190 mg, 0.52 mmol) was dissolved in MeOH (5 mL) and treated with 1 N NaOH (5 mL). The reaction mixture was stirred at room temperature for 12 h, and then the organics were removed in vacuo. The aqueous layer was acidified with 1 N HCl and then extracted with ethyl acetate (×3). The combined organics were washed with brine, dried over Na2SO4, and concentrated to afford 2-(2-methyl-6-oxo-5-((phenylmethyl)sulfonamido)pyrimidin-1(6H)-yl)acetic acid as an off-white solid (39 mg, 22% yield).

[0276] TIFF0007699389000130.tif25144 Step 4: 2-(2-Methyl-6-oxo-5-((phenylmethyl)sulfonamido)pyrimidin-1(6H)-yl)acetic acid (20 mg, 0.06 mmol) was dissolved in DCM (2 mL) and treated with NHS (8 mg, 0.07 mmol) and DCC (13 mg, 0.063 mmol). After 30 minutes, 5-(aminomethyl)-6-methylpyridin-2-amine (10 mg, 0.07 mmol) was added and the mixture was stirred for 30 minutes. Next, the reaction was concentrated, diluted with H2O, filtered, and purified by preparative HPLC (35 - 65% acetonitrile / H2O + TFA) to afford the title compound as a white solid (12 mg, 35% yield).

[0277] Example 2 Preparation of N-((6-Amino-2-methylpyridin-3-yl)methyl)-2-(2-methyl-6-oxo-5-(phenethylamino)pyrimidin-1(6H)-yl)acetamide, trifluoroacetate (Compound 2) TIFF0007699389000131.tif25128 Step 1 : Ethyl 2-(5-amino-2-methyl-6-oxopyrimidin-1(6H)-yl)acetate (385 mg, 1.8 mmol) and phenylacetaldehyde (213 μL, 2 mmol) were dissolved in 1,2-DCE (5 mL) and cooled to 0 °C. A solution of NaBH4 (79 mg, 2.1 mmol), acetic acid (361 μL, 6.3 mmol), and 1,2-DCE (5 mL) was added dropwise to the stirred mixture, and then the reaction was warmed to room temperature and stirred for 2 hours. Upon completion, saturated NaHCO3 was added to the reaction and the mixture was extracted three times with DCM. The combined organics were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography (90% ethyl acetate / hexane) to afford ethyl 2-(2-methyl-6-oxo-5-(phenethylamino)pyrimidin-1(6H)-yl)acetate as a yellow solid (138 mg, 24% yield).

[0278] TIFF0007699389000132.tif23146 Steps 2 - 3 : The title compound was prepared as a white powder according to Steps 3 - 4 of the procedure for Compound 1 using appropriate starting materials. Yield = 11 mg, 87%.

[0279] The following compounds were synthesized according to the procedure described above by replacing the appropriate amine starting materials. TIFF0007699389000133.tif21152

[0280] Example 3 Preparation of N-((2-Amino-1H-benzo[d]imidazol-6-yl)methyl)-2-(6-oxo-5-(phenethylamino)-2-phenylpyrimidin-1(6H)-yl)acetamide, trifluoroacetate (Compound 4) TIFF0007699389000134.tif25147 Step 1 : A mixture of tert-butyl 2-(5-bromo-2-(methylthio)-6-oxopyrimidin-1(6H)-yl)acetate (182 mg, 0.5 mmol), Cs2CO3 (326 mg, 1 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), and rac-BINAP (62 mg, 0.1 mmol) was combined in a high-pressure flask under an argon atmosphere, and toluene (5 mL) was added under Ar. Phenethylamine (126 μL, 1 mmol) was added, and the reaction was stirred at 120 °C for 16 h. The heterogeneous mixture was then cooled, filtered through a medium sintered glass funnel, washed with ethyl acetate, and the filtrate was concentrated. The crude material was purified by chromatography (0 - 60% ethyl acetate / hexane) to give tert-butyl 2-(2-(methylthio)-6-oxo-5-(phenethylamino)pyrimidin-1(6H)-yl)acetate as a white solid (166 mg, 82% yield).

[0281] TIFF0007699389000135.tif28145 Step 2: 2-(2-(Methylthio)-6-oxo-5-(phenethylamino)pyrimidin-1(6H)-yl)acetic acid tert-butyl (334 mg, 1 mmol), phenylboronic acid (244 mg, 2 mmol), CuTC (419 mg, 2.2 mmol), and Pd(PPh3)4 (116 mg, 10 mol%) were charged into a 100 mL pressure flask. Anhydrous THF (15 mL) was added under an argon atmosphere. The reaction was sealed and stirred at 55 °C for 18 h and monitored by LCMS. When the reaction was complete, the mixture was cooled to ambient temperature, ethyl acetate was added, and the mixture was filtered through a medium frit glass funnel. The filtrate was washed with brine and saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated to a viscous oil. The residue was purified by chromatography (40% ethyl acetate / hexane) to give 2-(6-oxo-5-(phenethylamino)-2-phenylpyrimidin-1(6H)-yl)acetic acid tert-butyl as a colorless solid (350 mg, 78% yield).

[0282] TIFF0007699389000136.tif27150 Step 3 : 2-(6-Oxo-5-(phenethylamino)-2-phenylpyrimidin-1(6H)-yl)acetic acid tert-butyl (110 mg, 0.27 mmol), TFA (5 mL), and DCM (10 mL) were charged into a 100 mL RBF equipped with a magnetic stir bar. The mixture was stirred at room temperature for 5 h and concentrated to give 2-(6-oxo-5-(phenethylamino)-2-phenylpyrimidin-1(6H)-yl)acetic acid as a yellow foam (75 mg, 80%).

[0283] TIFF0007699389000137.tif46147 Step 4: A mixture of 2-(6-oxo-5-(phenethylamino)-2-phenylpyrimidin-1(6H)-yl)acetic acid (35 mg, 0.1 mmol), 6-(aminomethyl)-1H-benzo[d]imidazole-2-amine dihydrochloride (31 mg, 0.13 mmol), DIEA (67 μL, 0.39 mmol), and DMF (1 mL) was combined in a 20 mL reaction vial. HBTU (46 mg, 0.12 mmol) was added all at once, and the reaction was stirred at room temperature until completion. The mixture was then concentrated and purified by preparative HPLC (H2O / acetonitrile + TFA) to afford the title compound as a white powder (30 mg, 50% yield).

[0284] Example 4 Preparation of N-((2-amino-1H-benzo[D]imidazol-6-yl)methyl)-2-(2-(methylthio)-6-oxo-5-(phenethylamino)pyrimidin-1(6H)-yl)acetamide (Compound 5) TIFF0007699389000138.tif54135 Steps 1 - 2 : Except for purification by chromatography (MeOH / DCM + NH3), the title compound was prepared as a white powder according to Steps 3 - 4 of Example 3 using appropriate starting materials. Yield = 5 mg, 54%.

[0285] Example 5 Preparation of N-((6-amino-2-methylpyridin-3-yl)methyl)-2-(6-oxo-5-(phenethylamino)-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 6) TIFF0007699389000139.tif37145 Except for purification by chromatography (MeOH / DCM + NH3), the title compound was prepared as a white fluffy powder according to Step 4 of Example 3 using appropriate starting materials. Yield = 8 mg, 40%.

[0286] Example 6 Preparation of N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-(6-methyl-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 7) TIFF0007699389000140.tif29150Except for purification by chromatography (MeOH / DCM + NH3), the title compound was prepared as a white powder (32 mg, 64% yield) according to Step 4 of Example 3 using appropriate starting materials.

[0287] Example 7 Preparation of N-((2-amino-1H-benzo[d]imidazol-6-yl)methyl)-2-(6-bromo-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 8) TIFF0007699389000141.tif22128 Step 1 : A mixture of 2-chloropyrazine (1.34 mL, 15 mmol) and phenethylamine (1.89 mL, 15 mmol) in NMP (5 mL) was heated to 150 °C for 15 minutes in a microwave reactor. The cooled reaction mixture was poured into ethyl acetate, and the organic layer was washed with saturated NaHCO3, brine (twice), dried over Na2SO4, and evaporated to dryness.

[0288] TIFF0007699389000142.tif16128 Step 2 : NBS (6.66 g, 37.5 mmol) was added portionwise to a stirred solution of N-phenethylpyrazin-2-amine (3 g, 15 mmol) in DMSO (30 mL) / H2O (0.75 mL) at 0 °C. The reaction mixture was then slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was then poured into ice-cold H2O and extracted with ethyl acetate (thrice). The combined organics were washed with saturated NaHCO3, brine (twice), dried, and 3,5-dibromo-N-phenethylpyrazin-2-amine was obtained as a brown oil (5.16 g, 97% yield in two steps).

[0289] TIFF0007699389000143.tif19128 Step 3: To a suspension of 3,5-dibromo-N-phenethylpyrazine-2-amine (2.83 g, 8 mmol) in dioxane (4 mL) / H2O (40 mL) was added KOH (2.25 g, 40 mmol) portionwise, and then the mixture was refluxed for 18 h. An additional 2 eq of KOH was added and the mixture was refluxed for an additional 6 h. The reaction was then cooled and filtered through Celite®. The filtrate was acidified with 3 N HCl, at which time a white precipitate formed and was collected by filtration to afford 6-bromo-3-(phenethylamino)pyrazin-2(1H)-one (2.25 g, 96% yield).

[0290] TIFF0007699389000144.tif24149 Step 4 : To a suspension of calcium hydride (505 mg, 12 mmol) in THF (8 mL) was added 6-bromo-3-(phenethylamino)pyrazin-2(1H)-one (1.465 g, 5 mmol) portionwise. The reaction mixture was refluxed for 30 min and then cooled to room temperature. tert-Butyl bromoacetate (886 μL, 6 mmol) in THF (4 mL) was added dropwise to the stirring reaction, and then the mixture was refluxed for 18 h. An additional 0.5 eq of tert-butyl bromoacetate (369 μL, 2.5 mmol) in THF (2 mL) was added and the reaction was refluxed for an additional 4 h. Upon cooling, the mixture was poured into ice-cold H2O and extracted with ethyl acetate (3×). The combined organics were washed with saturated NH4Cl, brine, dried over MgSO4, and evaporated to dryness. The crude material was purified by chromatography (20% ethyl acetate / hexanes) to afford tert-butyl 2-(6-bromo-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate as a white solid (904 mg, 44% yield).

[0291] TIFF0007699389000145.tif46145 Steps 5 - 6 : Except for purification by chromatography (amine column, 15 - 20% MeOH / DCM), the title compound was prepared as a white powder (19 mg, 52% yield) according to Steps 3 - 4 of Example 3 using the appropriate starting materials.

[0292] Example 8 Preparation of N-((2-amino-1H-benzo[d]imidazol-5-yl)methyl)-2-(2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetamide (Compound 9) TIFF0007699389000146.tif27139 Step 1 : To a 20 mL pressure vial were charged tert-butyl 2-(6-bromo-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate (163 mg, 0.4 mmol), phenylboronic acid (73 mg, 0.6 mmol), Pd(PPh3)4 (46 mg, 0.04 mmol) and Cs2CO3 (261 mg, 0.8 mmol). The vial was purged with argon, then THF (2 mL) and H2O (200 μL) were added, the reaction mixture was sealed and stirred at 65 °C for 12 h. Upon completion by LCMS, the mixture was diluted with ethyl acetate, washed with saturated NaHCO3, brine, dried over MgSO4 and evaporated to dryness. The crude material was purified by chromatography (35% ethyl acetate / hexane) to give tert-butyl 2-(2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetate as a yellow oil (116 mg, yield 72%).

[0293] TIFF0007699389000147.tif40145 Steps 2 - 3 : Except for purification by chromatography (amine column, 0 - 20% MeOH / DCM), the title compound was prepared as a white powder according to Steps 3 - 4 of Example 3 using the appropriate starting materials. Yield = 20 mg, 40%.

