PAD4 inhibitors and their uses

Abstract

The present disclosure provides compounds represented by structural formula (I0), or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, and their uses, e.g., in treating diseases or disorders associated with PAD4 activity. The disclosure also features compositions containing same, and methods of using and making same. TIFF2024543517000308.tif32104

Description

[Background technology]

[0001] Peptidylarginine deiminase catalyzes the post-translational modification of peptidylarginine to peptidylcitrulline. There are five known PAD isozymes with 45%-58% amino acid sequence identity between the human isozymes and at least 70% identity across each vertebrate ortholog. PADs have diverse tissue distribution, different putative physiological functions, and reported associations with various disease states. PAD6 is thought to be the only catalytically inactive PAD and is expressed primarily in oocytes, ovaries, and early embryos, where it is proposed to be involved in oocyte cytoskeletal sheet formation and female fertility. PAD1 and PAD3 are expressed in the epidermis and hair follicles and are proposed to be involved in keratinization of epidermal tissue, hair growth, and maintenance of the stratum corneum. PAD2 is more widely expressed and can be found in multiple tissues and cell types, including the brain, spinal cord, skeletal muscle, pituitary gland, spleen, neutrophils, and macrophages. It has been proposed to be involved in CNS plasticity, transcriptional regulation, chemokine signaling, and female reproduction.

[0002] PAD4 is involved in the deimination or citrullination of various proteins in vitro and in vivo, with the result of diverse functional responses in various diseases (Jones JE et al, Curr. Opin. Drug Discov. Devel, 12(5), (2009), 616-627). Exemplary disease examples include rheumatoid arthritis, neutrophil-contributing diseases to pathogenesis (e.g., vasculitis, systemic lupus erythematosus, ulcerative colitis), in addition to oncological indications. PAD4 inhibitors may also have broader applicability as tools and therapeutics for human diseases via epigenetic mechanisms.

[0003] Inhibitors of PAD4 may be useful against rheumatoid arthritis (RA). RA is an autoimmune disease that affects about 1% of the population (Wegner N. et al, Immunol. Rev., 233(1) (2010), 34-54). It is characterized by joint inflammation and debilitating destruction of bone and cartilage. A weak genetic association between PAD4 polymorphisms and susceptibility to RA has been suggested in some population studies, although not consistently (e.g., Kochi Y. et al, Ann. Rheum. Dis., 70, (2011), 512-515). PAD4 (along with family member PAD2) has been detected in synovial tissues, where it is involved in the deimination of various joint proteins. This process is presumed to result in the breakdown of tolerance to citrullinated substrates such as fibrinogen, vimentin and collagen in RA joints and the initiation of an immune response. These anti-citrullinated protein antibodies (ACPAs) contribute to disease pathogenesis and can also be used as diagnostic tests for RA (e.g., the commercially available CCP2 or cyclic citrullinated protein 2 test). In addition, increased citrullination may also provide a further direct contribution to disease pathogenesis through its ability to directly affect the function of several joint and inflammatory mediators (e.g., fibrinogen, antithrombin, multiple chemokines). In a smaller subset of RA patients, anti-PAD4 antibodies can be measured and may correlate with more aggressive forms of the disease (Darrah E et al, Sci Transl Med. 2013 May 22;5(186)).

[0004] PAD4 inhibitors may also be useful in reducing pathological neutrophil activity in various diseases. Studies suggest that the process of neutrophil extracellular trap (NET) formation, an innate defense mechanism that allows neutrophils to immobilize and kill pathogens, is associated with histone citrullination and is defective in PAD4 knockout mice (Neeli I. et al, J.Immunol, 180, (2008), 1895-1902 and Li P. et al, J.Exp.Med., 207(9), (2010), 1853-1862). Thus, PAD4 inhibitors may be applicable to diseases in which NET formation in tissues contributes to local injury and disease pathology. Such diseases include, but are not limited to, small vessel vasculitis (Kessenbrock K. et al, Nat. Med, 15(6), (2009), 623-625; Ohlsson SM et al, Clin Exp Immunol. 2014 Jun; 176(3): 363-72), systemic lupus erythematosus (Hakkim A. et al, Proc. Natl. Acad. Sci. USA, 107(21), (2010), 9813-9818 and Villanueva E. et al, J. Immunol, 187(1), (2011), 538-52), ulcerative colitis (Savchenko A. et al, Pathol. Int., 61(5), (2011), 290-7), cystic fibrosis (Dwyer M et al, J Innate Immun. 2014;6(6):765-79), asthma (Dworski R. et al, J. Allergy Clin. Immunol,127(5),(2011),1260-6), deep vein thrombosis (Fuchs T. et al, Proc. Natl. Acad. Sci. USA,107(36),(2010),15880-5), periodontitis (Vitkov L. et al, Ultrastructural Pathol,34(1),(2010),25-30), sepsis (Clark SR et al, Nat. Med,13(4),(2007),463-9), appendicitis (Brinkmann V. et al, Science,303,(2004),1532-5), type 2 diabetes and stroke.Furthermore, since there is evidence that NETs may contribute to pathology in diseases affecting the skin, such as cutaneous lupus erythematosus (Villanueva E. et al, J. Immunol, 187(1), (2011), 538-52) and psoriasis (Lin AM et al, J. Immunol, 187(1), (2011), 490-500), PAD4 inhibitors may show benefit in addressing NET skin diseases when administered systemically or via cutaneous routes. PAD4 inhibitors may affect additional functions within neutrophils, and have broader applicability to neutrophil diseases.

[0005] Studies have shown that collagen-induced arthritis (Willis VC et al, J. Immunol, 186(7), (2011), 4396-4404), dextran sulfate sodium (DSS)-induced experimental colitis (Chumanevich AA et al, Am. J. Physiol. Gastrointest. Liver Physiol, 300(6), (2011), G929-G938), lupus erythematosus-susceptible MRL / lpr mice, atherosclerosis and arterial thrombosis (Knight JS et al, Circ Res. 2014 Mar 14;114(6):947-56), spinal cord repair (Lange S.et al, Dev.Biol,355(2),(2011),205-14), and experimental autoimmune encephalomyelitis (EAE), have demonstrated the efficacy of tool PAD inhibitors (e.g., chloroamidine) in several animal models of disease. The DSS colitis report also demonstrated that chloroamidine drives apoptosis of inflammatory cells both in vitro and in vivo, suggesting that PAD4 inhibitors may be more generally effective in a wide range of inflammatory diseases.

[0006] PAD4 inhibitors may also be useful in the treatment of cancer (Slack.JLet al,Cell.Mol.Life Sci.,68(4),(2011),709-720). Overexpression of PAD4 has been demonstrated in a number of cancers (Chang X.et al,BMC Cancer,9,(2009),40). An antiproliferative role for PAD4 inhibitors has been suggested by the observation that PAD4 citrullinates arginine residues in histones in the promoters of p53 target genes, such as p21, which are involved in the induction of cell cycle arrest and apoptosis (Li P.et al,Mol.Cell Biol,28(15),(2008),4745-4758).

[0007] The aforementioned role of PAD4 in deimination of arginine residues in histones may indicate a general role for PAD4 in epigenetic regulation of gene expression. PAD4 is the primary PAD family member observed to be present in the nucleus as well as the cytoplasm. Early evidence that PAD4 may act as a histone demethyliminase as well as a deiminase has been inconsistent and unproven. However, it may indirectly reduce histone arginine methylation (and thus epigenetic regulation associated with this mark) via depletion of available arginine residues by conversion to citrulline. Thus, PAD4 inhibitors may be useful as epigenetic tools or therapeutics to affect the expression of various target genes in additional disease contexts. PAD4 inhibitors may also be effective in controlling citrullination levels and the switch between pluripotency and differentiation in stem cells (Christophorou MA et al, Nature. 2014 Mar 6;507(7490):104-8), and therefore may therapeutically impact the pluripotent state and differentiation potential of a variety of stem cells, including but not limited to embryonic stem cells, neural stem cells, hematopoietic stem cells, and cancer stem cells.

[0008] Thus, there is a need for inhibitors of PAD that have therapeutic potential in the treatment of diseases associated with the pathological consequences of citrullination and NETosis, including, for example, rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome, small vessel vasculitis, colitis, thrombosis, atherosclerosis, sepsis, diabetes, pulmonary infections and cancer. Summary of the Invention

[0009] Described herein is a compound of formula (I0), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof:

[0010] [ka]

[0011] In the formula, R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , X 5 , and ring T are defined herein.

[0012] Described herein are compounds of formula (I), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof:

[0013] [ka]

[0014] In the formula, W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, and n are as defined herein.

[0015] Also provided is a pharmaceutical composition comprising a compound of Formula (I0), (I), (II), (III), (IIIA), (IV), or (V), or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, and a pharma- ceutically acceptable carrier or excipient.

[0016] The disclosure further provides a method of mediating PAD4 in a patient, the method comprising administering to the patient a compound of Formula (I0), (I), (II), (III), (IIIA), (IV), or (V), or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

[0017] The present disclosure also provides a method of treating a disease or condition in a subject mediated at least in part by PAD4, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I0), (I), (II), (III), (IIIA), (IV), or (V), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

[0018] The disclosure further provides a method of treating a disease or condition in a patient in need of such treatment, comprising administering to the patient an effective amount of (1) a compound of Formula (I), (I), (II), (III), (IIIA), (IV), or (V), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or (2) a pharmaceutical composition comprising a compound of Formula (I), (I), (II), (III), (IIIA), (IV), or (V), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, and a pharma- ceutically acceptable carrier, wherein the disease or condition is a bacterial infection, a viral infection, a metabolic disease, an autoimmune disease, an autoinflammatory disease, cancer, or a septic condition.

[0019] The present disclosure also provides the use of a compound of formula (I), (I), (II), (III), (IIIA), (IV), or (V), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition comprising same, in any of the methods described herein. In one embodiment, a compound of formula (I), (I), (II), (III), (IIIA), (IV), or (V), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition comprising same, for use in any of the methods described herein is provided. In another embodiment, a use of a compound of formula (I), (I), (II), (III), (IIIA), (IV), or (V), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition comprising same, for the manufacture of a medicament for any of the methods described herein is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] 1.Compound In a first embodiment, the present disclosure provides a compound of formula (I0):

[0021] [ka]

[0022] or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein

[0023] [ka]

[0024] is a single bond or a double bond,

[0025] [ka]

[0026] is aromatic, R 1 teeth,

[0027] [ka]

[0028] is selected from the group consisting of During the ceremony, X is O or S; Ring A is a 4- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl; Ring B is a 3- to 6-membered monocyclic carbocyclyl or a 3- to 6-membered monocyclic heterocyclyl; R 2 Deuterium, halogens, CN, C 1~6 Alkyl, C 1~6 Alkoxyl or -NR a R b and X 1 is N or C, X 2 is N, X 3 is -N(R 3 )-or-C(R 3 )= X 4 is N or C, X 5 is N or CH, wherein R 3 is C 1~6 Alkyl, C 1~6 Alkoxyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -NR a R b , -CH 2 -3 to 8-membered cycloalkyl, -CH 2 -3 to 8 membered heterocyclyl, -CH 2 -6 to 10 membered aryl, or -CH 2 -5 to 10 membered heteroaryl, R 3 or R 3 In the group represented by 1~6 Alkyl, C 1~6 Alkoxyl, C 2~6 Alkenyl, C 2~6Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally selected from halogen, oxo, hydroxyl, C 1~6 Alkyl, haloC 1~6 Alkyl, Hydroxyl C 1~6 Alkyl, Methoxyl C 1~6 Alkyl, C 1~6 Alkoxyl, HaloC 1~6 Alkoxyl, HydroxylC 1~6 Alkoxyl, Methoxyl C 1~6 Alkoxyl and -NR a R b and is substituted with one or more groups selected from Ring T is

[0029] [ka]

[0030] is a tricyclic ring selected from the group consisting of During the ceremony, Z is -O- or -S-; W is -(CH 2 ) o -, -CH(R w )-, -C(=O)-, or -CH 2 -C(=O)-, where o is 1 or 2; R w is C 1~6 is alkyl, V is -N(R 6 )- or -C(=O)-, R 4 is hydrogen, deuterium, a halogen, or CN; R 5 is hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, Hydroxyl C 1~6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R 5The 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl represented by the formula (I) may optionally be selected from halogen, oxo, hydroxyl, C 1~6 Alkyl, haloC 1~6 Alkyl, Hydroxyl C 1~6 Alkyl, Methoxyl C 1~6 Alkyl, C 1~6 Alkoxyl, HaloC 1~6 Alkoxyl, Hydroxyl C 1~6 Alkoxyl, Methoxyl C 1~6 Alkoxyl and -NR a R b and is substituted with one or more groups selected from R 6 is hydrogen, C 1~6 Alkyl, C 1~6 Alkylene Hydroxyl, C 1~6 Alkyleneamine, Benzoyl, Carbonyl C 1~6 Alkyl, Carbonyl C 1~6 Alkylene Hydroxyl, C 1~6 Alkylene amides, C 1~6 Alkylene carbamates, C 1~6 Alkylene urea, 3-8 membered cycloalkyl, -CH 2 -6 to 10 membered aryl, or -CH 2 -5 to 10 membered heteroaryl, R 6 The C represented by 1~6 Alkyl, C 1~6 Alkylene Hydroxyl, C 1~6 Alkyleneamine, Benzoyl, Carbonyl C 1~6 Alkyl, Carbonyl C 1~6 Alkylene Hydroxyl, C 1~6 Alkylene amides, C 1~6 Alkylene carbamates, C 1~6 Alkylene urea, 3-8 membered cycloalkyl, -CH 2 -6 to 10 membered aryl, or -CH 2 - 5 to 10 membered heteroaryl is optionally selected from halogen, hydroxyl, amino, CN, C 1~6 Alkyl, C 1~6 Alkyl carbonyl, C 1~6Alkylene Hydroxyl, C 1~6 substituted with one or more groups selected from alkylcarbonylamino and 3- to 8-membered cycloalkyl; R 7 Deuterium, halogen, cyano, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NR a R b , -S(=O) 2 C 1~6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R 7 The C represented by 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkenyl, C 1~6 alkynyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are optionally substituted with one or more groups selected from halogen and hydroxyl; Y 1 is C or N, and Y 1 If is C, then

[0031] [ka]

[0032] is a double bond, and Y 1 If is N, then

[0033] [ka]

[0034] is a single bond, Y 2 -O-, -S-, -S(=O)-, -N(R d )-, -C(=O)-, -C(R d ) 2 - or -C(R e )= Y 3 is -CH 2 -, -CH 2 -CH 2 -, -HC=, -NH-, -N=, -C(=O)-, or -N(R f )-CH 2 - and Y 4 -NH-, -CH 2 - or -N=, wherein R d is hydrogen or C 1~6 is alkyl, R e is hydrogen, halogen, or C 1~6 is alkyl, R f is hydrogen, C 1~6 Alkyl, -C(=O)C 1~6 alkyl, or 3- to 6-membered cycloalkyl; R 11 is -CH 2 - 3 to 8 membered cycloalkyl; R 8 is halogen, CN, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, -NR a R b , -NR a C(=O)R b , -NR a C(=O)OR b , -NR a C(=O)NR b , -NR a SO 2 R b , -NR a S(=O)(=NR b )R c , 3- to 8-membered carbocyclyl, or 3- to 8-membered heterocyclyl, or two R 8 groups, together with the atom(s) to which they are attached, form a 3- to 8-membered carbocyclyl or a 3- to 8-membered heterocyclyl; R 9 and R 10 are independently hydrogen, deuterium, halogen, C 1~6is an alkyl group, 1~6 The alkyl is optionally substituted with one or more groups selected from halogen, hydroxyl, and methoxyl; R a , R b , and R c are independently hydrogen, deuterium, and C 1~6 selected from the group consisting of alkyl, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; m and n are independently 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, or 6; The heterocyclyl contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and the heteroaryl contains 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur.