[0294] The following compounds were prepared according to the foregoing procedure using the appropriate boronic acid and amine starting materials. TIFF0007699389000148.tif31148

[0295] The following compounds were prepared according to the foregoing procedure using the appropriate boronic acid and amine starting materials and purification via preparative HPLC (acetonitrile / H2O + TFA). TIFF0007699389000149.tif45158

[0296] Example 9 Preparation of 3-(4-(2-(((2-amino-1H-benzo[d]imidazol-6-yl)methyl)amino)-2-oxoethyl)-5-oxo-6-(phenethylamino)-4,5-dihydropyridin-3-yl)benzamide, trifluoroacetate (Compound 15) To a stirred solution of urea peroxide (38 mg, 0.4 mmol) in H2O (0.25 mL) was added NaOH (9.5 mg, 0.24 mmol). The resulting mixture was cooled in an ice bath and then a solution of N-((2-amino-1H-benzo[d]imidazol-6-yl)methyl)-2-(5-(3-cyanophenyl)-3-oxo-2-(phenethylamino)-3,4-dihydropyridin-4-yl)acetamide (35 mg, 0.07 mmol) in EtOH (1 mL) was added. The reaction mixture was stirred vigorously at room temperature for 2 h. The mixture was diluted with ethyl acetate and washed with H2O, saturated NaHCO3 and brine, then dried over MgSO4 and concentrated in vacuo. The residue was then purified by preparative HPLC (acetonitrile / H2O + TFA) to afford the title compound as a white powder (7.5 mg, 17% yield).

[0297] Example 10 Preparation of 3-(4-(2-(((2-amino-1H-benzo[d]imidazol-6-yl)methyl)amino)-2-oxoethyl)-5-oxo-6-(phenethylamino)-4,5-dihydropyridin-3-yl)benzoic acid, trifluoroacetate (Compound 16) Methyl 3-(4-(2-(((2-amino-1H-benzo[d]imidazol-6-yl)methyl)amino)-2-oxoethyl)-5-oxo-6-(phenethylamino)-4,5-dihydropyridin-3-yl)benzoate (14 mg, 0.02 mmol) in THF (1 mL) and H2O (1 mL) was stirred, and lithium hydroxide (5 mg, 0.2 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was then acidified with trifluoroacetic acid and purified by preparative HPLC (acetonitrile / H2O + TFA) to give the title compound as a white powder (2 mg, 13% yield).

[0298] Example 11 Preparation of N-((6-amino-2-methylpyridin-3-yl)methyl)-2-(6-(4-chlorophenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide, trifluoroacetate salt (Compound 17) To a stirred solution of 2-(6-(4-chlorophenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetic acid (9 mg, 0.02 mmol) in DMF (0.5 mL) were added EDC·HCl (5 mg, 0.025 mmol), HOBt (4 mg, 0.03 mmol) and DIEA (12 μL, 0.07 mmol). The resulting mixture was stirred for 5 minutes, then 5-(aminomethyl)-6-methylpyridin-2-amine (4 mg, 0.03 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with H2O and extracted with ethyl acetate (3 times). The organic layer was dried over MgSO4 and concentrated. The residue was then purified by preparative HPLC (acetonitrile / H2O + TFA) to give the title compound as a yellow powder (2.5 mg, 18% yield).

[0299] The following compounds were prepared according to the above procedure using the appropriate boronic acid or trifluoroborate and amine starting materials. TIFF0007699389000153.tif40155

[0300] Example 12 Preparation of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-oxo-3-(phenethylamino)-6-(4-(trifluoromethyl)phenyl)pyrazin-1(2H)-yl)acetamide, trifluoroacetate (Compound 21) To a solution of 2-(2-oxo-3-(phenethylamino)-6-(4-(trifluoromethyl)phenyl)pyrazin-1(2H)-yl)acetic acid (4.2 mg, 0.01 mmol) in DMF (0.2 mL) were added HATU (4.2 mg, 0.011 mmol) and DIEA (5 μL, 0.03 mmol). After 10 minutes, (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (2 mg, 0.012 mmol) was added and the reaction was stirred at room temperature until completion. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (acetonitrile / H2O + TFA) to afford the title compound as a white powder (2 mg, 30% yield).

[0301] The following compounds were prepared according to the above procedure using appropriate boronic acid and amine starting materials and purified by chromatography (C 18 , acetonitrile / H2O). TIFF0007699389000155.tif50152

[0302] Example 13 Preparation of N-((6-amino-2-methylpyridin-3-yl)methyl)-2-(2-oxo-3-(phenethylamino)-6-(phenylethynyl)pyrazin-1(2H)-yl)acetamide (Compound 26) TIFF0007699389000156.tif32136 Step 1: A 20 mL pressure vial was charged with tert-butyl 2-(6-bromo-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate (28 mg, 0.07 mmol), Pd(PPh3)2Cl2 (2.8 mg, 0.004 mmol), and copper(I) iodide (1.3 mg, 0.007 mmol). The reaction vessel was purged with argon, then DMF (1 mL), DIEA (24 μL, 0.14 mmol), and phenylacetylene (12 μL, 0.11 mmol) were added, and the mixture was stirred at 80 °C for 16 h. The reaction mixture was then concentrated, and the residue was purified by chromatography (20% ethyl acetate / hexane) to give tert-butyl 2-(2-oxo-3-(phenethylamino)-6-(phenylethynyl)pyrazin-1(2H)-yl)acetate (19 mg, 62% yield).

[0303] TIFF0007699389000157.tif30146 Step 2 : Using appropriate starting materials, 2-(2-oxo-3-(phenethylamino)-6-(phenylethynyl)pyrazin-1(2H)-yl)acetic acid was prepared as a white solid according to Step 3 of Example 3.

[0304] TIFF0007699389000158.tif44148 Step 3 : A 20 mL reaction vial was charged with 2-(2-oxo-3-(phenethylamino)-6-(phenylethynyl)pyrazin-1(2H)-yl)acetic acid (16 mg, 0.043 mmol), HOBt (6.4 mg, 0.047 mmol), DCM (0.5 mL), and DMF (0.5 mL). DCC (31 mg, 0.052 mmol) was added all at once, followed 10 min later by 5-(aminomethyl)-6-methylpyridin-2-amine (6.5 mg, 0.047 mmol) and NMM (14 μL, 0.13 mmol). The reaction mixture was then stirred at room temperature until completion, filtered through Celite® (i.e., diatomaceous earth) using DCM, and concentrated. The resulting residue was purified by chromatography (amine column, 0 - 20% MeOH / DCM) to give the title compound as a yellow powder (13.6 mg, 64% yield).

[0305] Example 14 Preparation of N-((6-Amino-2-methylpyridin-3-yl)methyl)-2-(6-(4-cyanophenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 27) TIFF0007699389000159.tif29139 Step 1 : To a 20 mL pressure vial were charged tert-butyl 2-(6-bromo-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate (41 mg, 0.1 mmol), 4-cyanophenylboronic acid (22 mg, 0.15 mmol), Pd(dppf)2Cl2 (7.3 mg, 0.01 mmol) and Cs2CO3 (65 mg, 0.2 mmol). The vial was purged with argon, then THF (1 mL) and H2O (100 μL) were added, and the reaction mixture was stirred at 55 °C for 12 h. After completion by LCMS, the mixture was evaporated to dryness. The crude material was purified by chromatography (ethyl acetate / hexane) to give tert-butyl 2-(6-(4-cyanophenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate as a yellow oil (40 mg, yield 96%).

[0306] TIFF0007699389000160.tif33148 Steps 2 - 3 : Except for purification by reverse phase chromatography (C18, acetonitrile / H2O), the title compound was prepared as a white powder according to Steps 2 - 3 of Example 13 using the appropriate starting materials. Yield = 13 mg, 28%.

[0307] The following compounds were prepared according to the above procedure using the appropriate boronic acid starting materials and purification by chromatography (MeOH / DCM). TIFF0007699389000161.tif21150

[0308] Using an appropriate boronic acid starting material, purification using chromatography (MeOH / DCM + NH3), treatment of the purified product with aqueous hydrochloric acid, and lyophilization, the following compound was prepared according to the aforementioned procedure to obtain the hydrochloride as a white powder. TIFF0007699389000162.tif31150

[0309] Example 15 Preparation of N-((6-amino-2-methylpyridin-3-yl)methyl)-2-(6-(4-aminophenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 31) TIFF0007699389000163.tif44136 Steps 1 - 3 : Prepared according to Example 14 using an appropriate starting material, except that N-((6-amino-2-methylpyridin-3-yl)methyl)-2-(6-(4-nitrophenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide was advanced to the next step without purification.

[0310] TIFF0007699389000164.tif43148 Step 4 : A 25 mL round-bottom flask was charged with N-((6-amino-2-methylpyridin-3-yl)methyl)-2-(6-(4-nitrophenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (51 mg, 0.1 mmol), a magnetic stir bar, and MeOH. The flask was evacuated and backfilled with argon (3 times), then a catalytic amount of 10% Pd / C was added. The reaction flask was then evacuated and backfilled with H2 (3 times) from a balloon and stirred at room temperature for 1 hour. The reaction was then filtered through a syringe filter (0.2 μm) and concentrated. The residue was then purified by chromatography (10% MeOH / DCM + NH3) to obtain the title compound as a white powder (7.7 mg, 17% yield over 3 steps).

[0311] Example 16 Preparation of N-((6-Amino-2-methylpyridin-3-yl)methyl)-2-(6-(3-(hydroxymethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 32) TIFF0007699389000165.tif27136 Steps 1 - 2 : 2-(6-(3-(Hydroxymethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetic acid was prepared as a white solid according to Steps 1-2 of Example 14 using appropriate starting materials.

[0312] TIFF0007699389000166.tif40146 Step 3 : A 20 mL reaction vial was charged with 2-(6-(3-(hydroxymethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetic acid (35 mg, 0.083 mmol), 5-(aminomethyl)-6-methylpyridin-2-amine (16 mg, 0.12 mmol), DCM (1 mL), and DMF (0.5 mL). After 5 minutes, HATU (42 mg, 0.11 mmol) and NMM (33 μL, 0.3 mmol) were also added, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was then evaporated to dryness, and the residue was purified by chromatography (amine column, 0-15% MeOH / DCM) to obtain the title compound as a white powder (31 mg, 67% yield).

[0313] The following compounds were prepared according to the aforementioned procedure using appropriate boronic acid starting materials. TIFF0007699389000167.tif26150

[0314] Example 17 Preparation of N-((6-Amino-2-methylpyridin-3-yl)methyl)-2-(3-methyl-2,6-dioxo-5-(phenethylamino)-3,6-dihydropyrimidin-1(2H)-yl)acetamide (Compound 34) TIFF0007699389000168.tif27128 Step 1: A magnetic stir bar, 1-methyl-5-nitropyrimidine-2,4(1H,3H)-dione (e.g., prepared in PCT Publication No. WO97 / 46207) (1 g, 5.8 mmol), K2CO3 (0.883 g, 6.4 mmol), and DMF (12 mL) were charged into a 250 mL RBF. After 10 minutes at room temperature, ethyl bromoacetate (713 μL, 6.4 mmol) was added, and the reaction mixture was stirred at 40 °C for 5 hours. The reaction mixture was diluted with ethyl acetate, washed with H2O and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (15% ethyl acetate / DCM) to obtain ethyl 2-(3-methyl-5-nitro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)acetate as a yellow solid (976 mg, 65%).

[0315] TIFF0007699389000169.tif22128 Step 2 : In a 100 mL RBF, ethyl 2-(3-methyl-5-nitro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)acetate (514 mg, 2 mmol) was dissolved in a mixture of EtOH (5 mL) and ethyl acetate (5 mL). The flask was evacuated and backfilled with argon (3 times), and then a catalytic amount of 10% Pd / C was added. The reaction flask was then evacuated and backfilled with H2 (3 times) from a balloon and stirred at room temperature for 1 hour. The reaction was then filtered through a syringe filter (0.2 μm) and concentrated. The residue was purified by chromatography (3% methanol / DCM + NH3) to obtain ethyl 2-(5-amino-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)acetate as a scaly solid (260 mg, 57% yield).

[0316] TIFF0007699389000170.tif27134 Step 3: 100 mL of RBF was charged with ethyl 2-(5-amino-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)acetate (114 mg, 0.5 mmol) and 1,2-DCE (5 mL). Subsequently, phenylacetaldehyde (61 μL, 0.55 mmol) and acetic acid (29 μL, 0.5 mmol) were added to the reaction, and the mixture was stirred at room temperature for 10 minutes. NaBH(OAc)3 (127 mg, 0.6 mmol) was added all at once, and the reaction mixture was stirred at room temperature for 4 hours. The reaction was then cooled to 0 °C, quenched with 1 N NaOH, and then extracted twice with DCM. The combined organics were washed with brine, dried over MgSO4, and purified by chromatography (40% ethyl acetate / DCM) to give ethyl 2-(3-methyl-2,6-dioxo-5-(phenethylamino)-3,6-dihydropyrimidin-1(2H)-yl)acetate as a white solid (58 mg, 37% yield).

[0317] TIFF0007699389000171.tif22146 Step 4 : To a stirred solution of ethyl 2-(3-methyl-2,6-dioxo-5-(phenethylamino)-3,6-dihydropyrimidin-1(2H)-yl)acetate (58 mg, 0.2 mmol) in MeOH (1 mL) was added 1 N NaOH (1 mL), and the resulting mixture was stirred at room temperature for 3 hours. The MeOH was then removed in vacuo, and the aqueous layer was washed with ethyl acetate (twice). The aqueous layer was then acidified with 1 N HCl and extracted with ethyl acetate (three times). The combined organics were dried over Na s SO4 and concentrated to give 2-(3-methyl-2,6-dioxo-5-(phenethylamino)-3,6-dihydropyrimidin-1(2H)-yl)acetic acid as a white solid (26 mg, 48% yield).

[0318] TIFF0007699389000172.tif24147 Step 5 : Except for purification by chromatography (15% MeOH / DCM), the title compound was prepared as a white powder (30 mg, 79% yield) according to Step 4 of Example 3 using appropriate starting materials.

[0319] Using appropriate amine starting materials and purification by preparative HPLC (45 - 75% acetonitrile / H2O + TFA), the following compounds were prepared according to the aforementioned procedure. TIFF0007699389000173.tif26150

[0320] Example 18 Preparation of N - ((6 - amino - 2 - methylpyridin - 3 - yl)methyl)-2-(3 - methyl - 2,6 - dioxo - 5 - ((phenylmethyl)sulfonamido)-3,6 - dihydropyrimidin - 1(2H)-yl)acetamide, trifluoroacetate (Compound 36) TIFF0007699389000174.tif22130 Steps 1 - 2 : 2-(3 - methyl - 2,6 - dioxo - 5 - ((phenylmethyl)sulfonamido)-3,6 - dihydropyrimidin - 1(2H)-yl)acetic acid was prepared as a white solid (82 mg, yield 89%) according to the procedure described in PCT Publication No. WO97 / 46207.

[0321] TIFF0007699389000175.tif33147 Step 3 : Using appropriate starting materials, the title compound was prepared as a white powder according to Step 4 of Example 1.

[0322] Example 19 Preparation of N - (4 - carbamimidoylbenzyl)-2-(3 - methyl - 2,6 - dioxo - 5 - ((phenylmethyl)sulfonamido)-3,6 - dihydropyrimidin - 1(2H)-yl)acetamide, trifluoroacetate (Compound 37) TIFF0007699389000176.tif26147 Step 1 : Using appropriate starting materials, (iminomethyl(4 - ((2-(3 - methyl - 2,6 - dioxo - 5 - ((phenylmethyl)sulfonamido)-3,6 - dihydropyrimidin - 1(2H)-yl)acetamido)methyl)phenyl)methyl)carbamic acid benzyl was prepared according to Example 11.

[0323] TIFF0007699389000177.tif24148 Step 2 :(Imino(4 - ((2 - (3 - methyl - 2,6 - dioxo - 5 - ((phenylmethyl)sulfonamido)-3,6 - dihydropyrimidin - 1(2H)-yl)acetamido)methyl)phenyl)methyl)carbamic acid benzyl was dissolved in MeOH (2 mL) and purged with Ar. A catalytic amount of 10% Pd / C was added to the reaction mixture, the flask was evacuated and refilled with H2 three times, and then stirred at room temperature for 3 hours. The reaction mixture was then filtered through a syringe filter (0.2 μm), concentrated, and the residue was purified by preparative HPLC to give the title compound as a white solid (2 mg, yield 34%).

[0324] Example 20 Preparation of 1-(4-(6 - amino - 2 - methylpyridin - 3 - yl)-2 - oxobutyl)-5 - chloro - 3-(methylamino)-6 - phenylpyrazin - 2(1H)-one (Compound 38) TIFF0007699389000178.tif35128 Step 1 : A solution of benzyl 2-(3,5 - dichloro - 2 - oxo - 6 - phenylpyrazin - 1(2H)-yl)acetate (300 mg, 0.77 mmol; prepared according to Bioorganic & Medicinal Chemistry Letters, 13(14), 2319 - 2325; 2003) in methylamine (2 M in THF, 5 mL) was stirred at room temperature for 1 hour. After evaporation to dryness, H2O (5 mL) and ethyl acetate (20 mL) were added and stirred for 10 minutes. The organic layer was dried over Na2SO4 and evaporated to give the product as a yellow solid (294 mg, yield 99%).

[0325] TIFF0007699389000179.tif35128 Step 2: A solution of benzyl 2-(5-chloro-3-(methylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (294 mg, 0.77 mmol) in MeOH / THF / H2O (2:1:1, 6 mL) containing lithium hydroxide (92 mg, 3.85 mmol) was stirred at room temperature overnight. After evaporation to dryness, H2O (5 ml) was added with vortexing and the pH was adjusted to about 3 by addition of 10% aqueous KHSO4. The solution was extracted with CH2Cl2 (2 × 10 ml), dried over Na2SO4 and evaporated to give the product as a yellow solid (214 mg, 95% yield).

[0326] TIFF0007699389000180.tif34128 Step 3 : NHS (86 mg, 0.75 mmol) was added to a solution of 2-(5-chloro-3-(methylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (200 mg, 0.68 mmol) in CH2Cl2 with stirring until dissolved. DCC (155 mg, 0.75 mmol) was added and the solution was stirred at room temperature for 30 minutes. The solution was filtered to remove DCU and 5-(aminomethyl)-6-methylpyridin-2-amine (0.82 mmol) was added to the filtrate with stirring at room temperature overnight. Following evaporation to dryness, the product was obtained as a yellow solid (147 mg, 51% yield) by chromatography (3% MeOH-NH3 / CH2Cl2).

[0327] Using appropriate starting materials, the following compounds were prepared according to the procedure described above. TIFF0007699389000181.tif31150

[0328] Example 21 Preparation of N-((6-amino-2-methylpyridin-3-yl)methyl)-2-(5-chloro-2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetamide (Compound 41) TIFF0007699389000182.tif35144 Steps 1 - 2: 2-(5-Chloro-2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetic acid was prepared as a white solid (19 mg, quantitative) according to Steps 1-2 of Example 20.

[0329] TIFF0007699389000183.tif35150 Step 3 : The title compound was prepared as a white fluffy powder (32.3 mg, yield 64%) according to Example 12, except for purification by chromatography (methanol / DCM).

[0330] The following compounds were prepared according to the above procedure using purification by chromatography (amine column, methanol / DCM). TIFF0007699389000184.tif21150

[0331] Example 22 Preparation of N-((6-Amino-2-methylpyridin-3-yl)methyl)-2-(2-oxo-6-phenyl-3-(pyrrolidin-1-yl)pyrazin-1(2H)-yl)acetamide (Compound 43) TIFF0007699389000185.tif35131 Step 1 : Pyrrolidine (134 mg, 1.9 mmol) was added to a solution of benzyl 2-(3,5-dibromo-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (300 mg, 0.63 mmol; prepared according to PCT International Application No. 2003029224 of April 10, 2003) in THF (5 mL) and stirred at room temperature overnight. After evaporation to dryness, H2O (5 mL) and ethyl acetate (20 mL) were added and stirred for 10 minutes. The organic layer was dried over Na2SO4 and evaporated to give the product as a yellow solid (290 mg, yield 99%).

[0332] TIFF0007699389000186.tif35131 Step 2: A solution of benzyl 2-(5-bromo-2-oxo-6-phenyl-3-(pyrrolidin-1-yl)pyrazin-1(2H)-yl)acetate (290 mg, 0.62 mmol) in ethanol (10 mL) was degassed by a stream of argon for about 2 - 3 minutes. 10% Pd / C (200 mg) was added and the mixture was hydrogenated at 80 psi for 48 hours. The catalyst was removed by filtration and evaporated to dryness to give 179 mg (96%) of a yellow solid, which was used in the next step without further purification.

[0333] TIFF0007699389000187.tif34128 Step 3 : NHS (73 mg, 0.63 mmol) was added to a solution of 2-(2-oxo-6-phenyl-3-(pyrrolidin-1-yl)pyrazin-1(2H)-yl)acetic acid (170 mg, 0.57 mmol) in CH2Cl2 with stirring until dissolved. DCC (133 mg, 0.63 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The solution was filtered to remove DCU and 5-(aminomethyl)-6-methylpyridin-2-amine (1.2 equiv, 0.68 mmol) was added to the filtrate with stirring at room temperature overnight. Following evaporation to dryness, the product was obtained as a yellow solid (81 mg, 34% yield) by chromatography (3% MeOH-NH3 / CH2Cl2).

[0334] Using appropriate starting materials, the following compounds were prepared according to the procedure described above. TIFF0007699389000188.tif30150

[0335] Example 23 Preparation of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-oxo-6-phenyl-3-(((3-phenyloxetan-3-yl)methyl)amino)pyrazin-1(2H)-yl)acetamide trifluoroacetate (Compound 47) TIFF0007699389000189.tif36139 Step 1: To a solution of benzyl 2-(3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (200 mg, 0.54 mmol, prepared according to the procedure described in Bioorganic & Medicinal Chemistry Letters, 13(14), 2319-2325; 2003) in MeCN (5 mL, 0.1 M) was added (3-phenyloxetan-3-yl)methanamine (137 mg, 0.77 mmol) and DIEA (0.27 mL, 1.54 mmol). After stirring at 70 °C for 18 h, the reaction mixture was cooled, washed with water, and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by chromatography (0-100% EtOAc-hexane) to give benzyl 2-(5-chloro-2-oxo-6-phenyl-3-(((3-phenyloxetan-3-yl)methyl)amino)pyrazin-1(2H)-yl)acetate (265 mg, 95% yield).

[0336] TIFF0007699389000190.tif32146 Step 2 : A solution of benzyl 2-(5-chloro-2-oxo-6-phenyl-3-(((3-phenyloxetan-3-yl)methyl)amino)pyrazin-1(2H)-yl)acetate (200 mg, 0.39 mmol) in EtOAc (3 mL) and MeOH (3 mL) was degassed with an argon stream for 1 min. 10% Pd / C (40 mg) was added, evacuated for 1 min, and a H2 balloon was added. Et3N (0.1 mL, 0.78 mmol) was added to the above mixture, and the reaction was stirred at room temperature for 16 h. The catalyst was removed by filtration, and the solution was evaporated to give 2-(2-oxo-6-phenyl-3-(((3-phenyloxetan-3-yl)methyl)amino)pyrazin-1(2H)-yl)acetic acid (152 mg, 99% yield).

[0337] TIFF0007699389000191.tif36147 Step 3: A solution of 2-(2-oxo-6-phenyl-3-(((3-phenyloxetan-3-yl)methyl)amino)pyrazin-1(2H)-yl)acetic acid (95 mg, 0.24 mmol) in DMF (4 mL, 0.06 M) was stirred while adding (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (43 mg, 0.29 mmol) until dissolved. HATU (92 mg, 0.24 mmol) and DIEA (0.15 mL, 0.88 mmol) were added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was purified using reverse-phase HPLC to give N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-oxo-6-phenyl-3-(((3-phenyloxetan-3-yl)methyl)amino)pyrazin-1(2H)-yl)acetamide trifluoroacetate (61 mg, yield 48%).