[0035] In a second embodiment, the disclosure provides a compound according to the first embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, the compound having formula (I):

[0036] [ka]

[0037] In the formula: W is -(CH 2 ) o -, -C(=O)-, or -CH 2 -C(=O)-, where o is 1 or 2; R 7 Deuterium, halogen, cyano, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NR a R b , 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R 7 The C represented by 1~6 Alkyl, C1~6 Alkoxy, C 1~6 Alkenyl, C 1~6 The alkynyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more groups selected from halogen and hydroxyl. Definitions of the other variables are provided in the first embodiment.

[0038] In a third embodiment, the present disclosure provides a compound according to the second embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 1 teeth,

[0039] [ka]

[0040] It is. The definitions of the other variables are provided in the second embodiment or formula (I0).

[0041] In a fourth embodiment, the present disclosure provides a compound according to the second embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 1 teeth,

[0042] [ka]

[0043] and Ring B is a 3-4 membered monocyclic heterocyclyl, preferably Ring B is oxetanyl. The definitions of the other variables are provided in the second embodiment or formula (I0).

[0044] In a fifth embodiment, the present disclosure provides a compound according to the second embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 1 teeth,

[0045] [ka]

[0046] and R 9 and R 10 are independently hydrogen, halo, or haloC 1~6 The definitions of the other variables are provided in the second embodiment or formula (I0).

[0047] In a sixth embodiment, the present disclosure provides a compound according to any one of the second to fifth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein W is -CH 2 - The definitions of other variables are provided in the second to fifth embodiments or formula (I0).

[0048] In a seventh embodiment, the present disclosure provides a compound according to any one of the second to sixth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein ring A is a 4-6 membered monocyclic heterocyclyl, a 6-9 membered fused heterocyclyl, a 6-9 membered bridged heterocyclyl, or a 6-9 membered spiroheterocyclyl. Definitions of other variables are provided in the second to sixth embodiments or formula (I0).

[0049] In an eighth embodiment, the present disclosure relates to a compound according to any one of the second to seventh embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein ring A is selected from the group consisting of:

[0050] [ka]

[0051] Definitions of other variables are provided in the second to seventh embodiments or formula (I0).

[0052] In a ninth embodiment, the present disclosure provides a compound according to any one of the second to eighth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 8 is a halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, -NR a Rb , -NR a (C=O)R b , or -NR a C(=O)OR b and p is 0, 1, 2, or 3. Definitions of other variables are provided in the second to eighth embodiments or formula (I0).

[0053] In a tenth embodiment, the present disclosure provides a compound according to any one of the second to ninth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 8 is a halogen, NH 2 , or C 1~3 alkyl, and p is 0, 1, or 2. Definitions of other variables are provided in the second to ninth embodiments or formula (I0).

[0054] In an eleventh embodiment, the present disclosure provides a compound according to any one of the second to tenth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2 is halogen, CN, C 1~6 Alkyl or C 1~6 alkoxyl and m is 0, 1, or 2. Definitions of other variables are provided in the second through tenth embodiments or formula (I0). In one embodiment, m is 1 and R 2 is R 1 It is in the meta position with respect to .

[0055] In a twelfth embodiment, the present disclosure provides a compound according to any one of the second to eleventh embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2 -F or -OCH 3 and m is 1. Definitions of other variables are provided in the second to eleventh embodiments or formula (I0). In one embodiment, m is 1 and R 2 is R 1 In the meta position with respect to R 2 is F.

[0056] In a thirteenth embodiment, the present disclosure provides a compound according to the second to twelfth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 3 is C 1~4 Alkyl, C 1~4 Alkoxyl, C 2~4 Alkynyl, -CH 2 -3 to 5-membered cycloalkyl, -CH 2 -3 to 5-membered heterocyclyl, -CH 2 -phenyl, or -CH 2 - 5-6 membered heteroaryl, R 3 or R 3 In the group represented by 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 The alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl are optionally selected from halogen, C 1~4 Alkyl, Hydroxyl, and C 1~4 The definitions of the other variables are provided in the second to twelfth embodiments or formula (I0). In one embodiment, R 3 is C 1~4 It is an alkyl.

[0057] In a fourteenth embodiment, the present disclosure provides a compound according to any one of the second to thirteenth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 3 is C 1~2 Alkyl, C 2~3 Alkynyl, -CH 2 -3-4 membered cycloalkyl, -CH 2 -3-4 membered heterocyclyl, -CH 2 -phenyl, or -CH 2 - 5-membered heteroaryl, R 3 or R 3 In the group represented by 1~2 Alkyl, C 1~2 Alkoxyl, C 2~3 The alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl are optionally selected from halogen, C 1~2Alkyl, and C 1~2 The definitions of the other variables are provided in the second to thirteenth embodiments or formula (I0).

[0058] In a fifteenth embodiment, the present disclosure provides a compound according to any one of the second to fourteenth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 3 is selected from the group consisting of:

[0059] [ka]

[0060] Definitions of other variables are provided in the second to fourteenth embodiments or formula (I0).

[0061] In a sixteenth embodiment, the present disclosure provides a compound according to any one of the second to fifteenth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 4 is hydrogen. Definitions of other variables are provided in the second to fifteenth embodiments or formula (I0).

[0062] In a seventeenth embodiment, the present disclosure provides a compound according to any one of the second to sixteenth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 5 is hydrogen, C 1~4 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R 5 The 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl represented by the formula (I) may optionally be selected from halogen, hydroxyl, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxyl C 1~4 Alkyl, Methoxyl C 1~6 Alkyl, C 1~6 Alkoxyl, HaloC 1~6 Alkoxyl, Hydroxyl C 1~6Alkoxyl, Methoxyl C 1~6 Alkoxyl and -NR a R b The definitions of other variables are provided in the second to sixteenth embodiments or formula (I0).

[0063] In an eighteenth embodiment, the present disclosure provides a compound according to any one of the second to seventeenth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 5 is hydrogen, C 1~3 alkyl, or 3- to 4-membered cycloalkyl. Definitions of other variables are provided in the second to seventeenth embodiments or formula (I0).

[0064] In a nineteenth embodiment, the present disclosure provides a compound according to any one of the second to eighteenth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 6 is hydrogen, C 1~4 Alkyl, C 1~4 Alkylene Hydroxyl, C 1~4 Alkyleneamine, Benzoyl, Carbonyl C 1~4 Alkyl, Carbonyl C 1~4 Alkylene Hydroxyl, C 1~4 Alkylene amides, C 1~4 Alkylene carbamates, C 1~4 Alkylene urea, 3-6 membered cycloalkyl, -CH 2 -6-membered aryl, or -CH 2 - 5 to 8 membered heteroaryl, R 6 The C represented by 1~4 Alkyl, C 1~4 Alkylene Hydroxyl, C 1~4 Alkyleneamine, Benzoyl, Carbonyl C 1~4 Alkyl, Carbonyl C 1~4 Alkylene Hydroxyl, C 1~4 Alkylene amides, C 1~4 Alkylene carbamates, C 1~4 Alkylene urea, 3-6 membered cycloalkyl, -CH 2 -6-membered aryl, or -CH 2- 5 to 8 membered heteroaryl is optionally selected from halogen, hydroxyl, amino, CN, C 1~4 Alkyl, C 1~5 Alkyl carbonyl, C 1~4 Alkylene Hydroxyl, C 1~4 and substituted with one or more groups selected from alkylcarbonylamino, and 3- to 6-membered cycloalkyl. Definitions of other variables are provided in the second to eighteenth embodiments or formula (I0).

[0065] In a twentieth embodiment, the present disclosure provides a compound according to any one of the second to nineteenth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 6 is hydrogen, C 1~3 Alkyl, C 1~3 Alkylene Hydroxyl, C 1~3 Alkyleneamine, Benzoyl, Carbonyl C 1~3 Alkyl, Carbonyl C 1~3 Alkylene Hydroxyl, C 1~3 Alkylene amides, C 1~3 Alkylene carbamates, C 1~3 Alkylene urea, 3-5 membered cycloalkyl, -CH 2 -6-membered aryl, or -CH 2 - 5-membered heteroaryl, R 6 The hydrogen represented by C 1~3 Alkyl, C 1~3 Alkylene Hydroxyl, C 1~3 Alkyleneamine, Benzoyl, Carbonyl C 1~3 Alkyl, Carbonyl C 1~3 Alkylene Hydroxyl, C 1~3 Alkylene amides, C 1~3 Alkylene carbamates, C 1~3 Alkylene urea, 3-5 membered cycloalkyl, -CH 2 -6-membered aryl, or -CH 2 -5-membered heteroaryl is optionally fluoro, hydroxyl, amino, CN, C 1~3 Alkyl, C 1~5 Alkyl carbonyl, C 1~3 Alkylene Hydroxyl, C 1~3The definitions of the other variables are provided in the second to nineteenth embodiments or formula (I0). In one embodiment, R 6 is hydrogen or C 1~3 It is an alkylene hydroxyl.

[0066] In a twenty-first embodiment, the present disclosure provides a compound according to any one of the second to twentieth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 6 is selected from the group consisting of:

[0067] [ka]

[0068] Definitions of other variables are provided in the second to twentieth embodiments or formula (I0).

[0069] In a twenty-second embodiment, the present disclosure provides a compound according to any one of the second to twenty-first embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 6 is selected from the group consisting of:

[0070] [ka]

[0071] Definitions of other variables are provided in the second to twenty-first embodiments or formula (I0).

[0072] In a twenty-third embodiment, the present disclosure provides a compound according to any one of the second to twenty-second embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 7 is halogen, cyano, C 1~4 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 7-membered heteroaryl; R 7 The C represented by 1~4The alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 7-membered heteroaryl is optionally substituted with one or more halogens, and n is 0 or 1. Definitions of other variables are provided in the second to twenty-second embodiments or formula (I0).

[0073] In a twenty-fourth embodiment, the present disclosure provides a compound according to any one of the second to twenty-third embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein n is 0. Definitions of other variables are provided in the second to twenty-third embodiments or formula (I0).

[0074] In a twenty-fifth embodiment, the present disclosure provides a compound according to any one of the second to twenty-fourth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is represented by formula (II):

[0075] [ka]

[0076] Definitions of other variables are provided in the second to twenty-fourth embodiments or formula (I0).

[0077] In a twenty-sixth embodiment, the present disclosure provides a compound according to any one of the second to twenty-fifth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 1 is selected from the following:

[0078] [ka]

[0079] Definitions of other variables are provided in the second to twenty-fifth embodiments or formula (I0). In one embodiment, R 1 teeth,

[0080] [ka]

[0081] It is.

[0082] In a twenty-seventh embodiment, the present disclosure provides a compound according to any one of the second to twenty-sixth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R a , R b , and R c are each independently hydrogen or C 1~6 alkyl. Definitions of other variables are provided in the second to twenty-sixth embodiments or formula (I0).

[0083] In a twenty-eighth embodiment, the present disclosure provides a compound according to formula (I0), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein:

[0084] [ka]

[0085] teeth,

[0086] [ka]

[0087] The definition of each variable is defined in the first and third to twenty-seventh embodiments.

[0088] In a twenty-ninth embodiment, the present disclosure provides a compound according to formula (I0), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein ring T is represented by formula (T1) or (T3):

[0089] [ka]

[0090] The definitions of the remaining variables are as defined in the first and third to twenty-eighth embodiments. The definitions of other variables are provided in the first embodiment.

[0091] In a thirtieth embodiment, the present disclosure provides a compound according to any one of the first, twenty-eight, and twenty-ninth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein W is -CH 2 -, -CH(CH 3 )-, or -C(=O)-, and the remaining variables are as defined in the first to fifth, seventh to twenty-fourth, and twenty-sixth to twenty-ninth embodiments.

[0092] In a thirty-first embodiment, the present disclosure provides a compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the first and twenty-eight to thirtieth embodiments, wherein V is -C(=O)-, and the remaining variables are as defined in the first, third to twenty-fourth, and twenty-sixth to thirtieth embodiments.