[0338] Using appropriate amine starting materials and purification via reverse-phase HPLC, the following compounds were prepared according to the procedure described above. TIFF0007699389000192.tif50150

[0339] Example 24 Preparation of tert-butyl 2-(4-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-3-oxo-5-phenyl-3,4-dihydropyrazin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (Compound 53) TIFF0007699389000193.tif32144 Step 1 : According to Step 1 of Example 23, tert-butyl 2-(4-(2-(benzyloxy)-2-oxoethyl)-6-bromo-3-oxo-5-phenyl-3,4-dihydropyrazin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (258 mg, yield 97%) was synthesized from benzyl 2-(3,5-dibromo-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (200 mg, 0.42 mmol, prepared according to the procedure described in PCT International Application No. 2003029224 of April 10, 2003).

[0340] TIFF0007699389000194.tif32149 Step 2 : According to Step 2 of Example 23, 2-(4-(2-(benzyloxy)-2-oxoethyl)-6-bromo-3-oxo-5-phenyl-3,4-dihydropyrazin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl (258 mg, 0.4 mmol) was used to synthesize 2-(3-(8-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-2-yl)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (177 mg, yield 90%).

[0341] TIFF0007699389000195.tif36149 Step 3 : 2-(3-(8-(tert-Butoxycarbonyl)-2,8-diazaspiro[4.5]decane-2-yl)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (94 mg, 0.2 mmol) was used to synthesize 2-(4-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-3-oxo-5-phenyl-3,4-dihydropyrazin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl (34 mg, yield 30%) according to the above procedure, except that the crude product was purified by chromatography (0 - 100% EtOAc - hexane).

[0342] The following compounds were prepared according to the above procedure using an appropriate amine starting material and purification via reverse-phase HPLC. TIFF0007699389000196.tif232148TIFF0007699389000197.tif119148

[0343] The following compounds were prepared according to the above procedure using an appropriate amine starting material and purification by chromatography (amine column, MeOH - CH2Cl2). TIFF0007699389000198.tif16148

[0344] Example 25 Preparation of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-oxo-6-phenyl-3-(2,8-diazaspiro[4.5]decane-2-yl)pyrazin-1(2H)-yl)acetamide di-trifluoroacetate (Compound 54) TIFF0007699389000199.tif34144To a solution of tert-butyl 2-(4-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-3-oxo-5-phenyl-3,4-dihydropyrazin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (34 mg, 0.06 mmol, prepared according to Steps 1 - 3 of Example 24) in CH2Cl2 (1.0 mL, 0.06 M) at 0 °C was added 20% TFA in CH2Cl2 (1.0 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The crude material was purified using reverse-phase HPLC to give N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-oxo-6-phenyl-3-(2,8-diazaspiro[4.5]decane-2-yl)pyrazin-1(2H)-yl)acetamide di-trifluoroacetate (31 mg, 74% yield).

[0345] Example 26 Preparation of N-((1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetamide trifluoroacetate (Compound 46) TIFF0007699389000200.tif35128 Step 1: A solution of 3-iodo-N-methylpyridin-4-amine (632 mg, 2.7 mmol) and 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (500 mg, 2.7 mmol) in DMF (10 mL, 0.3 mmol) was added with Pd(PPh3)2Cl2 (95 mg, 0.14 mmol), CuI (15 mg, 0.08 mmol), and Et3N (1.5 mL, 10.8 mmol). After stirring at 100 °C for 1.5 h, the reaction mixture was cooled to 50 °C and DBU (0.8 mL, 5.4 mmol) was added. After stirring at 50 °C for 30 min, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NH4Cl, water, and brine. The organic layer was dried over anhydrous NaSO4, filtered, and concentrated. The crude material was purified by chromatography (0 - 20% MeOH-CH2Cl2) to give 2-((1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)isoindoline-1,3-dione (62 mg, 8% yield).

[0346] TIFF0007699389000201.tif27128 Step 2 : 2-((1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)isoindoline-1,3-dione (62 mg, 0.21 mmol) was dissolved in hydrazine hydrate (80% solution, 0.06 mL). After stirring at room temperature for 4 h, the reaction mixture was concentrated under vacuum to give (1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (34 mg, 100%). The crude material was used in the next reaction without further purification.

[0347] TIFF0007699389000202.tif47145 Step 3: According to step 3 of Example 23, N-((1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetamide trifluoroacetate was synthesized from (1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (34 mg, 0.21 mmol) and 2-(2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetic acid (61 mg, 0.17 mmol, prepared according to steps 1-2 of Example 23 using 2-phenylethane-1-amine).

[0348] Example 27 Preparation of N-((6-methyl-1H-pyrrolo[3,2-C]pyridin-2-yl)methyl)-2-(2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetamide trifluoroacetate (Compound 67) TIFF0007699389000203.tif14128 Step 1 : Ts2O (209 mg, 0.64 mmol) was added to a 0 °C solution of 5-iodo-2-methylpyridin-4-amine (100 mg, 0.43 mmol) in pyridine (5 mL, 0.08 M) every 1 hour for 4 hours. The reaction mixture was washed with saturated aqueous NH4Cl and extracted with CH2Cl2. The organic layer was dried over anhydrous NaSO4, filtered, and concentrated. The crude material was purified by chromatography (0-100% EtOAc-hexane) to give N-(5-iodo-2-methylpyridin-4-yl)-4-methylbenzenesulfonamide (80 mg, yield 48%).

[0349] TIFF0007699389000204.tif34128 Step 2: According to Step 1 of Example 26, 2-((6-methyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)isoindoline-1,3-dione was synthesized from N-(5-iodo-2-methylpyridin-4-yl)-4-methylbenzenesulfonamide (269 mg, 0.69 mmol) and 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (642 mg, 3.46 mmol).

[0350] TIFF0007699389000205.tif27128 Step 3 : According to Step 2 of Example 26, (6-methyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine was synthesized from 2-((6-methyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)isoindoline-1,3-dione (120 mg, 0.27 mmol).

[0351] TIFF0007699389000206.tif14128 Step 4 : Cs2CO3 (247 mg, 0.76 mmol) was added to a solution of (6-methyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (80 mg, 0.25 mmol) in THF (3 mL) and MeOH (3 mL). After stirring at room temperature for 16 hours, the reaction mixture was concentrated and the residue was purified by reverse-phase HPLC to obtain (6-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine di-trifluoroacetate (24 mg, yield 60%).

[0352] TIFF0007699389000207.tif42145 Step 5 : According to Step 3 of Example 26, N-((6-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetamide trifluoroacetate was synthesized from (6-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine di-trifluoroacetate (24 mg, 0.15 mmol).

[0353] Using an appropriate amine starting material and purification via reverse-phase HPLC, the following compounds were prepared according to the aforementioned procedure. TIFF0007699389000208.tif35150

[0354] Using an appropriate iodide starting material and purification via reverse-phase HPLC, the following compounds were prepared according to the aforementioned procedure. TIFF0007699389000209.tif21150

[0355] Example 28 Preparation of N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-(benzylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamide trifluoroacetate (Compound 58) TIFF0007699389000210.tif34128 Step 1 : A 20 mL sealed tube was charged with benzyl 2-(3,5-dibromo-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (1.0 g, 2.09 mmol, prepared according to the procedure described in Bioorganic & Medicinal Chemistry Letters, 13(14), 2319 - 2325; 2003) in THF (10 mL, 0.2 M). NH3 gas was added by bubbling at -78 °C. After stirring at room temperature for 16 h, the reaction mixture was cooled to -78 °C and washed with H2O. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give benzyl 2-(3-amino-5-bromo-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (745 mg, yield 86%), which was used in the next step without further purification.

[0356] TIFF0007699389000211.tif34128 Step 2: According to Step 2 of Example 23, benzyl 2-(3-amino-5-bromo-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (866 mg, 2.09 mmol) was used to synthesize 2-(3-amino-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid.

[0357] TIFF0007699389000212.tif27128 Step 3 : To a solution of 2-(3-amino-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (171 mg, 0.7 mmol) in MeOH (3 mL, 0.23 M) at 0 °C was added TMSCH2N2 (10% in hexane, 2.3 mL, 1.4 mmol). After stirring at room temperature for 1 hour, the reaction mixture was concentrated under vacuum to give methyl 2-(3-amino-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (100 mg, 55% yield). The crude material was used in the next reaction without further purification.

[0358] TIFF0007699389000213.tif27128 Step 4 : To a suspension of methyl 2-(3-amino-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (100 mg, 0.39 mmol) in dichloroethane (3 mL) and acetic acid (3 drops) was added benzaldehyde (0.16 mL, 1.54 mmol). After stirring at 70 °C for 1 hour, the reaction mixture was concentrated under vacuum in a 40 °C water bath for 10 minutes. The crude oil was dissolved in dichloroethane (3 mL), and Na(OAc)3BH (409 mg, 1.93 mmol) was added. After stirring at 70 °C for 30 minutes, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified by chromatography (0 - 100% EtOAc - hexane) to give methyl 2-(3-(benzylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (57 mg, 42% yield).

[0359] TIFF0007699389000214.tif27128 Step 5: A solution of methyl 2-(3-(benzylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (57 mg, 0.16 mmol) in THF (8 mL), MeOH (4 mL), and H2O (4 mL) was added to LiOH (59 mg, 2.45 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated, 10% KHSO4 was added, and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(3-(benzylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (56 mg, yield 98%). The crude product was used in the next reaction without further purification.

[0360] TIFF0007699389000215.tif38142 Step 6 : N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-(benzylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamide trifluoroacetate was synthesized from 2-(3-(benzylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (56 mg, 0.16 mmol) according to the procedure of Step 3 of Example 23.

[0361] Example 29 Preparation of 2-(3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)-N-((6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)methyl)acetamide trifluoroacetate (Compound 69) TIFF0007699389000216.tif14128 Step 1: To a solution of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carbonitrile (200 mg, 1.38 mmol) in CH2Cl2 (7 mL, 0.2 M) were added Boc2O (300 mg, 1.38 mmol) and DMAP (169 mg, 1.38 mmol). After stirring at room temperature for 1 hour, the reaction mixture was concentrated and the residue was purified by chromatography (0 - 100% EtOAc - hexane) to afford tert-butyl 3-cyano-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (250 mg, 74% yield).

[0362] TIFF0007699389000217.tif14128 Step 2 : A solution of tert-butyl 3-cyano-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (250 mg, 1.02 mmol) in MeOH (3 mL) and 7N NH3 in MeOH (14 mL) was degassed twice under an Ar stream. Raney nickel (200 mg) was added and evacuated for 1 minute. A H2 balloon was added and the reaction mixture was stirred at room temperature for 16 hours. At completion, the reaction mixture was degassed twice under an Ar stream. The catalyst was removed by filtration through diatomaceous earth and the solution was concentrated. The residue was taken up in 5% H2O in MeOH, filtered (0.2 μm syringe filter), and the filtrate was concentrated under vacuum to afford tert-butyl 3-(aminomethyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (203 mg, 80% yield).

[0363] TIFF0007699389000218.tif38145 Step 3: Except for purifying the crude material by chromatography (0 - 100% EtOAc - hexane), 3-((2-(3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamido)methyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl was synthesized from tert-butyl 3-(aminomethyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (20 mg, 0.08 mmol) and 2-(3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (29 mg, 0.07 mmol, prepared according to Steps 1 - 2 of Example 23 using (1-(4-chlorophenyl)cyclopropyl)methanamine) according to Step 3 of Example 23.

[0364] TIFF0007699389000219.tif31147 Step 4 : Deprotection of 3-((2-(3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamido)methyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl (67 mg, 0.1 mmol) was carried out according to Step 1 of Example 25.