[0093] In a thirty-second embodiment, the present disclosure provides a compound according to the first embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, the compound having formula (III):

[0094] [ka]

[0095] In the formula: Ring A is

[0096] [ka]

[0097] is selected from the group consisting of R 2 is halogen, CN, C 1~6 Alkyl or C 1~6 is alkoxyl, R 3 is C 1~6 Alkyl, C 2~6 Alkynyl, -CH 2 -3 to 5-membered cycloalkyl, -CH 2-3 to 5-membered heterocyclyl, -CH 2 -phenyl, or -CH 2 - 5-membered heteroaryl, R 3 or R 3 In the group represented by 1~6 Alkyl, C 2~6 Alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl are optionally selected from halogen and C 1~6 substituted with 1 to 3 groups selected from alkyl; R 5 is hydrogen, C 1~3 alkyl, or 3- to 4-membered cycloalkyl; R 6 is hydrogen or C 1~6 is alkyl, R 6 The C represented by 1~6 The alkyl group may optionally include halogen, hydroxyl, and C 1~6 alkoxy; R 7 is halogen, cyano, C 1~6 Alkyl, haloC 1~6 Alkyl, or -S(=O) 2 C 1~3 is alkyl, R 8 is a halogen or NH 2 and p is 0, 1, or 2; n is 0 or 1.

[0098] Definitions of the other variables are provided in the first embodiment. In one particular embodiment,

[0099] [ka]

[0100] teeth,

[0101] [ka]

[0102] It is.

[0103] In a thirty-third embodiment, the disclosure provides a compound according to the first embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, the compound having formula (IIIA):

[0104] [ka]

[0105] In the formula: R 2 is halogen, CN, C 1~6 Alkyl or C 1~6 is alkoxyl, R 3 is C 1~4 is alkyl, R 5 is hydrogen, C 1~3 alkyl, or 3- to 4-membered cycloalkyl; R 6 is hydrogen or C 1~6 is alkyl, R 6 The C represented by 1~6 the alkyl is optionally substituted with 1 to 3 groups selected from halogen, hydroxyl, and methoxy; R 7 is halogen, cyano, C 1~6 Alkyl, haloC 1~6 Alkyl, or -S(=O) 2 C 1~3 is alkyl, n is 0 or 1. The definitions of the other variables are provided in the first embodiment.

[0106] In a thirty-fourth embodiment, the present disclosure provides a compound according to the thirty-third embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2 is fluoro and R 3 is methyl, R 5 is ethyl, isopropyl, or cyclopropyl; R 6is hydrogen or C 1~3 is alkyl, R 6 The C represented by 1~3 The alkyl is optionally substituted with hydroxyl, R 7 is cyano or -S(=O) 2 CH 3 and n is 0 or 1. Definitions of other variables are provided in the thirty-third embodiment.

[0107] In a thirty-fifth embodiment, the present disclosure provides a compound according to the first embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein ring T is represented by formula (T2) or (T4).

[0108] [ka]

[0109] The definitions of the other variables are provided in the first embodiment.

[0110] In a thirty-sixth embodiment, the disclosure provides a compound according to the first embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, the compound having formula (IV):

[0111] [ka]

[0112] In the formula: R 1 teeth,

[0113] [ka]

[0114] The definitions of the other variables are provided in the first embodiment.

[0115] In a thirty-seventh embodiment, the present disclosure provides a compound according to the thirty-sixth embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein Ring A is a 4- to 9-membered heterocyclyl. The definitions of the other variables are provided in the thirty-sixth embodiment.

[0116] In a thirty-eighth embodiment, the disclosure provides a compound according to the thirty-sixth or thirty-seventh embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein ring A is a 4- to 6-membered monocyclic heterocyclyl or a 6- to 8-membered bicyclic heterocyclyl. Definitions of the other variables are provided in the thirty-sixth or thirty-seventh embodiment.

[0117] In a thirty-ninth embodiment, the present disclosure provides a compound according to any one of the thirty-sixth to thirty-eighth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein ring A is

[0118] [ka]

[0119] The definitions of other variables are provided in the 36th to 38th embodiments.

[0120] In a fortieth embodiment, the present disclosure provides a compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the thirty-sixth to thirty-ninth embodiments, wherein R 8 is a halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, -NR a R b , -NR a (C=O)R b , or -NR a C(=O)OR b and p is 0, 1, 2, or 3. Definitions of other variables are provided in the thirty-sixth to thirty-ninth embodiments.

[0121] In a forty-first embodiment, the present disclosure provides a compound according to any one of the thirty-sixth to fortieth embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R8 NH 2 and p is 1. Definitions of other variables are provided in the 36th to 40th embodiments.

[0122] In a forty-second embodiment, the present disclosure provides a compound according to any one of the thirty-sixth to forty-first embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2 is halogen, CN, C 1~6 Alkyl or C 1~6 and m is 0, 1, or 2. Definitions of other variables are provided in the thirty-sixth through forty-first embodiments.

[0123] In a forty-third embodiment, the present disclosure provides a compound according to any one of the thirty-sixth to forty-second embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2 is -F and m is 1. Definitions of other variables are provided in the 36th to 42nd embodiments.

[0124] In a forty-fourth embodiment, the present disclosure provides a compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the thirty-sixth to forty-third embodiments, wherein R 3 is C 1~4 Alkyl, C 1~4 Alkoxyl, C 2~4 Alkynyl, -CH 2 -3 to 5-membered cycloalkyl, -CH 2 -3 to 5-membered heterocyclyl, -CH 2 -phenyl, or -CH 2 - 5-6 membered heteroaryl, R 3 or R 3 In the group represented by 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 The alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl are optionally selected from halogen, C 1~4 Alkyl, Hydroxyl, and C 1~4and substituted with 1 to 3 groups selected from alkoxyl. Definitions of other variables are provided in embodiments 36 to 43.

[0125] In a forty-fifth embodiment, the present disclosure provides a compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the thirty-sixth to forty-fourth embodiments, wherein R 3 is C 1~2 Alkyl, C 2~3 Alkynyl, -CH 2 -3-4 membered cycloalkyl, -CH 2 -3-4 membered heterocyclyl, -CH 2 -phenyl, or -CH 2 - 5-membered heteroaryl, R 3 or R 3 In the group represented by 1~2 Alkyl, C 1~2 Alkoxyl, C 2~3 The alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl are optionally selected from halogen, C 1~2 Alkyl, and C 1~2 and substituted with 1 to 3 groups selected from alkoxyl. Definitions of other variables are provided in embodiments 36 to 44.

[0126] In a forty-sixth embodiment, the present disclosure provides a compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the thirty-sixth to forty-fifth embodiments, wherein R 3 is -CH 3 The definitions of other variables are provided in the 36th to 45th embodiments.

[0127] In a forty-seventh embodiment, the present disclosure provides a compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the thirty-sixth to forty-sixth embodiments, wherein R 4 is hydrogen. Definitions of other variables are provided in the 36th to 46th embodiments.

[0128] In a forty-eighth embodiment, the present disclosure provides a compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the thirty-sixth to forty-seventh embodiments, wherein R 11 is -CH 2 -3 to 6 membered cycloalkyl. Definitions of other variables are provided in embodiments 36 to 47.

[0129] In a forty-ninth embodiment, the present disclosure provides a compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the thirty-sixth to forty-eighth embodiments, wherein R 11 teeth,

[0130] [ka]

[0131] The definitions of other variables are provided in the 36th to 48th embodiments.

[0132] In a 50th embodiment, the present disclosure provides a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, according to any one of the 36th to 49th embodiments,

[0133] [ka]

[0134] is selected from the group consisting of:

[0135] [ka]

[0136] Definitions of other variables are provided in the 36th to 49th embodiments.

[0137] In a fifty-first embodiment, the present disclosure provides a compound according to any one of the thirty-sixth to fifty-first embodiments, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R dis hydrogen or C 1~4 is alkyl, R e is hydrogen, halogen, or C 1~4 is alkyl, R f is hydrogen, C 1~4 Alkyl, -C(=O)C 1~4 alkyl, or 3- to 5-membered cycloalkyl. Definitions of other variables are provided in the 36th to 50th embodiments.

[0138] In a fifty-second embodiment, the present disclosure provides a compound according to the thirty-sixth embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound has formula (V):

[0139] [ka]

[0140] In the formula: R 2 is halogen, CN, C 1~6 Alkyl or C 1~6 is alkoxyl, R 3 is C 1~4 is alkyl, Y 2 -S-, -O-, -N(R d )-, -CH 2 - or -CH=; Y 3 is -CH 2 -, -HC=, -N=, or -CH 2 -CH 2 -It is. Definitions of other variables are provided in the thirty-sixth embodiment.

[0141] In a fifty-third embodiment, the present disclosure provides a compound according to the fifty-second embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2 is fluoro and R 3 is methyl. Definitions of other variables are provided in the 52nd embodiment.

[0142] In a fifty-fourth embodiment, the present disclosure provides a compound according to the thirty-fifth or thirty-sixth embodiment, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 1 teeth,

[0143] [ka]

[0144] It is.

[0145] In one embodiment, the disclosure provides a compound selected from the compounds disclosed in the Examples and Table 1, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

[0146] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0147] 2.Definition The term "deuterium" or "D" refers to an isotopic abundance of D relative to H (hydrogen) of at least 50%, at least 75%, or at least 90%.

[0148] As used herein, the term "halogen" refers to fluoride, chloride, bromide, or iodide.

[0149] The term “alkyl” used alone or as part of a larger moiety such as “alkoxy” or “haloalkyl” refers to a group of the formula —C n H (2n+1) Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms, i.e., C 1~6 As used herein, "C 1~6 An "alkyl" group means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, hexyl, and the like.

[0150] The term "alkoxy" refers to an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, "C 1~4 "Alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0151] The term "haloalkyl" refers to an alkyl optionally substituted with one or more halogen atoms. In one embodiment, the alkyl may be substituted with one to three halogens. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and the like.

[0152] The term "hydroxylalkyl" means an alkyl optionally substituted with one or more hydroxy groups.

[0153] The term "hydroxylalkoxyl" means an alkoxyl optionally substituted with one or more hydroxy groups.

[0154] The term "methoxylalkyl" means an alkyl optionally substituted with one or more methoxyl groups.

[0155] The term "methoxylalkoxyl" means an alkoxyl optionally substituted with one or more methoxyl groups.

[0156] As used herein, the term “alkylene” refers to a group of the formula —C n H 2n - means a linear or branched divalent hydrocarbon radical of the formula: -. Non-limiting examples include ethylene and propylene.

[0157] The term "haloalkylene" means an alkylene optionally substituted with one or more halogen atoms. In one embodiment, the alkylene is optionally substituted with 1 to 3 halogens.

[0158] The term "alkenyl" means an alkyl group in which one or more carbon / carbon single bonds are replaced by a double bond.

[0159] The term "alkynyl" means an alkyl group in which one or more carbon / carbon single bonds are replaced by a triple bond.

[0160] The term "alkyleneamine" refers to an alkyl group that is optionally substituted with one or more amine groups.

[0161] The term "alkyleneamide" refers to an alkyl group optionally substituted with one or more amide groups.

[0162] The term "alkylene carbamate" refers to an alkyl group optionally substituted with one or more carbamate groups.

[0163] The term "alkylene urea" refers to an alkyl group optionally substituted with one or more urea groups.

[0164] The term "benzoyl" means a phenylcarbonyl group.

[0165] The term "carbocyclyl" refers to any stable non-aromatic hydrocarbon ring having 3-12 membered carbocyclyl. In one embodiment, carbocyclyl is a 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic, or a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, or unsaturated. Any substitutable ring atom may be substituted (e.g., by one or more substituents). Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In one embodiment, carbocyclyl is intended to include bridged, fused, and spiro rings. In spirocyclic carbocyclyls, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiro[3.3]heptanyl. In bridged carbocyclyls, the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl. In fused ring carbocyclyl systems, two or more rings may be fused together such that two or more rings share one common bond. Examples of 2- or 3-fused ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl. In one embodiment, the carbocyclyl is a 3- to 12-membered cycloalkyl (preferably a 3- to 8-membered cycloalkyl).

[0166] The term "cycloalkyl" refers to a cyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon group having 3 to 12 ring carbons. In one embodiment, a cycloalkyl can have 3 to 7 ring carbons. Any substitutable ring atom can be substituted (e.g., by one or more substituents). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl can include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0167] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each of which is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone ("3- to 12-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, and sulfur ("3- to 7-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., bicyclic ("bicyclic heterocyclyl") or tricyclic ("tricyclic heterocyclyl") systems, where polycyclic ring systems include fused, bridged, or spiro ring systems). Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can include heteroatoms in one or more of the rings in the polycyclic ring system. Substituents can be present on one or more of the rings of the polycyclic ring system.

[0168] Spiroheterocyclyl refers to a 5-12 membered polycyclic heterocyclyl having rings connected through one common carbon atom (called a spiro atom), the rings having one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms being C, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Representative examples of spiroheterocyclyls include, but are not limited to, the following groups:

[0169] [ka]

[0170] Fused heterocyclyl refers to a 5-12 membered polycyclic heterocyclyl group, in which each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, and one or more rings may contain one or more double bonds, but at least one of the rings is not aromatic, and the ring has one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, and the remaining ring atoms are C. Representative examples of fused heterocyclyls include, but are not limited to, the following groups:

[0171] [ka]

[0172] Bridged heterocyclyl refers to a 5-12 membered polycyclic heterocyclyl group, in which any two rings in the group share two separate atoms, the rings may have one or more double bonds but do not have a fully conjugated pi-electron system, the rings have one or more heteroatoms as ring atoms selected from the group consisting of nitrogen, quaternary nitrogen, nitric oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, and the remaining ring atoms are C. Representative examples of bridged heterocyclyls include, but are not limited to, the following groups:

[0173] [ka]

[0174] In general, a carbocyclyl, cycloalkyl, or heterocyclyl may be unsubstituted or substituted, as valences allow, with one or more substituents, which may be independently selected from several groups, such as oxo, -CN, halogen, alkyl, and alkoxyl, and optionally the alkyl substituents may be further substituted.