[0365] Example 30 Preparation of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetamide trifluoroacetate (Compound 65) TIFF0007699389000220.tif21128 Step 1: A solution of ethyl 2-(3-chloro-2-oxopyrazin-1(2H)-yl)acetate (100 mg, 0.46 mmol) in acetonitrile (5 mL, 0.09 M) was added with (1-(4-chlorophenyl)cyclopropyl)methanamine (91 mg, 0.5 mmol), DIEA (0.28 mL, 1.61 mmol), and NaI (138 mg, 0.92 mmol). After stirring at 70 °C for 18 h, the reaction mixture was washed with H2O and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by chromatography (0 - 100% EtOAc - heptane) to give ethyl 2-(3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (80 mg, 48% yield).

[0366] TIFF0007699389000221.tif21128 Step 2 : NCS (30 mg, 0.23 mmol) was slowly added to a solution of ethyl 2-(3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (80 mg, 0.22 mmol) in acetonitrile (2 mL, 0.1 M). After stirring at 70 °C for 1.5 h, the reaction mixture was concentrated, and the residue was purified by chromatography (0 - 100% EtOAc - heptane) to give ethyl 2-(6-chloro-3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (69 mg, 79% yield).

[0367] TIFF0007699389000222.tif47138 Step 3: A solution of ethyl 2-(6-chloro-3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (69 mg, 0.17 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (44 mg, 0.21 mmol), and K2CO3 (72 mg, 0.52 mmol) in dioxane (2.4 mL) and H2O (0.6 mL) was added with Pd(PPh3)4 (72 mg, 0.52 mmol) under N2. After stirring at 100 °C for 18 h, the reaction mixture was diluted with methanol and concentrated. The residue was taken up in MeOH, filtered (0.2 μm syringe filter), and the filtrate was concentrated under vacuum. The residue was purified by chromatography (0 - 20% MeOH-CH2Cl2) to give 2-(3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetic acid (43 mg, 60% yield).

[0368] TIFF0007699389000223.tif39147 Step 4 : N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetamide trifluoroacetate was synthesized from 2-(3-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetic acid (43 mg, 0.1 mmol) according to the procedure of Step 3 of Example 23.

[0369] Example 31 Preparation of 2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)-N-((4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl)acetamide (Compound 78) TIFF0007699389000224.tif14128 Step 1 : A stirred solution of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (1.01 g, 3.58 mmol) in THF (7.5 mL) was set under a N2 atmosphere. A solution of 1 M BH3·THF (14 mL, 14 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature for 16 h. Saturated aqueous NaHCO3 was added dropwise at 0 °C. The reaction mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, vacuum filtered, and evaporated under reduced pressure. The crude product was dissolved in CH2Cl2 and adsorbed onto silica gel. Purification by chromatography (0 - 100% EtOAc - hexane) gave tert-butyl 2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (905 mg, 94% yield).

[0370] TIFF0007699389000225.tif13128 Step 2 : DIAD (0.3 mL, 1.53 mmol) and PPh3 (386 mg, 1.47 mmol) were added to a stirred solution of tert-butyl 2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (197 mg, 0.73 mmol) in THF (3.7 mL) at room temperature. After purging with N2, DPPA (0.32 mL, 1.48 mmol) was added at 0 °C. The reaction was stirred at room temperature for 5 h and quenched with water. The reaction mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, vacuum filtered, and evaporated under reduced pressure. The crude product was dissolved in CH2Cl2 and adsorbed onto silica gel. Purification by chromatography (0 - 10% EtOAc - hexane) gave tert-butyl 2-(azidomethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (97 mg, 45% yield).

[0371] TIFF0007699389000226.tif13128 Step 3To a stirred solution of tert-butyl 2-(azidomethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (97.2 mg, 0.33 mmol) in THF (1.2 mL) and water (0.14 mL) was added PPh3 (132 mg, 0.50 mmol). The reaction was stirred at room temperature for 16 h and quenched with 1 N KHSO4. The resulting mixture was washed three times with diethyl ether. The pH of the aqueous layer was adjusted to 12 by adding 5 N NaOH solution. The basic aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered through vacuum, and evaporated under reduced pressure. The crude product was dissolved in CH2Cl2 and adsorbed onto silica gel. Purification by chromatography (0 - 10% 7N NH3 in MeOH-CH2Cl2) gave tert-butyl 2-(aminomethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (61.2 mg, 69% yield).

[0372] TIFF0007699389000227.tif41145 Step 4: A stirred solution of 2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetic acid (31.4 mg, 0.09 mmol, prepared using the appropriate starting materials following the procedures described in Steps 1-4 of Example 7, Step 1 of Example 8, and Step 3 of Example 3) and tert-butyl 2-(aminomethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (30 mg, 0.11 mmol) in DMF (1 mL) was added with DIEA (50 μL, 0.29 mmol) at room temperature. After purging with N2 and cooling to 0 °C, HATU (37 mg, 0.097 mmol) was added. The reaction was stirred at room temperature for 16 h and evaporated to dryness under reduced pressure. The crude product was dissolved in CH2Cl2 and adsorbed onto silica gel. Purification by chromatography (0-10% MeOH-CH2Cl2) gave tert-butyl 2-((2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamido)methyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (38.7 mg, 72% yield).

[0373] TIFF0007699389000228.tif34145 Step 5 : To a stirred solution of tert-butyl 2-((2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamido)methyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (38.7 mg, 0.064 mmol) in CH2Cl2 (1 mL) was added TES (100 μL, 0.63 mmol) at room temperature, followed by TFA (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The volatiles were evaporated under reduced pressure. The crude product was purified by chromatography using (0-10% 7N NH3 in MeOH-CH2Cl2) to give 2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)-N-((4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl)acetamide (25.3 mg, 78% yield).

[0374] Using appropriate amine starting materials, the following compounds were prepared according to the aforementioned procedure. TIFF0007699389000229.tif21148

[0375] Example 32 Preparation of 2-(6-(1-Methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)-N-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)acetamide (Compound 80) TIFF0007699389000230.tif38147 Step 1 : 6-((2-(6-(1-Methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl was synthesized according to Step 4 of Example 31.

[0376] TIFF0007699389000231.tif40147 Step 2 : The title compound was synthesized according to Step 5 of Example 31.

[0377] Example 33 Preparation of 2-(2-Oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)-N-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)methyl)acetamide (Compound 83) TIFF0007699389000232.tif44143 According to step 3 of Example 23, 2-(2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)-N-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)methyl)acetamide was synthesized from (4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)methanamine (35 mg, 0.2 mmol) and 2-(2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetic acid (60 mg, 0.17 mmol, prepared according to steps 1-2 of Example 23 using 2-phenylethane-1-amine).

[0378] Example 34 Preparation of N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 81) TIFF0007699389000233.tif42144 N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide was synthesized by coupling 2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetic acid with (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (described in PCT Publication No. 2019 / 231935) according to step 4 of Example 31, except that the final product was purified by chromatography using (MeOH-CH2Cl2 with 0-10% 7N NH3).

[0379] The following compounds were prepared according to the procedure described in PCT Publication No. 2019 / 231935 using appropriate nitrile starting materials and purification via reverse-phase HPLC. TIFF0007699389000234.tif21148

[0380] Example 35 Preparation of N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-(2-fluorophenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide trifluoroacetate (Compound 86) TIFF0007699389000235.tif31143 Step 1 : To a 20 mL pressure vial were charged tert-butyl 2-(6-bromo-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate (61 mg, 0.15 mmol), 4-fluorophenylboronic acid (32 mg, 0.23 mmol), Pd(dppf)Cl2 (11 mg, 0.015 mmol), and K2CO3 (41 mg, 0.3 mmol). The vial was purged with argon, then 1,4-dioxane (1.5 mL) and H2O (150 μL) were added, the reaction vessel was sealed, and the mixture was stirred at 80 °C for 12 h. After completion by LCMS, the mixture was evaporated to dryness. The crude material was then purified by chromatography (55% EtOAc - heptane) to give tert-butyl 2-(6-(2-fluorophenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate as a colorless oil (43 mg, yield 68%).

[0381] TIFF0007699389000236.tif37148 Steps 2 - 3 : Using the appropriate amine starting material, the title compound was prepared as a white powder (14 mg, yield 22%) according to the procedure described in Steps 3 - 4 of Example 3.

[0382] Using the appropriate starting materials, the following compounds were prepared according to the above procedure. TIFF0007699389000237.tif30150

[0383] Example 36 Preparation of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-(5-chlorothiophen-2-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 89) TIFF0007699389000238.tif28147 Steps 1 - 2 : Using an appropriate boronic acid, 2-(6-(5-chlorothiophen-2-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetic acid was prepared as a colorless oil (9 mg, yield 52%) according to Steps 1-2 of Example 35.

[0384] TIFF0007699389000239.tif37149 Step 3 : Using an appropriate amine starting material, the title compound was prepared as a yellow powder (7 mg, yield 61%) according to Step 3 of Example 23, except that the crude material was purified by chromatography (0-10% 7N NH3 in MeOH-CH2Cl2).

[0385] Using appropriate boronic acids and amine starting materials, the following compounds were prepared according to the above-described procedure. TIFF0007699389000240.tif80159

[0386] Using appropriate boronic acids and amine starting materials and purification via column chromatography (amine, MeOH-CH2Cl2), the following compounds were prepared according to the above-described procedure. TIFF0007699389000241.tif41150

[0387] Example 37 Preparation of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-oxo-3-(phenethylamino)-6-(3-(prop-1-en-2-yl)phenyl)pyrazin-1(2H)-yl)acetamide (Compound 91) The title compound was isolated as a by-product (38 mg, yield 49%) from the preparation of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-(3-(2-hydroxypropan-2-yl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide.

[0388] Example 38 Preparation of 2-(3-(1-(2-(((1H-pyrrolo[3,2-C]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-5-(phenethylamino)-1,6-dihydropyrazin-2-yl)phenyl)acetic acid trifluoroacetate (Compound 94) Using the procedure described in Example 10, the title compound was prepared as a white powder (48 mg, yield 53%) from methyl 2-(3-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-5-(phenethylamino)-1,6-dihydropyrazin-2-yl)phenyl)acetate.

[0389] Example 39 Preparation of N-((1H-pyrrolo[3,2-C]pyridin-2-yl)methyl)-2-(6-(3-(methylsulfonamidomethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 95) TIFF0007699389000244.tif28148 Step 1: tert-Butyl 2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate (240 mg, 0.45 mmol, prepared according to Step 1 of Example 36) was dissolved in EtOAc (5 mL) and cooled to 0 °C. HCl gas was bubbled in, and the resulting solution was left at room temperature for 1 hour. The reaction mixture was then concentrated, taken up in MeCN / H2O, and lyophilized to give tert-butyl 2-(6-(3-(aminomethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate hydrochloride (212 mg, yield 100%) as a white solid.

[0390] TIFF0007699389000245.tif29147 Step 2 : tert-Butyl 2-(6-(3-(aminomethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate hydrochloride (70 mg, 0.15 mmol) was suspended in CH2Cl2 (1.5 mL) and treated with Et3N (73 μL, 0.5 mmol). After 5 minutes, methanesulfonyl chloride (12 μL, 0.15 mmol) was added, and the reaction mixture was stirred for 1 hour. Upon completion, the reaction was diluted with CH2Cl2 and then washed with saturated NH4Cl and brine. The organic layer was then dried over Na2SO4, filtered, and concentrated to give tert-butyl 2-(6-(3-(methylsulfonamidomethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate. The crude product was carried on to the next step without further purification.

[0391] TIFF0007699389000246.tif31147 Step 3 : 2-(6-(3-(Methylsulfonamidomethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetic acid was prepared as a colorless oil according to the procedure described in Step 3 of Example 3.