[0175] The term "aryl" refers to an all-carbon monocyclic ring or polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group that contains a fully conjugated pi-electron system. In one embodiment, the term "aryl" refers to a 6-12, 6-10, or 6-membered all-carbon monocyclic ring that contains a fully conjugated pi-electron system. The term "aryl" may be used interchangeably with the terms "aryl ring," "carbocyclic aromatic ring," "aryl group," and "carbocyclic aromatic group." Representative examples of aryl are phenyl and naphthyl.

[0176] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic aromatic hydrocarbon in which at least one of the ring carbon atoms is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur. In one embodiment, a heteroaryl is a C 1 -C 2 -C 1 -H 2 -O 3 -C 1 ... 5~10 Based on aryl. In one embodiment, heteroaryl refers to a 5-12 membered, 5-10 membered, or 5-6 membered monocyclic aryl having one or more of its ring carbon atoms replaced by a heteroatom. Heteroaryl groups can be attached through a ring carbon atom or, if valences permit, through a ring nitrogen atom. In general, heteroaryls can be unsubstituted or substituted, as valences permit, with one or more substituents, which can be independently selected from halogen, OH, alkyl, alkoxyl, and amino (e.g., NH 2 , NH alkyl, N(alkyl) 2 ) wherein optionally the alkyl may be further substituted.

[0177] Examples of monocyclic 5- to 6-membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., Examples include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl group), tetrazolyl (e.g., tetrazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrimidinyl, pyridinyl and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. A "substituted heteroaryl group" is substituted at any one or more substitutable ring atoms that are bonded to a hydrogen atom, which may be a ring carbon or ring nitrogen atom.

[0178] As used herein, many moieties (e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are referred to as either "substituted" or "optionally substituted". When a moiety is modified by one of these terms, unless otherwise stated, it indicates that any portion of the moiety known to one of skill in the art as available for substitution may be substituted, which includes one or more substituents. When two or more substituents are present, each substituent may be independently selected. Such means for substitution are well known in the art and / or taught by this disclosure. An optional substituent may be any substituent suitable for binding to a moiety.

[0179] If suitable substituents are not specifically recited, exemplary substituents include: 1~5 Alkyl, C 1~5 Hydroxyalkyl, C 1~5 Haloalkyl, C 1~5 Alkoxy, C 1~5 Haloalkoxy, halogen, hydroxyl, cyano, amino, -CN, -NO 2 , -OR c1 , -NR a1 R b1 , -S(O) i R a1 , -NR a1 S(O) i R b1 , -S(O) i NR a1 R b1 , -C(=O)OR a1 , -OC(=O)OR a1 , -C(=S)OR a1 , -O(C=S)R a1 , -C(=O)NR a1 R b1 , -NR a1 C(=O)R b1 , -C(=S)NR a1 R b1 , -C(=O)R a1 , -C(=S)R a1 , N.R. a1 C(=S)R b1 , -O(C=O)NR a1R b1 , -NR a1 (C=S)OR b1 , -O(C=S)NR a1 R b1 , -NR a1 (C=O)NR a1 R b1 , -NR a1 (C=S)NR a1 R b1 , phenyl, or 5-6 membered heteroaryl. a1 and each R b1 are independently -H and C 1~5 alkyl, optionally hydroxyl or C 1~3 alkoxy-substituted, R c1 -H, C 1~5 Haloalkyl or C 1~5 alkyl, wherein C 1~5 The alkyl is optionally hydroxyl or C 1 ~C 3 It is substituted with alkoxy.

[0180] As used herein, the symbol "

[0181] [ka]

[0182] " refers to the point where the moieties are attached.

[0183] Pharmaceutically acceptable salts The term "pharmaceutical acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic reaction within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmacologically acceptable salts in J.Pharm.Sci.,1977,66,1-19.

[0184] Pharmaceutically acceptable salts of the compounds of any one of the above formulas include acid addition and base salts.

[0185] The present teachings include pharma- ceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharma- ceutically acceptable salts with pharma- ceutically acceptable acids. Suitable pharma- ceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings having an acidic group, such as a carboxylic acid, can form pharma- ceutically acceptable salts with pharma- ceutically acceptable bases. Suitable pharma- ceutically acceptable base salts include ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts).

[0186] A pharma- ceutically acceptable salt of a compound of any one of the above formulas is (i) by reacting a compound of any one of the above formulae with a desired acid or base; (ii) by removing an acid or base labile protecting group from a suitable precursor of a compound of any one of the above formulae, or by ring opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid or base; or (iii) by converting one salt of a compound of any one of the above formulas to another salt by reaction with an appropriate acid or base, or by a suitable ion exchange column.

[0187] All three reactions are typically carried out in solution. The resulting salt may precipitate and be collected by filtration or may be collected by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to nearly non-ionized.

[0188] Compounds of any one of the above formulas, and pharma- ceutically acceptable salts thereof, may exist in unsolvated and solvated forms.

[0189] Stereoisomers and other variations Compounds of any one of the above formulae may exhibit one or more types of isomers (e.g., optical, geometric, or tautomeric isomers). Such variations are implicit to the compounds of any one of the above formulae defined by reference to their structural features and therefore within the scope of the present disclosure.

[0190] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration, or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers with two or more chiral centers that are not identical and are not mirror images of each other.

[0191] When a compound is designated by its chemical name (e.g., when the structure is designated with "R" or "S") or its structure (e.g., when the structure is designated with a "wedge" bond) that denotes a single enantiomer, unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the named or depicted enantiomer in a mixture divided by the total weight of the mixture of both enantiomers.

[0192] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all stereoisomers.

[0193] Where two stereoisomers are depicted by their chemical names or structures and the chemical names or structures are connected by "and", a mixture of the two stereoisomers is intended.

[0194] When two stereoisomers are depicted by their chemical names or structures and the names or structures are connected by "or", either one or the other of the two stereoisomers is intended, but not both.

[0195] When a disclosed compound having a chiral center is depicted by a structure without indicating the configuration at that chiral center, the structure is meant to encompass compounds having an S configuration at that chiral center, compounds having an R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating the configuration at that chiral center with "S" or "R," the name is meant to encompass compounds having an S configuration at that chiral center, compounds having an R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center.

[0196] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, the name or structure is understood to encompass both possible enantiomeric forms of the compound (e.g., both enantiomerically pure, enantiomerically enriched, or racemic). When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral center, the name or structure is understood to encompass all possible diastereomeric forms (e.g., diastereomerically pure, diastereomerically enriched, and equimolar mixtures) of one or more diastereomers of the compound (e.g., racemic mixture).

[0197] The term "geometric isomer" refers to isomers that differ in the orientation of substitute atoms in relationship to a carbon-carbon double bond, a carbocyclic ring, or a bridged bicyclic system. Substituted atoms (other than hydrogen) on each side of a carbon-carbon double bond may be in the E or Z configuration according to the Cahn-Ingold-Prelog priority rules. In the "E" configuration, the highest priority substituents are on opposite sides in relationship to the carbon-carbon double bond. In the "Z" configuration, the highest priority substituents are oriented on the same side in relationship to the carbon-carbon double bond.

[0198] Substituents around a carbon-carbon double bond may also be designated "cis" or "trans", with "cis" representing substituents on the same side of the double bond and "trans" representing substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring may also be designated as "cis" or "trans". The term "cis" represents substituents on the same side of the plane of the ring and the term "trans" represents substituents on opposite sides of the plane of the ring. Mixtures of compounds in which substituents are located both on the same and opposite sides of the plane of the ring are designated "cis / trans".

[0199] Tautomeric isomerism ("tautomerism") can occur where structural isomers are interconvertible via a low energy barrier. This can take the form of, for example, proton tautomerism in compounds of any one of the above formulae containing an imino, keto, or oxime group, or so-called valence tautomerism in compounds containing an aromatic moiety. Thus, a single compound may exhibit more than one type of isomer.

[0200] In certain instances, tautomeric forms of the disclosed compounds exist as shown in the tautomeric structures below.

[0201] [ka]

[0202] When a geometric isomer is designated by name or structure, it is understood that the named or depicted isomer is present to a greater extent than another isomer, i.e., the geometric isomeric purity of the named or depicted geometric isomer is greater than 50% by weight, e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0203] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0204] Conventional techniques for the preparation / isolation of individual enantiomers / diastereomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), for example using chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol, or, if the compound of any one of the above formulas contains an acidic or basic moiety, a base or acid, for example 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers may be converted to the corresponding pure enantiomer by means well known to those skilled in the art. Chiral compounds of any one of the above formulas (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0-50% by volume of isopropanol, typically 2-20% by volume, and 0-5% by volume of an alkylamine, typically 0.1% diethylamine. The concentration of the eluent provides an enriched mixture. Chiral chromatography using subcritical and supercritical fluids may be used. Methods for chiral chromatography useful in some embodiments of the present disclosure are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein). Columns can be obtained from Chiral Technologies, Inc., West Chester, Pa., USA (a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan).

[0205] It must be emphasized that the compounds of any one of the above formulas are depicted herein in a single tautomeric form, and all possible tautomeric forms are included within the scope of the present disclosure.

[0206] 3. Administration and Dosing Typically, the compound of the present disclosure is administered in an amount effective for treating the conditions described herein.The compound of the present disclosure can be administered as the compound itself or alternatively as a pharmaceutically acceptable salt.For the purpose of administration and dosing, the compound itself or its pharmaceutically acceptable salt is simply referred to as the compound of the present disclosure.

[0207] The compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition suitable for such route, and in a dose effective for the intended treatment. The compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally, or topically.

[0208] Compounds of the present disclosure may be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used by which the compound enters the blood stream directly from the mouth.

[0209] In another embodiment, the compound of the present disclosure may also be administered directly into the bloodstream, into muscle, or into internal organs.Suitable means for parenteral administration include intravenous administration, intraarterial administration, intraperitoneal administration, intrathecal administration, intraventricular administration, intraurethral administration, intrasternal administration, intracranial administration, intramuscular administration, and subcutaneous administration.Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0210] In another embodiment, the compounds of the present disclosure may be administered topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the present disclosure may be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure may be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure may be administered directly to the eye or ear.

[0211] The dosage regimen of the disclosed compounds and / or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient, the severity of the condition, the route of administration, and the activity of the particular compound used. Thus, the dosage regimen may vary widely. In one embodiment, the total daily dose of the disclosed compounds is typically about 0.001 to about 100 mg / kg (i.e. mg compound of the disclosed compounds per kg body weight) for the treatment of the indications discussed herein.

[0212] For oral administration, the composition may be provided in the form of a tablet containing 0.1 to 500 milligrams of active ingredient for symptomatic adjustment of dosage to the patient. The pharmaceutical preparation typically contains about 0.01 mg to about 500 mg of active ingredient. For intravenous administration, the dose may range from about 0.01 to about 10 mg / kg / min during a constant rate infusion.

[0213] Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammals such as primates, rodents (mouse, rats, hamsters, rabbits, etc.). In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.

[0214] 4. Pharmaceutical Compositions In another embodiment, the present disclosure includes a pharmaceutical composition. Such a pharmaceutical composition includes the compound of the present disclosure, its pharma- ceutically acceptable salt, or its stereoisomer, and a pharma- ceutically acceptable carrier or excipient. Other pharmacologically active substances may also be present.

[0215] As used herein, "a pharma- ceutically acceptable carrier or excipient" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Examples of pharma- ceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof, and may include isotonic agents, e.g., sugars, sodium chloride, or polyalcohols such as mannitol or sorbitol, in the composition. Pharmaceutically acceptable substances that enhance the shelf life or effectiveness of the antibody or antibody portion, such as wetting agents or minor amounts of auxiliary substances, e.g., wetting agents or emulsifying agents, preservatives or buffers.

[0216] The compositions of the present disclosure may be in a variety of forms, including, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0217] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those typically used for passive immunization of humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0218] Oral administration in solid dosage form may be presented in separate units, such as, for example, hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present disclosure. In another embodiment, oral administration may be in the form of powder or granules. In another embodiment, oral dosage form is a sublingual dosage form, such as, for example, lozenges. In such solid dosage forms, the compound of any one of the above formulas is usually combined with one or more adjuvants. Such capsules or tablets may contain controlled release formulations. In the case of capsules, tablets, and pills, dosage forms may also include buffering agents or be prepared with enteric coatings.

[0219] In another embodiment, oral administration may be in liquid dosage form.Liquid dosage forms for oral administration include, for example, pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs that contain inert diluents (e.g., water) that are commonly used in the art.Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweeteners), and / or aromatic agents.

[0220] In another embodiment, the present disclosure comprises a parenteral dosage form.

[0221] "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to known techniques using suitable dispersing agents, wetting agents, and / or suspending agents.

[0222] In another embodiment, the present disclosure comprises a topical dosage form.

[0223] "Topical administration" includes transdermal administration, for example, via a transdermal patch or iontophoretic device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present disclosure are administered by a transdermal device, administration is accomplished using a patch, either of the reservoir and porous membrane type, or of the solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated. See, e.g., Finnin and Morgan, J. Pharm. Sci., 88:955-958, 1999.

[0224] Formulations suitable for topical administration to the eye include, for example, eye drops in which the compound of the present disclosure is dissolved or suspended in a suitable carrier. A typical formulation suitable for ocular or aural administration may be in the form of droplets of micronized suspension or solution in isotonic pH-adjusted sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and particulate or vesicular systems such as niosomes or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum may be incorporated together with a preservative such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0225] For intranasal administration or administration by inhalation, the compounds of the present disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is pressed or pumped by the patient, or in the form of an aerosol spray from a pressurized container or nebulizer, using a suitable propellant.The formulation suitable for intranasal administration is typically administered in the form of a dry powder from a dry powder inhaler (alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle mixed with a phospholipid, for example, phosphatidylcholine), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to generate a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.For intranasal use, the powder can include a bioadhesive agent, for example, chitosan or cyclodextrin.

[0226] In another embodiment, the present disclosure includes a rectal dosage form. Such a rectal dosage form may be, for example, in the form of a suppository. Cocoa butter is a traditional suppository base, although various alternatives may be used as appropriate.

[0227] Other carrier materials and modes of administration known in the pharmaceutical art may also be used.The pharmaceutical compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, including effective formulation and administration procedures.

[0228] The above considerations regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks. Drug formulations are described, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3 rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0229] 5. Treatment Methods The compounds and compositions described herein are generally useful for inhibiting PAD4.

[0230] The activity of the compounds utilized in the present disclosure as inhibitors of PAD4 can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of PAD4. The detailed conditions for assaying the compounds utilized in the present disclosure as inhibitors of PAD4 are described in the following examples. In some embodiments, provided compounds selectively inhibit PAD4 compared to PAD2.

[0231] As used herein, the terms "treatment," "treat," and "treating," as described herein, refer to reversing, alleviating, slowing, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the development of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or slow their recurrence.

[0232] The provided compounds are inhibitors of PAD4, and are therefore useful for treating one or more diseases or disorders associated with PAD4 enzyme activity.Accordingly, in certain embodiments, the present disclosure provides a method for treating a disease or disorder associated with / mediated by PAD4 enzyme activity, comprising administering to a patient in need of treatment a compound of the present disclosure, or a pharma-ceutically acceptable composition thereof.

[0233] In one embodiment, the disease or disorder associated with / mediated by PAD4 enzyme activity is a disease, condition, or disorder mediated by inappropriate PAD4 activity. In some embodiments, the disease or disorder associated with / mediated by PAD4 enzyme activity is selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. In a further embodiment, the disease or disorder associated with PAD4 enzyme activity is rheumatoid arthritis. In a further embodiment, the disease or disorder associated with PAD4 enzyme activity is systemic lupus erythematosus. In a further embodiment, the disease or disorder associated with PAD4 enzyme activity is vasculitis. In a further embodiment, the disease or disorder associated with PAD4 enzyme activity is cutaneous lupus erythematosus. In a further embodiment, the disease or disorder associated with PAD4 enzyme activity is psoriasis.

[0234] In one embodiment, the disclosure provides a method for treating a subject having a disease or condition, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein the disease or condition is a bacterial infection, a viral infection, a metabolic disease, an autoimmune disease, an autoinflammatory disease, cancer, or a septic condition.

[0235] In one embodiment, the disclosure provides a method for treating a subject having a disease or condition, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein the disease or condition is pulmonary infection (e.g., Covid-19), acute lymphocytic leukemia, ankylosing spondylitis, asthma, breast cancer, lung cancer, colon cancer, pancreatic cancer, hematological cancer, neurological cancer, skin cancer, chronic lymphocytic leukemia, cutaneous lupus erythematosus, gout, inflammatory bowel disease (IBD), type 2 diabetes, obesity, type 1 diabetes mellitus (T1DM), cystic fibrosis, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, or vasculitis.

[0236] In one embodiment, the disclosure provides a method for treating a subject having a disease or condition, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein the disease or condition is cancer, and the cancer has metastasized.

[0237] In one embodiment, the disclosure provides a method of treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cystic fibrosis, asthma, gout, cutaneous lupus erythematosus, or psoriasis, comprising administering to a human subject in need of treatment a therapeutically effective amount of a provided compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

[0238] In one embodiment, a method of treating rheumatoid arthritis is provided, the method comprising administering to a human subject in need of treatment a therapeutically effective amount of a provided compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

[0239] In one embodiment, a method of treating systemic lupus erythematosus is provided, the method comprising administering to a human subject in need of treatment a therapeutically effective amount of a provided compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

[0240] In one embodiment, a method of treating vasculitis is provided, the method comprising administering to a human subject in need of treatment a therapeutically effective amount of a provided compound, a pharma- ceutically acceptable salt, or a stereoisomer thereof. In one embodiment, a method of treating cutaneous lupus erythematosus is provided, the method comprising administering to a human subject in need of treatment a therapeutically effective amount of a provided compound, a pharma- ceutically acceptable salt, or a stereoisomer thereof. In one embodiment, a method of treating psoriasis is provided, the method comprising administering to a human subject in need of treatment a therapeutically effective amount of a provided compound, a pharma- ceutically acceptable salt, or a stereoisomer thereof.

[0241] In some embodiments, the disease or disorder associated with PAD4 enzyme activity is acid induced lung injury, acne (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenal insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopneumonia, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina pectoris, angioedema, anhidrotic ectodermal dysplasia ID, ankylosing spondylitis, anterior segment inflammation, antiphospholipid syndrome, apnea. pharyngitis, appendicitis, arthritis, asthma, arteriosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Behcet's disease, Behcet's syndrome, Bell's palsy, beryllium disease, Blau syndrome, bone pain, bronchitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease of prematurity, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue diseases, corneal ulcers, Crohn's disease, cryopyrin-associated periodic syndrome, cryptococcosis , cystic fibrosis, deficiency of interleukin-1 receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloidotic polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, intestinal disease, head injury, headache, hearing loss, cardiac disease, hemolytic anemia, Henoch-Schönlein purpura, hepatitis, hereditary periodic fever syndromes, shingles and herpes simplex, HIV-1, Hodgkin's Huntington's disease, pulmonary hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia with recurrent fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect irritant inflammation, irritant-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney damage due to parasitic infections, kidney damage due to parasitic infections, kidney transplant rejection prevention, leptospirosis, leukemia, Löffler's syndrome, lung injury, lupus,Lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticarial deafness amyloidosis), multiple sclerosis, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, rhinosinusitis, necrotizing enterocolitis, neonatal-onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neurological disorders, neuropathological disorders, non-allergen-induced asthma, obesity, ocular allergy, optic neuritis, organ transplantation, metastatic Osteoarthropathy, Otitis media, Paget's disease, Pain, Pancreatitis, Parkinson's disease, Pemphigus, Pericarditis, Periodic fever, Periodontitis, Peritoneal endometriosis, Whooping cough, Pharyngitis and adenitis (PFAPA syndrome), Plant irritant induced inflammation, Pneumonia, Pneumonitis, Pulmonary cyst infection, Poison ivy / sumac oil induced inflammation, Polyarteritis nodosa, Polychondritis, Polycystic kidney disease, Polymyositis, Psoriasis, Psychosocial stress disorders, Lung diseases, Pulmonary hypertension, Pulmonary fibrosis, Pyoderma gangrenosum, Suppuration Aseptic arthritis, renal disease, retinal disease, rheumatic carditis, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced disease, Sjogren's syndrome, skin disease, sleep apnea, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplants, TNF receptor-associated periodic syndrome (TNF-receptor-associated periodontitis) TRAPS), toxoplasmosis, transplant, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, Wegener's granulomatosis, interstitial lung disease, psoriatic arthritis, juvenile idiopathic arthritis, Sjogren's syndrome, antineutrophil cytoplasmic antibody (ANCA)-fusion vasculitis, antiphospholipid syndrome, sepsis, deep venous vasculopathy, fibrosis, Alzheimer's disease, scleroderma, and CREST syndrome.

[0242] In one embodiment, the disclosure provides a compound, a pharma- ceutically acceptable salt, or a stereoisomer thereof for use in treatment. In another embodiment, the disclosure provides a compound, a pharma- ceutically acceptable salt, or a stereoisomer thereof for use in treatment of a disease or disorder mediated by inappropriate PAD4 activity. In another embodiment, the disclosure provides a compound, a pharma- ceutically acceptable salt, or a stereoisomer thereof for use in treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. In another embodiment, the disclosure provides a compound, a pharma- ceutically acceptable salt, or a stereoisomer thereof for use in treatment of rheumatoid arthritis. In another embodiment, the disclosure provides a compound, a pharma- ceutically acceptable salt, or a stereoisomer thereof for use in treatment of systemic lupus erythematosus. In another embodiment, the disclosure provides a compound, a pharma- ceutically acceptable salt, or a stereoisomer thereof for use in treatment of vasculitis. In another embodiment, the present disclosure provides a compound, its pharma- ceutically acceptable salt, or its stereoisomer for use in treating cutaneous lupus erythematosus. In another embodiment, the present disclosure provides a compound, its pharma- ceutically acceptable salt, or its stereoisomer for use in treating psoriasis. In another embodiment, the present disclosure provides the use of a compound, its pharma- ceutically acceptable salt, or its stereoisomer in the manufacture of a medicament for use in treating a disorder mediated by inappropriate PAD4 activity. In another embodiment, the present disclosure provides the use of a compound of formula (I0), (I), (II), (III), (IIIA), (IV), or (V), its pharma- ceutically acceptable salt, or its stereoisomer for use in the manufacture of a medicament for use in treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. In another embodiment, the disclosure provides the use of a compound of Formula (I0), (I), (II), (III), (IIIA), (IV), or (V), a pharma- ceutically acceptable salt, or a stereoisomer thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis.In another embodiment, the disclosure provides the use of a compound of Formula (I), (I), (II), (III), (IIIA), (IV), or (V), a pharma- ceutically acceptable salt, or a stereoisomer thereof, in the manufacture of a medicament for use in the treatment of systemic lupus erythematosus. In another embodiment, the disclosure provides the use of a compound of Formula (I), (I), (II), (III), (IIIA), (IV), or (V), a pharma- ceutically acceptable salt, or a stereoisomer thereof, in the manufacture of a medicament for use in the treatment of vasculitis. In another embodiment, the disclosure provides the use of a compound of Formula (I), (I), (II), (III), (IIIA), (IV), or (V), a pharma- ceutically acceptable salt, or a stereoisomer thereof, in the manufacture of a medicament for use in the treatment of cutaneous lupus erythematosus. In another embodiment, the present disclosure provides the use of a compound of formula (I0), (I), (II), (III), (IIIA), (IV), or (V), a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for use in the treatment of psoriasis. In a further embodiment, the present disclosure provides a pharmaceutical composition for the treatment or prevention of a disease or disorder mediated by inappropriate PAD4 activity, comprising a provided compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for the treatment or prevention of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, comprising a provided compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for the treatment or prevention of rheumatoid arthritis, comprising a provided compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition comprising a provided compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, for the treatment or prevention of systemic lupus erythematosus.In a further embodiment, the present disclosure provides a pharmaceutical composition comprising a provided compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, for the treatment or prevention of vasculitis.In a further embodiment, the present disclosure provides a pharmaceutical composition comprising a provided compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, for the treatment or prevention of cutaneous lupus erythematosus.In a further embodiment, the present disclosure provides a pharmaceutical composition comprising a provided compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, for the treatment or prevention of psoriasis.

[0243] 6. Medical Kit One aspect of the present disclosure relates to a kit for conveniently and effectively carrying out the method or use according to the present disclosure. In general, a pharmaceutical pack or kit comprises one or more containers filled with one or more of the components of the pharmaceutical composition of the present disclosure. Such kits are particularly suitable for the delivery of solid oral forms such as tablets or capsules. Such kits preferably include several unit dosages and may also include a card with the dosages weighted in the order of their intended use. Optionally, the card designates, for example, the days of the treatment schedule on which the dosages can be administered. Memory aids in the form of numbers, letters, or other markings, or by calendar inserts, can be provided. Optionally, associated with such containers can be a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical products, which notice reflects the approval by the agency of manufacture, use, or sale for human administration.

[0244] The following representative examples contain important additional information, exemplification, and guidance that can be adapted to the practice of the present disclosure in its various embodiments and equivalents thereof. These examples are intended to help illustrate the present disclosure, and are not intended to, and should not be construed to, limit its scope. Indeed, various modifications of the present disclosure and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art upon review of the specification, including the following examples, and upon reference to the scientific and patent literature cited herein.

[0245] To help describe the state of the art, the contents of the cited documents are incorporated herein by reference.

[0246] Further, for purposes of this disclosure, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "Organic Chemistry," Morrison & Boyd (3d Ed), the contents of both of which are incorporated herein by reference.

[0247] 7. Preparation Any one of the compounds of the above formulas can be prepared by the general and specific methods described below using the common general knowledge of a person skilled in the art of synthetic organic chemistry. Such common general knowledge can be found in standard reference books such as Comprehensive Organic Chemistry, Ed. Barton and Ollis, Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Vol. I-XII (published by Wiley-Interscience). The starting materials used herein are commercially available or can be prepared by routine methods known in the art.

[0248] It should be noted that in the preparation of compounds of any one of the above formulas, some of the preparation methods described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in any one of the above precursor formulas). The need for such protection varies depending on the nature of the remote functionality and the conditions of the preparation method. The need for such protection is readily determined by one skilled in the art. The use of such protection / deprotection methods is within the skill of the art. For a general description of protecting groups and their use, see Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0249] For example, certain compounds contain primary amine or carboxylic acid functionalities that, if left unprotected, may prevent reaction at other sites on the molecule. Thus, such functionalities may be protected by appropriate protecting groups that can be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those commonly used in peptide synthesis (such as Nt-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids), which are generally not chemically reactive under the described reaction conditions and can typically be removed without chemically altering other functionalities in any one of the compounds of the above formulas.

[0250] The schemes described below are intended to provide a general description of the methods used to prepare the compounds of the present disclosure. Some of the compounds of the present disclosure may contain single or multiple chiral centers with stereochemical designation (R) or (S). It will be apparent to one skilled in the art that all of the synthetic transformations can be carried out in a similar manner, regardless of whether the material is enantiomerically enriched or racemic. Furthermore, resolution into the desired optically active substances can be carried out at any desired point in the sequence using well-known methods as described herein and in the chemical literature. EXAMPLES

[0251] Abbreviation

[0252] [Table 2-1] [Table 2-2]

[0253] Synthesis Examples Example 1 Synthesis of N-(3-(5-(5-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-82-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)propyl)acetamide

[0254] [ka]

[0255] [ka]

[0256] Step 1: To a solution of ethyl 7-nitro-1H-indole-2-carboxylate (6.0 g, 25.62 mmol) in anhydrous DMF (50 mL) was added KOH (1.87 g, 33.30 mmol, 916.02 μL) and tert-butyl 2-bromoacetate (5.75 g, 29.46 mmol, 4.32 mL). The reaction mixture was stirred at room temperature for 2 h, diluted with EA (200 mL), washed with water (20 mL x 3) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (eluted with 0-20% EA / PE) to give 1-(2-tert-butoxy-2-oxo-ethyl)-7-nitro-indole-2-carboxylate (8.2 g, 23.54 mmol, 91.89% yield) as a yellow solid. LC / MS(ESI + ) [(M-55) + ]: 292.8.