[0392] TIFF0007699389000247.tif34148 Step 4: A 20 mL reaction vial was charged with 2-(6-(3-(methylsulfonamidomethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetic acid (68 mg, 0.15 mmol), NHS (21 mg, 0.18 mmol), and CH2Cl2 (1.5 mL). DCC (35 mg, 0.17 mmol) was added all at once, followed by addition to 5-(aminomethyl)-6-methylpyridin-2-amine (26 mg, 0.18 mmol) in DMF (1 mL) after 10 minutes. The reaction mixture was then stirred at room temperature until completion, filtered through Celite® using CH2Cl2, and concentrated. The resulting residue was purified by chromatography (0 - 10% 7N NH3 in MeOH-CH2Cl2) to afford the title compound as a white powder (4.2 mg, 5% yield over 3 steps).

[0393] Example 40 Preparation of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-(3-(aminomethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 96) TIFF0007699389000248.tif36145 According to Steps 3 - 4 of Example 39, the title compound was prepared as an off-white powder (6 mg, 16% yield) from tert-butyl 2-(6-(3-(aminomethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate hydrochloride.

[0394] Example 40 Preparation of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-(3-(1-hydroxyethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 100) TIFF0007699389000249.tif29136 Step 1: Using an appropriate boronic acid, tert-butyl 2-(6-(3-(1-hydroxyethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate was prepared as a white powder (33 mg, yield 57%) according to the procedure of Step 1 of Example 35.

[0395] TIFF0007699389000250.tif29146 Step 2 : tert-Butyl 2-(6-(3-(1-hydroxyethyl)phenyl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate (33 mg, 0.07 mmol) was dissolved in MeOH (1 mL) and treated with 1N NaOH (1 mL). Upon completion, the reaction mixture was concentrated under vacuum and then taken up in a minimum amount of DMF, filtered through a fine filter funnel, and advanced to the next step.

[0396] TIFF0007699389000251.tif37146 Step 3 : According to the procedure of Step 4 of Example 39, the title compound was prepared as a white powder (9 mg, yield 25% over two steps).

[0397] Example 41 Preparation of N-((6-amino-2-methylpyridin-3-yl)methyl)-2-(6-(2-aminopyridin-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 84) TIFF0007699389000252.tif36147 Step 1: 2-(6-Bromo-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetic acid tert-butyl (41 mg, 0.1 mmol), (2-aminopyridin-4-yl)boronic acid (21 mg, 0.15 mmol), Pd-XPhos-G2 (4 mg, 0.005 mmol), and K3PO4 (43 mg, 0.2 mmol) were charged into a 20 mL pressure vial. The vial was purged with argon, then 1,4-dioxane (1 mL) and H2O (100 μL) were added, the reaction vessel was sealed, and stirred at 80 °C for 16 h. LCMS showed conversion to both the desired product and the dehalogenated starting material. The mixture was evaporated to dryness and purified by chromatography (amine column, 50% EtOAc-hexane) to give tert-butyl 2-(6-(2-aminopyridin-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate as a yellow solid (21 mg, 43% yield).

[0398] TIFF0007699389000253.tif50147 Steps 2 - 3 : Using the appropriate amine starting material, the title compound was prepared as a yellow powder (35 mg, 72% yield) according to the procedure of steps 2 - 3 of Example 36.

[0399] Using the appropriate boronic acid and amine starting materials and purification via amine column chromatography (MeOH-CH2Cl2), the following compounds were prepared according to the aforementioned procedure. TIFF0007699389000254.tif125150

[0400] Using the appropriate boronic acid and amine starting materials and purification via preparative HPLC, the following compounds were prepared according to the aforementioned procedure. TIFF0007699389000255.tif21150

[0401] Example 42 Preparation of N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide hydrochloride (Compound 112) TIFF0007699389000256.tif561443-(4-(1-(2-(((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-5-(phenethylamino)-1,6-dihydropyrazin-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylic acid tert-butyl (851477, 19 mg, 0.03 mmol, prepared according to Example 40 using the appropriate boronic acid) was treated with 3 M HCl in iPrOH (1 mL), stirred for 1 hour, and then concentrated under vacuum. The residue was then redissolved in acetonitrile / H2O and lyophilized to give the title compound as a white powder (16 mg, yield 100%).

[0402] Example 43 Preparation of N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-bromo-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 109) TIFF0007699389000257.tif30147The title compound was prepared as a white powder (250 mg, yield 52%) from tert-butyl 2-(6-bromo-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetate according to Steps 2-3 of Example 36.

[0403] Example 44 Preparation of N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-butoxy-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 162) N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-bromo-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide was prepared as a white powder (4 mg, yield 9%) from N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-bromo-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide according to the procedure of Step 1 of Example 35, except that it was in undiluted n-BuOH (1 mL) and purified by chromatography (amine column, MeOH-CH2Cl2).

[0404] Example 45 Preparation of (4-(2-(((1H-Pyrrolo[3,2-C]pyridin-2-yl)methyl)amino)-2-oxoethyl)-3-oxo-5-phenyl-3,4-dihydropyrazin-2-yl)glycine trifluoroacetate (Compound 118) (4-(2-(((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-3-oxo-5-phenyl-3,4-dihydropyrazin-2-yl)glycine ethyl ester was prepared as a white powder (16 mg, yield 26%) from (4-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-3-oxo-5-phenyl-3,4-dihydropyrazin-2-yl)glycine ethyl ester according to the procedure described in Example 10.

[0405] Using appropriate starting materials, the following compounds were prepared according to the above-described procedure. TIFF0007699389000260.tif21150

[0406] Example 45 Preparation of N-((1H-Pyrrolo[3,2-C]pyridin-2-yl)methyl)-2-(3-((3-ethoxypropyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamide trifluoroacetate (Compound 126) TIFF0007699389000261.tif21128 Step 1: 3-Chloropyrazin-2(1H)-one (5 g, 38 mmol), ethyl 2-bromoacetate (4.4 mL, 42 mmol), and potassium carbonate (11.2 g, 81 mmol) were dissolved in DMF (76 mL). The reaction was stirred at room temperature for 1 hour. The crude material was diluted with 200 mL of EtOAc and washed with 200 mL of 1N HCl and 200 mL of brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography (0 - 100% EtOAc - heptane) to give ethyl 2-(3-chloro-2-oxopyrazin-1(2H)-yl)acetate (5.23 g, 63% yield).

[0407] TIFF0007699389000262.tif20133 Step 2 : Ethyl 2-(3-chloro-2-oxopyrazin-1(2H)-yl)acetate (250 mg, 1.15 mmol), 3-ethoxypropan-1-amine (131 mg, 1.27 mmol), and DIEA (400 uL, 2.3 mmol) were dissolved in acetonitrile (5 mL). After stirring at 65 °C for 2 hours, the crude material was concentrated and purified by chromatography (0 - 100% EtOAc - heptane) to give ethyl 2-(3-((3-ethoxypropyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (159 mg, 48% yield).

[0408] TIFF0007699389000263.tif21132 Step 3 : To a solution of ethyl 2-(3-((3-ethoxypropyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (159 mg, 0.56 mmol) in 2 mL of acetonitrile was added dropwise NCS (75 mg, 0.56 mmol) dissolved in 1 mL of acetonitrile. After stirring at 60 °C for 16 hours, the crude material was concentrated and purified by chromatography (0 - 100% EtOAc - heptane) to give ethyl 2-(6-chloro-3-((3-ethoxypropyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (143 mg, 80% yield).

[0409] TIFF0007699389000264.tif29143Step 4 : Ethyl 2-(6-chloro-3-((3-ethoxypropyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (45 mg, 0.14 mmol), phenylboronic acid (26 mg, 21 mmol), tetrakis(triphenylphosphine)palladium(0) (16 mg, 14 μmol), and potassium carbonate (58 mg, 0.43 mmol) were added to 1.1 mL of dioxane and 0.4 mL of water. The reaction was purged with nitrogen for 2 minutes, heated to 100 °C, and stirred for 1 hour. The crude material was concentrated and purified by silica gel chromatography (0 - 20% MeOH - CH2Cl2) to obtain ethyl 2-(3-((3-ethoxypropyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (18.5 mg, 40% yield).

[0410] TIFF0007699389000265.tif27137 Step 5 : Ethyl 2-(3-((3-ethoxypropyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (18.5 mg, 51.5 μmol) and potassium hydroxide (8.6 mg, 154 μmol) were dissolved in 416 μL of THF and 100 μL of water. The reaction was heated to 60 °C and stirred for 1 hour. The crude 2-(3-((3-ethoxypropyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (17 mg, 100% yield) was concentrated and used in the next reaction without further purification.

[0411] TIFF0007699389000266.tif36148 Step 6: 2-(3-((3-Ethoxypropyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (25 mg, 75.5 μmol), 1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (17 mg, 113 μmol), HATU (42 mg, 113 μmol), and DIEA (80 μL, 453 μmol) were dissolved in DMF (750 μL). After stirring for 2 hours, the crude material was purified using reverse-phase HPLC to obtain N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-((3-ethoxypropyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamide trifluoroacetate (17 mg, yield 49%) as a white solid.

[0412] Using appropriate boronate starting materials, the following compounds were prepared according to the above procedure. TIFF0007699389000267.tif26150

[0413] Using appropriate amine starting materials and boronate starting materials, the following compounds were prepared according to the above procedure. The equivalent of the boronate was changed from 1.5 equivalents to 1.3 equivalents. TIFF0007699389000268.tif35150

[0414] Example 46 Preparation of N-((1H-pyrrolo[3,2-C]pyridin-2-yl)methyl)-2-(3-((4-methoxybutyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetamide trifluoroacetate (Compound 122) TIFF0007699389000269.tif36148 Step 1: Ethyl 2-(6-chloro-3-((4-methoxybutyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (50 mg, 0.157 mmol, prepared according to Steps 1-3 of Example 45 using the appropriate amine), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40 mg, 0.188 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 16 μmol), and potassium carbonate (65 mg, 0.47 mmol) were added to 1 mL of dioxane and 0.4 mL of water. The reaction was purged with nitrogen for 2 minutes, heated to 100 °C, and stirred for 1 hour. The crude material was concentrated and purified by chromatography (0-20% MeOH-CH2Cl2) to obtain 2-(3-((4-methoxybutyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetic acid (30 mg, 57% yield).

[0415] TIFF0007699389000270.tif38147 Step 2 : 2-(3-((4-methoxybutyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetic acid (15 mg, 44.8 μmol), 1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (7 mg, 44.8 μmol), HATU (25 mg, 67.2 μmol), and DIEA (46 μL, 268 μmol) were dissolved in DMF (500 μL). After stirring for 1 hour, the crude material was purified using reverse-phase HPLC to obtain N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-((4-methoxybutyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetamide trifluoroacetate (14 mg, 70% yield) as a white solid.

[0416] Example 47 Preparation of N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-((2,2-difluoro-2-phenylethyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetamide Trifluoroacetate (Compound 123) TIFF0007699389000271.tif27129 Step 1 : Ethyl 2-(3-chloro-2-oxopyrazin-1(2H)-yl)acetate (100 mg, 0.46 mmol, prepared according to Step 1 of Example 45), 2,2-difluoro-2-phenylethane-1-amine hydrochloride (89 mg, 0.46 mmol), sodium iodide (138 mg, 0.92 mmol) and DIEA (300 uL, 1.6 mmol) were dissolved in acetonitrile (4 mL). The reaction was stirred via microwave irradiation at 70 °C for 1 hour and then at 130 °C for 20 minutes. The crude material was diluted with 50 mL of EtOAc and washed with 50 mL of 1N HCl and 50 mL of brine. The organic layer was dried over sodium sulfate and concentrated to give ethyl 2-(3-((2,2-difluoro-2-phenylethyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (72.5 mg, yield 50%).

[0417] TIFF0007699389000272.tif22133 Step 2 : According to Step 3 of Example 45, ethyl 2-(6-chloro-3-((2,2-difluoro-2-phenylethyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (34.8 mg, yield 44%) was synthesized from ethyl 2-(3-((2,2-difluoro-2-phenylethyl)amino)-2-oxopyrazin-1(2H)-yl)acetate.