[0257] Step 2: A mixture of ethyl 1-(2-tert-butoxy-2-oxo-ethyl)-7-nitro-indole-2-carboxylate (1.1 g, 3.16 mmol) and 10% palladium on carbon (200 mg, 631.55 μmol) was dissolved in THF (20 mL) under an atmosphere of hydrogen (balloon) (3.16 mmol) at room temperature for 4 h until the starting material was consumed and the desired signal was found by LC / MS. The reaction mixture was filtered through Celite and the filtrate was evaporated in vacuum under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with 0-80% EA / PE) to give 7-amino-1-(2-tert-butoxy-2-oxo-ethyl)indole-2-carboxylate (850 mg, 2.67 mmol, 84.55% yield) as a white solid. LC / MS (ESI + ) [(M-55) + ]: 262.8.

[0258] Step 3: Ethyl 7-amino-1-(2-tert-butoxy-2-oxo-ethyl)indole-2-carboxylate (850 mg, 2.67 mmol) was dissolved in pyridine (20 mL). The reaction mixture was stirred and refluxed at 110 °C for 4 h. After the solvent was removed in vacuo, the residue was purified by flash column chromatography on silica gel (eluted with 0-50% EA / PE) to give ethyl 10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-2-carboxylate (500 mg, 2.05 mmol, 76.67% yield) as a pale yellow solid. LC / MS (ESI + ) [(M+H) + ]: 244.8.

[0259] Step 4: To a solution of ethyl 10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-2-carboxylate (4.5 g, 18.42 mmol) in THF (50 mL) was added lithium aluminum hydride (2.10 g, 55.35 mmol) at 0 °C. After 1 h at 0 °C, the mixture was stirred at room temperature overnight. The mixture was then slowly mixed with 1 mL of water, 1 mL of sodium hydroxide solution (15%), and 3 mL of water. The resulting suspension was then decanted from the solid and the supernatant was collected. The solid was briefly treated with tetrahydrofuran (50 mL) and ethyl acetate (50 mL) in an ultrasonic bath and then decanted. The combined supernatant was mixed with water and the phases were separated. The organic phase was washed once with saturated sodium chloride solution and then dried over sodium sulfate. After filtration, the reaction mixture was concentrated in vacuo to give 1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-ylmethanol (2.7 g, 14.34 mmol, 77.86% yield) as a pale yellow oil, which was used in the next step without further purification. LC / MS (ESI + ) [(M+H) + ]: 188.9.

[0260] Step 5: A mixture of 1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-ylmethanol (2.7 g, 14.34 mmol) and di-tert-butyl decarbonate (6.25 g, 28.62 mmol, 6.57 mL) was dissolved in toluene (50 mL). The resulting mixture was stirred at 90 °C for 3 h. The desired signals were found by LC / MS. After removal of the solvent and residue, it was purified by flash column chromatography on silica gel (eluted with 0-40% EA / PE) to obtain tert-butyl 2-(hydroxymethyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-9-carboxylate (3.5 g, 12.14 mmol, 84.62% yield) as a colorless liquid oil. LC / MS(ESI + ) [(M+H) + ]: 288.9.

[0261] Step 6: To tert-butyl 2-(hydroxymethyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-9-carboxylate (2.7 g, 9.36 mmol) in chloroform (30 mL) was added manganese dioxide (2.44 g, 28.09 mmol). The suspension was stirred at room temperature overnight and then filtered through Celite, washing with 30 mL of chloroform. The filtrate was concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography on silica gel (eluted with 0-50% EA / PE) to give tert-butyl 2-formyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-9-carboxylate (2.5 g, 8.73 mmol) as a colorless oil. LC / MS(ESI + ) [(M+H) + ]: 286.8.

[0262] Step 7: A mixture of tert-butyl 2-formyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-9-carboxylate (2.5 g, 8.73 mmol), methyl 3-methoxy-4-(methylamino)-5-nitro-benzoate (2.1 g, 8.73 mmol) and sodium dithionite (3.0 g, 17.46 mmol) was dissolved in EtOH / water (50 mL). The resulting mixture was stirred at 100° C. overnight. The desired signal was found by LC / MS. After the solvent was removed in vacuo, the residue was purified by flash column chromatography on silica gel (eluted with 0-100% EA / PE) to give tert-butyl 2-(7-methoxy-5-methoxycarbonyl-1-methyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (4 g, 8.39 mmol, 96.14% yield) as a liquid oil. Chemical formula: C 26 H 28 N 4 O 5 LC / MS (ESI + ) [(M+H) + ]:476.8.

[0263] Step 8: tert-Butyl 2-(7-methoxy-5-methoxycarbonyl-1-methyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-carboxylate (4 g, 8.39 mmol) was dissolved in HCl / ethyl acetate (20 mL). After stirring at room temperature for 3 h, the resulting mixture was filtered and the filter cake was dried in vacuum to give methyl 2-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazole-5-carboxylate (3 g, 7.97 mmol, 94.95% yield) as a pale yellow solid. LC / MS (ESI + ) [(M+H) + ]:376.8.

[0264] Step 9: A mixture of ethyl 2-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazole-5-carboxylate (200 mg, 531.34 μmol) and 3-bromopropanenitrile (71.2 mg, 43.94 μL) was dissolved in DMF (10 mL). 2 CO 3 (518.1 mg, 1.59 mmol) was added and the mixture was heated at 100 °C for 18 h. The crude reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel (eluting with 0-70% EA / PE) to give 2-[9-(2-cyanoethyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (50 mg, 116.42 μmol, 21.91% yield, crude) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:429.7.

[0265] Step 10: To a solution of methyl 2-[9-(2-cyanoethyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (50 mg, 116.42 μmol) in methanol (20 mL) was added Raney nickel, activated catalyst (10.0 mg, 116.42 μmol) in water. The reaction mixture was stirred for 2 h at 37° C. for 1 h at 37° C. for 1 h at 37° C. for 1 h at 37° C. 2The mixture was stirred overnight at room temperature under a hydrogen atmosphere (balloon). The mixture was then filtered, washed with methanol, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 0-50% MeOH / DCM) to give methyl 2-[9-(3-aminopropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (25 mg, 57.67 μmol, 49.53% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:433.8.

[0266] Step 11: A solution of 2-[9-(3-aminopropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (25 mg, 57.67 μmol) and DIPEA (22.4 mg, 173.01 μmol, 30.13 μL) in dichloromethane (5 mL) was added dropwise to a solution of acetyl chloride (4.5 mg, 57.67 μmol, 3.51 μL) in dichloromethane (2 mL). After stirring at room temperature for 1 h, water (1 mL) was added. The layers were separated and the organic layer was washed with saturated ammonium chloride (10 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 0-30% MeOH / DCM) to give methyl 2-[9-(3-acetamidopropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (20 mg, 42.06 μmol, 72.93% yield) as a colorless oil. LC / MS (ESI + ) [(M+H) + ]:475.8.

[0267] Step 12: To a solution of methyl 2-[9-(3-acetamidopropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (10 mg, 21.03 μmol) in THF (1 mL) was added LiOH (aq, 1N) (105.14 μmol, 2 mL). The reaction mixture was stirred at room temperature overnight. The pH was adjusted to acidic with 2 mol / L HCl. After removing the solvent in vacuo, the crude product 2-[9-(3-acetamidopropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (9 mg, 19.50 μmol, 92.74% yield) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]: 461.8. The crude product was used in the next reaction without further purification.

[0268] Step 13: A mixture of 2-[9-(3-acetamidopropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (9 mg, 19.50 μmol), tert-butyl N-[(3R,5R)-5-methyl-3-piperidyl]carbamate (4.2 mg, 19.50 μmol), HATU (7.4 mg, 19.50 μmol) and DIPEA (5.0 mg, 39.00 μmol, 6.79 μL) was dissolved in DMF (2 mL). The resulting mixture was stirred at 50° C. for 10 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give tert-butyl N-[(3R,5R)-1-[2-[9-(3-acetamidopropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-5-fluoro-3-piperidyl]carbamate (10 mg, 15.11 μmol, 77.49% yield) as a yellow oil. LC / MS (ESI) + ) [(M+H) + ]:661.7.

[0269] Step 14: tert-Butyl N-[(3R,5R)-1-[2-[9-(3-acetamidopropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-5-fluoro-3-piperidyl]carbamate (10 mg, 15.11 μmol) was dissolved in HCl / EA (3 mL). The resulting solution was stirred at room temperature for 30 min. After removal of the solvent in vacuo and purification by pre-HPLC, N-[3-[2-[5-[(3R,5R)-3-amino-5-fluoro-piperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]propyl]acetamide (7 mg, 12.46 μmol, 82.48% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:561.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.24 (s, 1H), 7.90 (d, J = 5.8 Hz, 1H), 7.31 (d, J = 1.1 Hz, 1H), 7.02 - 6.90 (m, 3H), 6.85 (d, J = 1.2 Hz, 1H), 6.41 (dd, J = 7.1, 1.3 Hz, 1H), 5.05 - 4.76 (m, 2H), 4.63 (t, J = 5.0 Hz, 2H), 4.23 (s, 3H), 3.99 (s, 3H), 3.55 (t, J = 5.1 Hz, 3H), 3.17 (q, J = 6.5 Hz, 3H), 3.03 (d, J = 10.8 Hz, 1H), 2.19 (s, 1H), 1.84 (s, 3H), 1.78 (q, J = 7.1 Hz, 2H), 1.64 - 1.48 (m, 1H).

[0270] Example 2 Preparation of (R)-(3-aminopiperidin-1-yl)(2-(2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0271] [ka]

[0272] [ka]

[0273] Step 1: EtOH (4 mL) and H 2 tert-Butyl 2-formyl-1,9-diazatricyclo[6.3.1.0]dihydrochloride (6.3.1.0) in a mixture of 2,4-dichloro-1,2,4-tetrahydrofuran (1,2,4-tetrahydrofuran) and 1,2,4-tetrahydrofuran (1,2,4-tetrahydrofuran) 4,12 A suspension of ]dodeca-2,4(12),5,7-tetraene-9-carboxylate (24 mg, 83.82 μmol), tert-butyl N-[(3R)-1-[3-methoxy-4-(methylamino)-5-nitro-benzoyl]-3-piperidyl]carbamate (45 mg, 110.17 μmol) and sodium dithionite (43.8 mg, 251.46 μmol) was stirred at reflux overnight at 96° C., cooled and diluted with DCM (40 mL). The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (DCM / MeOH=15 / 1) to give tert-butyl 2-[5-[(3R)-3-(tert-butoxycarbonylamino)piperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraene-9-carboxylate (46 mg, 71.34 μmol, 85.12% yield) was obtained as a white solid. LC / MS (ESI + )[(M+H) + ]:644.8.

[0274] Step 2: tert-Butyl 2-[5-[(3R)-3-(tert-butoxycarbonylamino)piperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.0 4,12 To a solution of [(3R)-3-amino-1-piperidyl]-[2-(1,9-diazatricyclo[6.3.1.0]-2,4-dihydro-1,5-diphenyl-2,6-dihydro-1,7-triazabicyclo[6.3.1.0]-2,5-dihydro-1,7-triazabicyclo[6.3.1.0] ... 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazol-5-yl]methanone (25 mg, 56.24 μmol) was obtained as an off-white solid. LC / MS (ESI + ) [(M+H) + ]:544.8.

[0275] The following compounds were prepared similarly: Example 3: Report of the synthesis of (R)-N-(3-(5-(5-(3-aminopiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)propyl)acetamide

[0276] [ka]

[0277] Prepared in the same manner as in Example 1. LC / MS (ESI + ) [(M+H) + ]:543.8.

[0278] Example 4 Synthesis report of 1-(3-(5-(5-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)propyl)-3-cyclopropylurea

[0279] [ka]

[0280] Prepared in the same manner as in Example 1. LC / MS (ESI + ) [(M+H) + ]:602.8.

[0281] Example 5: Report of the synthesis of (R)-1-(3-(5-(5-(3-aminopiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)propyl)-3-cyclopropylurea

[0282] [ka]

[0283] Prepared in the same manner as in Example 1. LC / MS (ESI + ) [(M+H) + ]:584.8.

[0284] Example 6: Synthesis report of 1-(3-(5-(5-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)propyl)-3-cyclopropylurea

[0285] [ka]

[0286] Prepared in the same manner as in Example 1. LC / MS (ESI + ) [(M+H) + ]:596.8. 1 H NMR (400 MHz, DMSO) δ 8.19 (s, 1H), 7.46 (s, 1H), 7.35 (s, 1H), 7.01 - 6.92 (m, 4H), 6.40 (d, J = 7.0 Hz, 1H), 6.10 (d, J = 2.6 Hz, 1H), 5.96 (t, J = 5.8 Hz, 1H), 4.63 (s, 2H), 4.22 (d, J = 3.1 Hz, 3H), 4.00 (s, 3H), 3.78 (s, 1H), 3.55 (t, J = 5.1 Hz, 3H), 3.21 - 2.99 (m, 6H), 2.42 (dt, J = 6.8, 3.4 Hz, 1H), 2.23 (s, 1H), 1.98 (t, J = 12.3 Hz, 2H), 1.77 (dt, J = 15.9, 8.2 Hz, 3H), 1.45 (s, 1H), 0.60 - 0.55 (m, 2H), 0.37 - 0.33 (m, 2H).