[0418] TIFF0007699389000273.tif36146 Step 3: Ethyl 2-(6-chloro-3-((2,2-difluoro-2-phenylethyl)amino)-2-oxopyrazin-1(2H)-yl)acetate (34.8 mg, 93.8 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24 mg, 115 μmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 9.4 μmol), and potassium carbonate (38 mg, 281 μmol) were dissolved in 800 μL of dioxane and 200 μL of water. The reaction was purged with nitrogen for 2 minutes, heated to 100 °C, and stirred for 0.5 hour. The crude material was concentrated and purified by chromatography (0 - 100% EtOAc - heptane) to give ethyl 2-(3-((2,2-difluoro-2-phenylethyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetate (20 mg, 51% yield).

[0419] TIFF0007699389000274.tif31135 Step 4 : Ethyl 2-(3-((2,2-difluoro-2-phenylethyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetate (20 mg, 47.9 μmol) and potassium hydroxide (8 mg, 148 μmol) were dissolved in 800 μL of THF and 200 μL of water. The reaction was heated to 40 °C and stirred for 2 hours. The crude 2-(3-((2,2-difluoro-2-phenylethyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetic acid (18.7 mg, 100% yield) was concentrated and used in the next reaction without further purification.

[0420] TIFF0007699389000275.tif39145 Step 5: 2-(3-((2,2-difluoro-2-phenylethyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetic acid (18.7 mg, 47.9 μmol), 1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (8 mg, 52.7 μmol), HATU (27 mg, 52.7 μmol), and DIEA (50 μL, 288 μmol) were dissolved in DMF (500 μL). After stirring for 1 hour, the crude material was purified using reverse-phase HPLC to obtain N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-((2,2-difluoro-2-phenylethyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrazin-1(2H)-yl)acetamide trifluoroacetate (13 mg, yield 52%) as a white solid.

[0421] Example 48 Preparation of N-((1H-pyrrolo[3,2-C]pyridin-2-yl)methyl)-2-(3-methyl-2,6-dioxo-5-(phenethylamino)-3,6-dihydropyrimidin-1(2H)-yl)acetamide (Compound 161) Coupling was carried out using the procedure from Step 4 of Example 1 in Step 5 of TIFF0007699389000276.tif34128, except that the procedure of Example 17 was followed to synthesize N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-methyl-2,6-dioxo-5-(phenethylamino)-3,6-dihydropyrimidin-1(2H)-yl)acetamide. The product was purified by chromatography (amine column, hexane followed by 0 - 20% MeOH-CH2Cl2).

[0422] Example 49 Preparation of N-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 131) TIFF0007699389000277.tifA solution of 2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetic acid (25 mg, 0.07 mmol, prepared according to Example 41) and (1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (13 mg, 0.085 mmol) in DMF (0.23 mL) was added with HATU (40 mg, 0.11 mmol) and DIEA (60 μL, 0.35 mmol). The reaction was stirred at room temperature until completion, concentrated, and the residue was purified by chromatography (amine column: hexane followed by 0 - 20% MeOH-CH2Cl2) to give N-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (15.9 mg, 47% yield).

[0423] Using appropriate amine starting materials, the following compounds were prepared according to the above procedure. TIFF0007699389000278.tif21152

[0424] Example 50 Preparation of N-((7-chloro-1H-benzo[d]imidazol-5-yl)methyl)-2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide (Compound 130) TIFF0007699389000279.tif53144N-((7-chloro-1H-benzo[d]imidazol-5-yl)methyl)-2-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)acetamide was synthesized from (7-chloro-1H-benzo[d]imidazol-5-yl)methanamine (prepared according to the procedure described in PCT Publication No. WO2019 / 231935) according to Example 41.

[0425] Example 51 Preparation of 2-(6-(1-Methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)-N-(thieno[3,2-c]pyridin-2-ylmethyl)acetamide (Compound 133) TIFF0007699389000280.tif11128 Step 1 : A solution of methyl thieno[3,2-c]pyridinecarboxylate (200 mg, 1 mmol, 1 equiv) in anhydrous tetrahydrofuran (3.3 mL, 0.3 M) was cooled to 0 °C, and lithium aluminum hydride (60 mg, 1.55 mmol, 1.5 equiv) was added. After stirring for 1 hour, the reaction mixture was quenched with saturated ammonium chloride and filtered. The filtrate was diluted with EtOAc and washed with brine. The organic layer was concentrated to obtain the product, which was carried on to the next step without further purification.

[0426] TIFF0007699389000281.tif12128 Step 2 : A solution of thieno[3,2-c]pyridin-2-ylmethanol (165 mg, 1 mmol) and diphenylphosphoryl azide (323 μL, 1.5 mmol) in anhydrous tetrahydrofuran (2.5 mL, 0.4 M) was cooled to 0 °C, and DBU (224 μL, 1.5 mmol) was added. The reaction mixture was sealed and warmed to 65 °C for 16 hours. The reaction mixture was then partitioned between diethyl ether and water, and the aqueous layer was extracted twice with diethyl ether. The combined organic extracts were washed with brine, dried over Na2SO4, concentrated, and purified by chromatography (0 - 100% EtOAc - heptane) to give 2-(azidomethyl)thieno[3,2-c]pyridine (126 mg, 66% yield over 2 steps) as a white solid.

[0427] TIFF0007699389000282.tif12128 Step 3: A solution of 2-(azidomethyl)thieno[3,2-c]pyridine (126 mg, 0.66 mmol) and triphenylphosphine (350 mg, 1.3 mmol) in anhydrous tetrahydrofuran (2.2 mL, 0.3 M) was added with 28% ammonium hydroxide in water (84 μL, 7.9 M). The reaction mixture was sealed and warmed to 40 °C for 16 h. The reaction mixture was cooled to room temperature, concentrated, and purified by chromatography (0 - 20% MeOH - CH2Cl2) to afford thieno[3,2-c]pyridin-2-ylmethanamine (92 mg, 85% yield) as a white solid.

[0428] TIFF0007699389000283.tif14128 Step 4 : 2-(6-(1-Methyl-1H-pyrazol-4-yl)-2-oxo-3-(phenethylamino)pyrazin-1(2H)-yl)-N-(thieno[3,2-c]pyridin-2-ylmethyl)acetamide was synthesized from thieno[3,2-c]pyridin-2-ylmethanamine according to Example 41.

[0429] Example 52 Preparation of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-(isopropylamino)-2-(methylthio)-6-oxopyrimidin-1(6H)-yl)acetamide (Compound 158) TIFF0007699389000284.tif35129 Steps 1 - 2 : The title compound was synthesized according to the procedure described in Example 4 using (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine.

[0430] Example 53 Preparation of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-(isopropylamino)-6-oxo-5-(((1-phenylcyclobutyl)methyl)amino)pyrimidin-1(6H)-yl)acetamide di-trifluoroacetate (Compound 157) TIFF0007699389000285.tif22128 Step 1: A solution of 2-(methylthio)-5-nitropyrimidin-4(3H)-one (550 mg, 2.67 mmol) in THF (20 mL) and DMF (5 mL) was added with tert-butyl 2-bromoacetate (1 mL) followed by CaH2 (powder, 335 mg, 7.97 mmol). After stirring at 80 °C for 4 h, tert-butyl 2-bromoacetate (0.5 mL) was added following 3 mL of DMF. After stirring at 100 °C for 2 h, the reaction mixture was quenched slowly with ice-cold water and extracted with EtOAc (2×10 mL). The organic extract was dried over anhydrous NaSO4, filtered, and concentrated. The residue was purified by chromatography (0~100% EtOAc-heptane) to afford tert-butyl 2-(2-(methylthio)-5-nitro-6-oxopyrimidin-1(6H)-yl)acetate (300 mg, yield 37%) as a yellow solid.

[0431] TIFF0007699389000286.tif29128 Step 2 : Isopropylamine (0.1 mL) and DIEA (0.2 mL) were added to a suspension of tert-butyl 2-(2-(methylthio)-5-nitro-6-oxopyrimidin-1(6H)-yl)acetate (100 mg, 0.33 mmol) in acetonitrile (2 mL). After stirring at 40 °C for 1 h, the reaction mixture was concentrated and used in the next step without further purification.

[0432] TIFF0007699389000287.tif28128 Step 3 : 10% Pd / C (20 mg) was added to a solution of tert-butyl 2-(2-(isopropylamino)-5-nitro-6-oxopyrimidin-1(6H)-yl)acetate (103 mg, 0.33 mmol) in MeOH (10 mL, 0.03 M), and the mixture was stirred under H2 atmosphere for 1 h. The reaction mixture was filtered through Celite® (registered trademark), rinsed with MeOH, and concentrated. The crude material was used in the next step without further purification.

[0433] TIFF0007699389000288.tif28128 Step 4: A suspension of tert-butyl 2-(5-amino-2-(isopropylamino)-6-oxopyrimidin-1(6H)-yl)acetate (80 mg, 0.28 mmol) in DCE (2 mL) was followed by acetic acid (0.05 mL), and then 1-phenylcyclobutane-1-carbaldehyde (200 mg, 1.28 mmol) was added. After stirring at 40 °C for 10 minutes, the reaction mixture was concentrated in a warm bath at 40 °C under vacuum. The residue was dissolved in DCE (2 mL), and then sodium triacetoxyborohydride (250 mg, 4.2 mmol) was added. After stirring at 40 °C for 20 minutes, the crude mixture was poured into saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 20 mL). The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography (1% 7N NH3 in MeOH-EtOAc) to give tert-butyl 2-(2-(isopropylamino)-6-oxo-5-(((1-phenylcyclobutyl)methyl)amino)pyrimidin-1(6H)-yl)acetate (25 mg, 18% yield in 3 steps).

[0434] TIFF0007699389000289.tif28129 Step 5 : tert-Butyl 2-(2-(isopropylamino)-6-oxo-5-(((1-phenylcyclobutyl)methyl)amino)pyrimidin-1(6H)-yl)acetate (23 mg, 0.054 mmol) was dissolved in TFA (2 mL), and the reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated under vacuum and used in the next step without further purification.

[0435] TIFF0007699389000290.tif38145 Step 6A solution of 2-(2-(isopropylamino)-6-oxo-5-(((1-phenylcyclobutyl)methyl)amino)-pyrimidin-1(6H)-yl)acetic acid (25 mg, 0.069 mmol) in DMF (0.5 mL) and DIEA (0.2 mL) was added with NHS (12 mg, 0.1 mmol), DCC (20 mg, 0.1 mmol), and 1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (20 mg, 0.13 mmol). After stirring at room temperature for 36 h, the reaction mixture was filtered and washed with CH2Cl2. The filtrate was concentrated and purified by reverse-phase HPLC to give N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-(isopropylamino)-6-oxo-5-(((1-phenyl-cyclobutyl)methyl)amino)pyrimidin-1(6H)-yl)acetamide di-trifluoroacetate (9 mg, 33% yield in two steps) as a white solid.

[0436] Using appropriate aldehyde starting materials, the following compounds were prepared according to the procedure described above. TIFF0007699389000291.tif21152

[0437] Using appropriate aldehyde starting materials, the following compounds were prepared according to the procedure described above, except that the amid coupling reaction in Step 6 was carried out according to the procedure described in Example 4. TIFF0007699389000292.tif21152

[0438] Example 54 Preparation of N-((1H-pyrrolo[3,2-C]pyridin-2-yl)methyl)-2-(3-(isopropylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamide (Compound 134) TIFF0007699389000293.tif33128 Step 1: To a solution of benzyl 2-(3,5-dibromo-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (200 mg, 0.42 mmol) in acetonitrile (5 mL, 0.08 M) were added isopropylamine (37 mg, 0.63 mmol) and DIEA (108 mg, 0.84 mmol). After stirring at 70 °C for 6 h, the reaction mixture was evaporated to dryness, washed with water, and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by chromatography (20% EtOAc - hexane) to give benzyl 2-(5-bromo-3-(isopropylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (177 mg, 92% yield).

[0439] TIFF0007699389000294.tif33128 Step 2 : A solution of benzyl 2-(5-bromo-3-(isopropylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (170 mg, 0.37 mmol) and DIEA (96 mg, 0.74 mmol) in MeOH (5 mL) was degassed by Ar flow for 1 min. 10% Pd / C (40 mg) was added, the mixture was evacuated for 1 min, and the mixture was hydrogenated at 120 psi overnight. The catalyst was removed by filtration and the solution was evaporated to give 2-(3-(isopropylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (106 mg, 100% yield), which was used in the next step without further purification.

[0440] TIFF0007699389000295.tif37128 Step 3: To a solution of 2-(3-(isopropylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (106 mg, 0.37 mmol) in DMF (3 mL), NHS (51 mg, 0.44 mmol) was added with stirring until dissolved, and then DCC (91 mg, 0.44 mmol) was further added with stirring for an additional 15 minutes. 1H-Pyrrolo[3,2-c]pyridin-2-yl)methanamine (65 mg, 0.44 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was evaporated to dryness, and the residue was combined and sonicated in 3% 7N NH3 in CH2Cl2 (5 mL). The mixture was filtered, evaporated to dryness, and purified by chromatography (3% 7N NH3 in MeOH-CH2Cl2) to give N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-(isopropylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamide (69 mg, 45% yield) as an off-white solid.

[0441] Using appropriate amine starting materials, the following compounds were prepared according to the procedure described above. TIFF0007699389000296.tif149150

[0442] Example 55 Preparation of N-((1H-pyrrolo[3,2-C]pyridin-2-yl)methyl)-2-(3-((4-fluorobenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamide (Compound 147) TIFF0007699389000297.tif33141 Step 1 : Benzyl 2-(5-bromo-3-((4-fluorobenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate was prepared according to Step 1 of Example 54.

[0443] TIFF0007699389000298.tif33144 Step 2: 2-(3-((4-Fluorobenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid was prepared according to Step 2 of Example 54, except that the reaction time was reduced to 3 hours and the catalyst charge was reduced to half.

[0444] TIFF0007699389000299.tif37143 Step 3 : N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-((4-fluorobenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamide was prepared according to Step 3 of Example 54.

[0445] The following compounds were prepared according to the foregoing procedure using appropriate amine starting materials. TIFF0007699389000300.tif80150

[0446] The compounds of the examples described above and additional compounds that can be prepared according to methods similar to those described for the compounds above and other methods known to those skilled in the art are listed in Table 1. In some embodiments, the compounds are selected from Table 1.

[0447] (Table 1) Exemplary compounds of Structures (I), (II), (III), and (IV) TIFF0007699389000301.tif167152TIFF0007699389000302.tif210152TIFF0007699389000303.tif185152TIFF0007699389000304.tif196152TIFF0007699389000305.tif211152TIFF0007699389000306.tif216152TIFF0007699389000307.tif216152TIFF0007699389000308.tif213152TIFF0007699389000309.tif232152TIFF0007699389000310.tif226152TIFF0007699389000311.tif217152TIFF0007699389000312.tif229152TIFF0007699389000313.tif229152TIFF0007699389000314.tif229152TIFF0007699389000315.tif232152TIFF0007699389000316.tif229152TIFF0007699389000317.tif229152TIFF0007699389000318.tif209152TIFF0007699389000319.tif202152TIFF0007699389000320.tif188152TIFF0007699389000321.tif219152TIFF0007699389000322.tif199152TIFF0007699389000323.tif220152TIFF0007699389000324.tif200152TIFF0007699389000325.tif194152TIFF0007699389000326.tif190152TIFF0007699389000327.tif218152TIFF0007699389000328.tif230152TIFF0007699389000329.tif198152TIFF0007699389000330.tif192152TIFF0007699389000331.tif202152TIFF0007699389000332.tif229152TIFF0007699389000333.tif229152TIFF0007699389000334.tif229152TIFF0007699389000335.tif229152TIFF0007699389000336.tif226152TIFF0007699389000337.tif232152.

[0448] Example 56 Enzyme assay for MASP-2 The MASP-2 assay utilizes a fluorogenic substrate based on the cleavage site of its natural substrate C2. The assay is performed at room temperature in assay buffer containing 20 mM HEPES, pH 7.4, 140 mM NaCl and 0.1% Tween 20. The assay parameters are adjusted so that the assay is proportional to time, enzyme, and substrate concentration. Under these optimized assay conditions, except for some cases of "tight-binding" inhibitors, the IC 50 value is equivalent to the Ki value. For "tight-binding" or possible "slow-binding" inhibitors, it is handled by the methods described in Copeland R.A. (2013) Evaluation of Enzyme Inhibitors in Drug Discovery. 2nd Ed., John Wiley and Sons, Inc., Chapters 5-7.

[0449] The MASP-2 assay protocol is performed as follows. The test compound is serially diluted with DMSO and 100 nL of each dilution is transferred to the assay plate. 10 μL of assay buffer is added, followed by 15 μL of the enzyme MASP-2 (CCP1-CCP2-SP) in assay buffer. Then 15 μL of the substrate in assay buffer is added, mixed to initiate the reaction. After 20 minutes at room temperature, 15 μL of stop solution (0.1 M acetic acid) is added, mixed, and the plate is read on a SpectraMax i3x microplate reader and exported as an Excel file. Each assay plate included a "no inhibitor" (DMSO only) control, an "enzyme-free" control, and a reference inhibitor control. % Activity value = 100 *(Average test compound fluorescence - average "no enzyme" fluorescence) / (average "DMSO only" fluorescence - average "no enzyme" fluorescence). IC 50 And the Ki values are highly reproducible and well within ±2-fold.

[0450] The results of the biological assays for the compounds listed in Table 1 are listed in Table 2 below.

[0451] (Table 2) MASP-2 inhibition for each compound in Table 1 TIFF0007699389000338.tif41150TIFF0007699389000339.tif233150TIFF0007699389000340.tif36150MASP-2 inhibition K i Value: * K above 10 μM i ** K between 2.5 - 10 μM i *** K between 0.5 - 2.5 μM i **** K below 0.5 μM i -- Not tested

[0452] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes are suggested to those skilled in the art in view of them and are included within the spirit and scope of this application and the scope of the appended claims. Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety for all purposes.

[0453] This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 943,599, filed on December 4, 2019, which is hereby incorporated by reference in its entirety.

Claims

1. A compound having the following structure (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: Wherein, R 1 is a substituted or unsubstituted heteroaryl; R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 3 is hydrogen or alkyl; R 4 is alkyl, substituted or unsubstituted arylalkyl, or heterocyclyl substituted with a substituent selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridinyl, or R 3 and R 4 together with the nitrogen to which they are attached form an optionally substituted 4- to 10-membered heterocyclyl; R 5a is hydrogen or a halo; R 5b is hydrogen, alkyl, haloalkyl, (C=O)alkyl, (C=O)Oalkyl, (C=O)cycloalkyl, (C=O)Ocycloalkyl, (C=O)aryl, (C=O)Oaryl, (C=O)heteroaryl, (C=O)Oheteroaryl, (C=O)heterocyclyl, (C=O)Oheterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, or substituted or unsubstituted heterocyclylalkyl; L 1 is a direct bond, -CH 2 -, -S(O) t -, NR 5b , -O-, -C=C-, or -C≡C-; and t is 0, 1, or 2, provided that However, A) R 2 has the following structure: Does not have one of; B) R 1 has the following structure: Does not have one of; and C) R 2 When R is unsubstituted phenyl, R 1 has the following structure: Does not have one of.

2. R 1 is replaced by one or more of R 1a R 1b R 1c R 1d and R 1e , where R 1a R 1b R 1c R 1d and R 1e are each independently C 1～6 alkyl, C 1～6 deuterated alkyl, C 2～6 alkenyl, C 2～6 alkynyl, halo, C 1～6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a SR a C(O)R a C(O)NR a R b C(O)OR a OC(O)R a OC(O)OR a OC(O)NR a R b NR a R b N(R a )C(O)R b N(R a )C(O)NR b R c N(R a )C(O)OR b C(=NR a )NR b R c C(=NOR a )NR b R c C(=NOC(O)R a )NR b R c C(=NR a )N(R b )C(O)OR c N(R a )C(=NR b )NR c R d S(O)R a S(O)NR a R b , S(O) 2 R a , N(R a )S(O) 2 R b , S(O) 2 NR a R b , substituted or unsubstituted C 6～10 aryl, substituted or unsubstituted C 6～10 arylalkyl, substituted or unsubstituted C 6～10 aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, and is selected from the group consisting of Here, R a 、R b 、R c 、and R d are, each time they appear, independently selected from the group consisting of hydrogen, C 1～6 alkyl, C 2～6 alkenyl, C 2～6 alkynyl, hydroxyl, C 1～6 alkoxy, aryl, arylalkyl, C 1～6 haloalkyl, C 1～6 haloalkoxy, C 1～6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl The compound according to Claim 1.

3. R 1 has the following structure: The compound according to Claim 1, having one of.

4. R 2 The compound according to claim 1, wherein R is a substituted or unsubstituted phenyl.

5. R 2 has the following structure: The compound according to Claim 1, having one of.

6. R 2 The compound according to claim 1, wherein R is a substituted or unsubstituted 5- to 10-membered heteroaryl.

7. R 2 The compound according to claim 1, wherein R is a substituted or unsubstituted pyridinyl, a substituted or unsubstituted pyrrolyl, a substituted or unsubstituted pyrimidinyl, a substituted or unsubstituted isoquinolinyl, a substituted or unsubstituted pyrazolyl, a substituted or unsubstituted pyrrolopyridinyl, or a substituted or unsubstituted benzimidazolyl.

8. R 2 has the following structure: The compound according to Claim 1, having one of.

9. R 3 The compound according to claim 1, wherein R is hydrogen or methyl.

10. R 3 and R 4 The compound according to claim 1, wherein together with the nitrogen to which they are attached, they form an optionally substituted 4- to 10-membered heterocyclyl.

11. R 3 and R 4 together with the nitrogen to which they are attached form the following structure: The compound according to Claim 1, forming one of.

12. R 4 is methyl or has the following structure: The compound according to Claim 1, having one of.

13. R 4 The compound according to claim 1, wherein R is a substituted or unsubstituted arylalkyl.

14. R 4 has the following structure: The compound according to Claim 1, having.

15. R 4 The compound according to claim 1, wherein R is a heterocyclyl substituted with a substituent selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridinyl.

16. R 4 has the following structure: The compound according to Claim 1, having one of.

17. L 1 is a direct bond, -CH 2 -, or -C≡C-, the compound according to claim 1.

18. R 5a The compound according to claim 1, wherein R is hydrogen, F, Br, or Cl.

19. A compound having the following structure (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: Wherein, R 6 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 7 is alkyl, -NR 10a R 10b -, -SR 10c , or unsubstituted aryl; R 8 is hydrogen, alkyl, haloalkyl, cycloalkyl, or substituted or unsubstituted arylalkyl; R 9 is alkyl, substituted or unsubstituted -S(O) 2 -arylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or R 8 and R 9 together with the nitrogen to which they are attached form an optionally substituted 4- to 10-membered heterocyclyl; R 10a 、R 10b 、and R 10c are each independently hydrogen, alkyl, haloalkyl, or cycloalkyl, provided that However, When R 7 is unsubstituted phenyl, R 6 has the following structure: Or, Does not have.

20. A compound having the following structure (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: Wherein, R 11 has the following structure: Has one of; R 12 is methyl, alkoxy, or halo; R 13 is a substituted or unsubstituted aryl; and n is 1 or 2, provided that However, The compound of structure (III) does not have the following structure: Does not have.

21. A compound having the following structure (IV) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: Wherein, R 14 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 15 is a substituted or unsubstituted arylalkyl or a substituted or unsubstituted heteroarylalkyl; L 2 is a direct bond, -C(=O), or -S(=O) t -; and t is 0, 1, or 2.

22. Structure: A compound having, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising the compound according to Claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

24. A pharmaceutical composition for treating a MASP-2 related disease or disorder in a subject in need thereof, the pharmaceutical composition comprising an effective amount of the compound according to Claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

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