[0287] Example 7: Report of the synthesis of (R)-1-(3-(5-(5-(3-aminopiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)propyl)-3-cyclopropylurea

[0288] [ka]

[0289] Prepared in the same manner as in Example 1. LC / MS (ESI + ) [(M+H) + ]:501.8. 1H NMR (400 MHz, DMSO) δ 8.37 (s, 2H), 7.30 (d, J = 1.2 Hz, 1H), 7.02 - 6.93 (m, 3H), 6.86 (d, J = 1.2 Hz, 1H), 6.47 (d, J = 7.1 Hz, 1H), 4.64 (t, J = 5.2 Hz, 2H), 4.23 (s, 3H), 4.00 (s, 3H), 2.87 (t, J = 7.3 Hz, 2H), 2.78 (d, J = 7.5 Hz, 2H), 1.91 (t, J = 7.5 Hz, 3H), 1.71 (s, 1H), 1.55 - 1.26 (m, 3H).

[0290] Example 8 Preparation of (R)-6-(5-(3-aminopiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-[1,4]diazepino[3,2,1-hi]indol-2(1H)-one

[0291] [ka]

[0292] [ka]

[0293] Step 1: To a solution of ethyl 7-nitro-1H-indole-2-carboxylate (1.08 g, 4.61 mmol) in ethanol (30 mL) and ethyl acetate (30 mL) was added palladium on carbon (100 mg, 939.67 μmol) at room temperature. The reaction mixture was cooled to 5° C. for 1 hour and then cooled to 5° C. 2 The mixture was stirred at room temperature under atmospheric pressure for 16 hours and then filtered. The filtrate was concentrated in vacuo to give ethyl 7-amino-1H-indole-2-carboxylate (940 mg, 4.60 mmol, 99.82% yield) as a pale yellow solid. LC / MS (ESI + ) [(M+H) + ]:205.

[0294] Step 2: To a solution of ethyl 7-amino-1H-indole-2-carboxylate (100 mg, 489.66 μmol) in DCM (2 mL) was added 3-bromopropanoyl chloride (167.87 mg, 979.31 μmol) followed by N-ethyl-N-isopropyl-propan-2-amine (316.42 mg, 2.45 mmol, 426.44 μL) at room temperature. The reaction mixture was stirred at room temperature for 2 h, diluted with DCM (10 mL) and quenched with water (10 mL). The two phases were separated and the aqueous phase was extracted with DCM (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give crude ethyl 7-(3-bromopropanamido)-1H-indole-2-carboxylate (160 mg, 471.72 μmol, 96.34% yield). LC / MS (ESI + ) [(M+H) + ]:340.

[0295] Step 3: To a solution of ethyl 7-(3-bromopropanamido)-1H-indole-2-carboxylate (160 mg, 471.72 μmol) in DMF (3 mL) was added cesium carbonate (460.0 mg, 1.42 mmol) at room temperature. The reaction mixture was stirred at 106° C. for 16 h. The mixture was cooled to 10° C. and cooled to 3° C. with ice H. 2 The mixture was quenched with 2,4-dimethylformamide (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (PE / EA=1 / 0 to 1 / 1) to give ethyl 10-oxo-1,9-diazatricyclo[6.4.1.04,13]trideca-2,4(13),5,7-tetraene-2-carboxylate (80 mg, 308.88 μmol, 65.48% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:259.

[0296] Step 4: Ethyl 10-oxo-1,9-diazatricyclo[6.4.1.0] in a mixed solvent of methanol (5 mL) and water (1 mL). 4,13 A mixture of 10-oxo-1,9-diazatricyclo[6.4.1.0]trideca-2,4(13),5,7-tetraene-2-carboxylate (80 mg, 309.75 μmol) and lithium hydroxide (7.4 mg, 309.75 μmol) was stirred at 65° C. for 16 h and concentrated in vacuo. The residue was acidified to about pH 5 with 2N aqueous HCl, filtered and purified to give 10-oxo-1,9-diazatricyclo[6.4.1.0]trideca-2,4(13),5,7-tetraene-2-carboxylate (80 mg, 309.75 μmol) and lithium hydroxide (7.4 mg, 309.75 μmol). 4,13 ]Trideca-2,4(13),5,7-tetraene-2-carboxylic acid (60 mg, 260.62 μmol, 84.14% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:231.

[0297] Step 5: 10-Oxo-1,9-diazatricyclo[6.4.1.0] in DMF (2 mL) 4,13 To a solution of 13,5,7-tetraene-2-carboxylic acid (23 mg, 99.90 μmol), methyl 3-amino-5-methoxy-4-(methylamino)benzoate (73.0 mg, 347.24 μmol), and dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (42 mg, 110.46 μmol), N-ethyl-N-isopropyl-propan-2-amine (64.6 mg, 499.52 μmol, 87.01 μL) was added at room temperature. The reaction mixture was stirred at room temperature for 5 min and purified by reverse phase chromatography to give methyl 3-methoxy-4-(methylamino)-5-[(10-oxo-1,9-diazatricyclo[6.4.1.0 4,13 ]trideca-2,4(13),5,7-tetraene-2-carbonyl)amino]benzoate (29 mg, 68.65 μmol, 68.72% yield) and its isomers were obtained as white solids. LC / MS (ESI + ) [(M+H) + ]:423.

[0298] Step 6: Methyl 3-methoxy-4-(methylamino)-5-[(10-oxo-1,9-diazatricyclo[6.4.1.0 4,13 A mixture of methyl 7-methoxy-1-methyl-2-(10-oxo-1,9-diazatricyclo[6.4.1.0]trideca-2,4(13),5,7-tetraene-2-carbonyl)amino]benzoate (29 mg, 68.65 μmol) was stirred at 125° C. for 3 h. After cooling to room temperature, the resulting mixture was concentrated in vacuo to give crude methyl 7-methoxy-1-methyl-2-(10-oxo-1,9-diazatricyclo[6.4.1.0]trideca-2,4(13),5,7-tetraene-2-carbonyl)amino]benzoate (29 mg, 68.65 μmol). 4,13 ]trideca-2,4(13),5,7-tetraen-2-yl)benzimidazole-5-carboxylate (27 mg, 66.76 μmol, 97.25% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:405.

[0299] Step 7: Methyl 7-methoxy-1-methyl-2-(10-oxo-1,9-diazatricyclo[6.4.1.0 4,13 To a mixture of 7-methoxy-1-methyl-2-(10-oxo-1,9-diazatricyclo[6.4.1.0]trideca-2,4(13),5,7-tetraen-2-yl)benzimidazole-5-carboxylate (25 mg, 61.82 μmol) was added lithium hydroxide hydrate (13.0 mg, 309.09 μmol, 8.59 μL) and the resulting mixture was stirred at 60° C. for 16 h, cooled, and concentrated in vacuo. The residue was acidified to approximately pH 5 with 2N aqueous HCl, filtered, and purified to give 7-methoxy-1-methyl-2-(10-oxo-1,9-diazatricyclo[6.4.1.0]trideca-2,4(13),5,7-tetraen-2-yl)benzimidazole-5-carboxylate (25 mg, 61.82 μmol). 4,13 ]trideca-2,4(13),5,7-tetraen-2-yl)benzimidazole-5-carboxylic acid (20 mg, 51.23 μmol, 82.9% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:391.

[0300] Step 8: 7-Methoxy-1-methyl-2-(10-oxo-1,9-diazatricyclo[6.4.1.04,13 ]trideca-2,4(13),5,7-tetraen-2-yl)benzimidazole-5-carboxylic acid (10 mg, 25.62 μmol), tert-butyl N-[(3R)-3-piperidyl]carbamate (6.2 mg, 30.74 μmol), and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (48.7 mg, 128.08 μmol) were added to N-ethyl-N-isopropyl-propan-2-amine (3.6 mg, 28.18 μmol, 4.91 μL) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h and purified by preparative HPLC to give tert-butyl N-[(3R)-1-[7-methoxy-1-methyl-2-(10-oxo-1,9-diazatricyclo[6.4.1.0 4,13 ]trideca-2,4(13),5,7-tetraen-2-yl)benzimidazole-5-carbonyl]-3-piperidyl]carbamate (10 mg, 17.46 μmol, 68.17% yield) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:573.

[0301] Step 9: tert-Butyl N-[(3R)-1-[7-methoxy-1-methyl-2-(10-oxo-1,9-diazatricyclo[6.4.1.0 4,13 To a solution of 2-[5-[(3R)-3-aminopiperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.4.1.0]trideca-2,4(13),5,7-tetraen-2-yl)benzimidazole-5-carbonyl]-3-piperidyl]carbamate (10 mg, 17.46 μmol) was added a 4.0 M solution of hydrogen chloride in dioxane (2 mL) at room temperature. The mixture was stirred at room temperature for 2 h, concentrated in vacuo and the residue was triturated in EA / PE (1 / 10, 11 mL). The white solid was collected by filtration to give 2-[5-[(3R)-3-aminopiperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.4.1.0]trideca-2,4(13),5,7-tetraen-2- ... 4,13]Trideca-2,4(13),5,7-tetraen-10-one was obtained (8 mg, 16.93 μmol, 96.95% yield). LC / MS (ESI + ) [(M+H) + ]:473.

[0302] The following compounds were prepared similarly: Example 9 (R)-5-(5-(3-aminopiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0303] [ka]

[0304] Prepared in a similar manner to Example 8. LC / MS (ESI + ) [(M+H) + ]:458.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (d, J = 3.3 Hz, 1H), 7.36 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.19 (s,1H), 7.05 - 6.99 (m, 1H), 6.88 (s, 1H), 6.68 (d, J = 7.3 Hz, 1H), 5.32 (s, 2H), 4.27 (s, 3H), 4.00 (s, 3H),3.00 (s, 3H), 2.82 (s, 2H), 1.91 (s, 1H), 1.71 (s, 1H), 1.50 (s, 1H), 1.34 (s, 1H).

[0305] Example 10: Synthesis report of (R)-(3-aminopiperidin-1-yl)(2-(1-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0306] [ka]

[0307] [ka]

[0308] Step 1: To a solution of methyl 2-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazole-5-carboxylate (20.0 mg, 53.13 μmol) in acetonitrile (5 mL) and DIPEA (13.7 mg, 106.26 μmol, 18.5 μL) was added 2-bromoethanol (6.6 mg, 53.1 μmol) at room temperature and the reaction mixture was heated at 80° C. for 2 h by microwave. The solution was purified by pre-HPLC to give methyl 2-[9-(2-hydroxyethyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (15.0 mg, 35.68 μmol, 67.14% yield). LC / MS (ESI + ) [(M+H) + ]:420.8.

[0309] Step 2: To a solution of 2-[9-(2-hydroxyethyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (15.0 mg, 35.68 μmol) in THF (2 mL) was added LiOH (aq, 1N) (76.40 μmol, 5 mL). The resulting mixture was stirred at room temperature overnight. The pH of the reaction solution was adjusted to less than 7.0 with 2 mol / L HCl. After removing the solvent in vacuo, the crude product 2-[9-(2-hydroxyethyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (12 mg, 29.53 μmol, 82.8% yield) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]: 406.8. The crude product was used in the next step reaction without further purification.

[0310] Step 3: A mixture of 2-[9-(2-hydroxyethyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (12 mg, 29.53 μmol), tert-butyl N-[(3R)-3-piperidyl]carbamate (5.9 mg, 29.53 μmol), HATU (11.2 mg, 29.53 μmol) and DIPEA (11.5 mg, 88.58 μmol, 15.43 μL) was dissolved in DMF (5 mL). The resulting mixture was stirred at 50° C. for 30 min. The reaction was diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give tert-butyl N-[(3R)-1-[2-[9-(2-hydroxyethyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-3-piperidyl]carbamate (10 mg, 16.99 μmol, 57.53% yield) as a yellow oil. LC / MS (ESI) + ) [(M+H) + ]:588.8.

[0311] Step 4: tert-Butyl N-[(3R)-1-[2-[9-(2-hydroxyethyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-3-piperidyl]carbamate (10 mg, 16.99 μmol) was dissolved in HCl / ethyl acetate (5 mL). The resulting mixture was stirred at room temperature for 30 minutes. After removing the solvent in vacuo, the residue was purified by pre-HPLC to give [(3R)-3-amino-1-piperidyl]-[2-[9-(2-hydroxyethyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazol-5-yl]methanone (5 mg, 10.23 μmol, 60.25% yield) as a pale yellow solid. LC / MS (ESI + ) [(M+H) + ]:488.8.

[0312] The following compounds were prepared similarly: Example 11: Synthesis report of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0313] [ka]

[0314] Prepared in a similar manner to Example 10. LC / MS (ESI + ) [(M+H) + ]:500.8.

[0315] Example 12: Synthesis report of (R)-(3-aminopiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0316] [ka]

[0317] Prepared in a similar manner to Example 10. LC / MS (ESI + ) [(M+H) + ]:502.8.

[0318] Example 13: Synthesis report of (3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0319] [ka]

[0320] Prepared in a similar manner to Example 10. LC / MS (ESI + ) [(M+H) + ]:520.7.

[0321] Example 14: Synthesis report of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0322] [ka]

[0323] Prepared in a similar manner to Example 10. LC / MS (ESI + ) [(M+H) + ]:614.8.

[0324] Example 15 (R)-(3-aminopyrrolidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0325] [ka]

[0326] Prepared in a similar manner to Example 10. LC / MS (ESI+) [(M+H) + ]:488.8.

[0327] Example 16 (R)-(3-amino-3-methylpiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0328] [ka]

[0329] Prepared in a similar manner to Example 10. LC / MS (ESI+) [(M+H) + ]:516.8.

[0330] Example 17 ((3R,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0331] [ka]

[0332] Prepared in a similar manner to Example 10. LC / MS (ESI+) [(M+H) + ]:570.8.

[0333] Example 18 (R)-(5-amino-3,3-difluoropiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0334] [ka]

[0335] Prepared in a similar manner to Example 10. LC / MS (ESI+) [(M+H) + ]:538.8.

[0336] Example 19 (S)-(3-amino-3-methylpiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0337] [ka]

[0338] Prepared in a similar manner to Example 10. LC / MS (ESI+) [(M+H) + ]:516.8.

[0339] Example 20 ((3S,4R)-3-amino-4-fluoropiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0340] [ka]

[0341] Prepared in a similar manner to Example 10. LC / MS (ESI+) [(M+H) + ]:520.8

[0342] Example 21: Synthesis report of (R)-(3-aminopiperidin-1-yl)(7-methoxy-2-(1-(3-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0343] [ka]

[0344] Prepared in a similar manner to Example 10. LC / MS (ESI + ) [(M+H) + ]:514.9.

[0345] Example 22 ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(2-(2-hydroxyethoxy)ethyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0346] [ka]

[0347] Prepared in a similar manner to Example 10. LC / MS (ESI+) [(M+H) + ]:550.8

[0348] Example 23 ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)methanone

[0349] [ka]

[0350] Prepared in a similar manner to Example 10. LC / MS (ESI+) [(M+H) + ]:588.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.38 (s, 1H), 7.02 (s, 1H), 7.00 - 6.91 (m, 3H), 6.44 (dd, J = 6.4, 1.9 Hz, 1H), 5.54 (q, J = 8.6 Hz, 2H), 5.07 - 4.77 (m, 2H), 4.44 (t, J = 4.9 Hz, 4H), 4.02 (s, 3H), 3.55 (t, J = 5.8 Hz, 4H), 3.49 - 3.41 (m, 4H), 3.03 (t, J = 10.9 Hz, 1H), 2.18 (s, 1H), 1.85 - 1.76 (m, 2H), 1.64 - 1.48 (m, 1H).

[0351] Example 24 Preparation of (R)-(3-aminopiperidin-1-yl)(2-(1-benzyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0352] [ka]

[0353] Prepared in a similar manner to Example 10. LC / MS (ESI + ) [(M+H) + ]:535.

[0354] Example 25 Preparation of ((R)-(3-aminopiperidin-1-yl)(7-methoxy-1-methyl-2-(1-methyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0355] [ka]

[0356] Prepared in a similar manner to Example 10. LC / MS (ESI + ) [(M+H) + ]:459.

[0357] Example 26 ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(7-methoxy-1-methyl-2-(1-((1-methyl-1H-pyrazol-4-yl)methyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0358] [ka]

[0359] Prepared in a similar manner to Example 10. LC / MS (ESI+) [(M+H) + ]:556.8. 1 H NMR (400 MHz, DMSO-d 6) δ 7.69 (s, 1H), 7.44 (s, 1H), 7.29 (d, J = 1.2 Hz, 1H), 7.02 - 6.95 (m, 3H), 6.84 (s, 1H), 6.60 (d, J = 7.2 Hz, 1H), 4.65 - 4.61 (m, 2H), 4.44 (s, 2H), 4.21 (s, 3H), 3.99 (s, 3H), 3.79 (s, 3H), 3.50 (t, J = 5.2 Hz, 2H), 3.01 (s, 3H), 2.16 (s, 2H), 1.48 (s, 2H).

[0360] Example 27: Report of the synthesis of (R)-3-(5-(5-(3-aminopiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)propyl cyclopropylcarbamate

[0361] [ka]

[0362] [ka]

[0363] Step 1: Methyl 2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (50 mg, 115.08 μmol) was dissolved in acetonitrile (10 mL), and then N,N'-disuccinimidyl carbonate (44.2 mg, 172.62 μmol) and N,N'-dimethylammopyridine (14.1 mg, 115.08 μmol) were added thereto, and the mixture was stirred at room temperature for 16 hours. Then, cyclopropanamine (13.2 mg, 230.16 μmol, 15.95 μL) was added thereto, and the mixture was stirred at room temperature for 1 hour. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution ethyl acetate:PE0:100 to 80:20 gradient) to methyl 2-[9-[3-(cyclopropylcarbamoyloxy)propyl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate.

[0364] Step 2: Methyl 2-[9-[3-(cyclopropylcarbamoyloxy)propyl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (20 mg, 38.64 μmol) was dissolved in THF (1 mL). LiOH (aq, 1N) (38.64 μmol, 2 mL) was added to the solution. The reaction mixture was stirred at room temperature overnight. The pH of the reaction mixture was adjusted to acidic with 2 mol / L HCl. After removing the solvent in vacuum, the crude product 2-[9-[3-(cyclopropylcarbamoyloxy)propyl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (15 mg, 29.79 μmol, 77.09% yield) was obtained as a yellow solid. The crude product was used in the next reaction without further purification. LC / MS (ESI + ) [(M+H) + ]:503.8.

[0365] Step 3: A mixture of 2-[9-[3-(cyclopropylcarbamoyloxy)propyl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (15 mg, 29.79 μmol), tert-butyl N-[(3R)-3-piperidyl]carbamate (6.0 mg, 29.79 μmol), HATU (11.3 mg, 29.79 μmol), and DIPEA (11.6 mg, 89.37 μmol, 15.57 μL) was dissolved in DMF (3 mL). The resulting mixture was stirred at 50° C. for 10 min, diluted with EtOAc (50 mL), and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give 3-[2-[5-[(3R)-3-(tert-butoxycarbonylamino)piperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatrichloro[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]propyl N-cyclopropylcarbamate (15 mg, 21.87 μmol, 73.42% yield) as a yellow oil. LC / MS (ESI + ) [(M+H) + ]:685.8.

[0366] Step 4: 3-[2-[5-[(3R)-3-(tert-butoxycarbonylamino)piperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]propyl N-cyclopropylcarbamate (15 mg, 21.87 μmol) was dissolved in HCl / EA (2 mL). The reaction mixture was stirred at room temperature for 30 min. After removing the solvent in vacuo, the residue was purified by pre-HPLC to give 3-[2-[5-[(3R)-3-aminopiperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]propyl N-cyclopropylcarbamate (10 mg, 17.07 μmol, 78.06% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:585.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.26 (s, 1H), 7.33 (s, 2H), 7.01 - 6.93 (m, 3H), 6.87 (d, J = 1.2 Hz, 1H), 6.42 (d, J = 7.1 Hz, 1H), 4.63 (t, J = 5.1 Hz, 2H), 4.23 (s, 3H), 4.07 (d, J = 6.8 Hz, 2H), 4.00 (s, 3H), 3.56 (d, J = 5.3 Hz, 4H), 3.01 (s, 2H), 2.88 (d, J = 9.5 Hz, 3H), 1.94 (s, 3H), 1.72 (s, 1H), 1.54 - 1.35 (m, 3H), 0.59 (d, J = 6.4 Hz, 2H), 0.45 - 0.40 (m, 2H).

[0367] Example 28: Synthesis report of 1-(5-(5-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)-2-hydroxyethan-1-one

[0368] [ka]

[0369] [ka]

[0370] Step 1: Methyl 2-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazole-5-carboxylate (50 mg, 132.83 μmol) and DIPEA (51.5 mg, 398.50 μmol, 69.41 μL) were dissolved in dichloromethane (5 mL). The mixture was stirred at 0° C. and (2-chloro-2-oxoethyl)acetate (18.1 mg, 132.83 μmol) was added dropwise to the mixture at 0° C. The reaction mixture was stirred at room temperature for 5 min until the desired signal was found by LC / MS. After the solvent was removed in vacuo, the residue was purified by flash column chromatography on silica gel (eluted with 0-80% EA / PE) to give methyl 2-[9-(2-acetoxyacetyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (50 mg, 104.94 μmol, 79.00% yield) as a yellow oil. LC / MS (ESI + ) [(M+H) + ]:476.7.

[0371] Step 2: Methyl 2-[9-(2-acetoxyacetyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (50 mg, 104.94 μmol) was dissolved in THF (1 mL). LiOH (aq, 1N) (105.14 μmol, 2 mL) was added to the solution. The reaction mixture was stirred overnight at room temperature. After removal of the solvent, the residue was dissolved in THF (5 mL). The mixture was stirred at 0° C. and 2-chloro-2-oxoethyl acetate (14.33 mg, 104.94 μmol) was added dropwise to the mixture at 0° C. After the solvent was removed in vacuo, the residue was purified by flash column chromatography on silica gel (eluted with 0-80% EA / PE) and pre-HPLC to give 2-[9-(2-acetoxyacetyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (30 mg, 64.87 μmol, 61.82% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:462.7.

[0372] Step 3: A mixture of 2-[9-(2-acetoxyacetyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (30 mg, 64.87 μmol), tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate (14.2 mg, 64.87 μmol), HATU (24.7 mg, 64.87 μmol) and DIPEA (25.2 mg, 194.61 μmol, 33.90 μL) was dissolved in DMF (3 mL). The reaction mixture was stirred at 50° C. for 10 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give [2-[2-[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-piperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]-2-oxo-ethyl]acetate (20 mg, 30.18 μmol, 46.52% yield) as a yellow oil. LC / MS (ESI) + ) [(M+H) + ]:662.7.

[0373] Step 4: [2-[2-[5-[(3R,5R)-3-(tert-butoxycarbonylamino)-5-fluoro-piperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]-2-oxo-ethyl]acetate (15 mg, 22.63 μmol) was dissolved in THF (1 mL). LiOH (aq, 1N) (38.64 μmol, 2 mL) was added to the solution. The reaction mixture was stirred at room temperature for 10 min. The solvent was then removed in vacuum and HCl / EA (2 mL) was added to the mixture. The mixture was stirred at room temperature for 10 min and concentrated in vacuum. The residue was purified by pre-HPLC to give 1-[2-[5-[(3R,5R)-3-amino-5-fluoro-piperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]-2-hydroxy-ethanone (5 mg, 9.61 μmol, 42.44% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:520.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 ​​(s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.16 (s, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.86 (s, 1H), 5.01 (s, 1H), 4.66 (s, 2H), 4.44 (d, J = 3.8 Hz, 2H), 4.25 (s, 3H), 4.13 (s, 2H), 4.00 (s, 3H), 3.02 (s, 2H), 2.68 (s, 1H), 2.17 (s, 2H), 1.61 - 1.49 (m, 2H).

[0374] The following compounds were prepared similarly: Example 29: Synthesis report of 2-(5-(5-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)-2-oxoethyl acetate

[0375] [ka]

[0376] Prepared in a similar manner to Example 28. LC / MS (ESI+) [(M+H) + ]:562.7.

[0377] Example 30: Synthesis report of 3-(5-(5-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)-3-oxopropanenitrile

[0378] [ka]

[0379] Prepared in a similar manner to Example 28. LC / MS (ESI + ) [(M+H) + ]:529.8.

[0380] Example 31 Synthesis of (R)-(3-aminopiperidin-1-yl)(2-(1-benzoyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0381] [ka]

[0382] Prepared in a similar manner to Example 28. LC / MS (ESI + ) [(M+H) + ]:549.

[0383] Example 32 Preparation of (R)-(2-(1-(3-aminocyclobutyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)(3-aminopiperidin-1-yl)methanone

[0384] [ka]

[0385] [ka]

[0386] Step 1: To a solution of ethyl 7-nitro-1H-indole-2-carboxylate (2 g, 8.54 mmol) in ethanol (50 mL) and ethyl acetate 99% (50 mL) was added palladium (200 mg, 1.88 mmol) at room temperature. The reaction mixture was stirred for 1 h. 2 The mixture was purged with ethyl acetate, stirred at room temperature for 16 h, and filtered. The filtrate was concentrated in vacuo and the residue was triturated in EA / PE (1 / 10, 110 mL). The light brown solid was collected by filtration and dried in vacuo to give ethyl 7-amino-1H-indole-2-carboxylate (1.7 g, 8.32 mmol, 97.48% yield). LC / MS (ESI + ) [(M+H) + ]:205.

[0387] Step 2: To a solution of ethyl 7-amino-1H-indole-2-carboxylate (1 g, 4.90 mmol) and tert-butyl N-(3-oxocyclobutyl)carbamate (1.09 g, 5.88 mmol) in DCM (100 mL) was added sodium triacetoxyborane (5.19 g, 24.48 mmol) portionwise at room temperature. The resulting reaction mixture was stirred at room temperature for 48 h and quenched with ice (100 mL). The two phases were separated and the aqueous phase was extracted with DCM (60 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (PE / EA: 3 / 1, Rf=0.5) to give ethyl 7-[[3-(tert-butoxycarbonylamino)cyclobutyl]amino]-1H-indole-2-carboxylate (1.65 g, 4.42 mmol, 90.23% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:374.

[0388] Step 3: To a solution of ethyl 7-[[3-(tert-butoxycarbonylamino)cyclobutyl]amino]-1H-indole-2-carboxylate (1.5 g, 4.02 mmol) in anhydrous DMF (40 mL) was added cesium carbonate (3.93 g, 12.05 mmol) and 1,2-dibromoethane (830.03 mg, 4.42 mmol, 380.75 μL) at room temperature. The reaction mixture was stirred at 126° C. for 48 h (conversion was only 25%), cooled to room temperature and filtered. The filtrate was diluted with EA (300 mL), washed with water (50 mL×5) and brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (PE / EA: 3 / 1, Rf=0.55) to give ethyl 9-[3-(tert-butoxycarbonylamino)cyclobutyl]-1,9-diazatricyclo[6.3.1.0 4,12 ] dodeca-2,4,6,8(12)-tetraene-2-carboxylate (100 mg, 250.32 μmol, 6.23% yield).+ ) [(M+H) + ]:400.

[0389] Step 4: Ethyl 9-[3-(tert-butoxycarbonylamino)cyclobutyl]-1,9-diazatricyclo[6.3.1.0 4,12 To a solution of ]dodeca-2,4,6,8(12)-tetraene-2-carboxylate (40 mg, 100.13 μmol), aluminum;lithium (2.5 M, 160.21 μL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h, cooled to 0° C., quenched with EA (10 mL) and stirred for 30 min. The mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl N-[3-[2-(hydroxymethyl)-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-9-yl]cyclobutyl]carbamate (35 mg, 97.92 μmol, 97.79% yield) was obtained as a pale yellow solid. LC / MS (ESI + ) [(M+H) + ]:358.

[0390] Step 5: tert-Butyl N-[3-[2-(hydroxymethyl)-1,9-diazatricyclo[6.3.1.0] in chloroform, 99.8%, ACS reagent (10 mL) 4,12 To a solution of tert-butyl N-[3-(2-formyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4,6,8(12)-tetraen-9-yl]cyclobutyl]carbamate (35 mg, 97.92 μmol) was added manganyl oxygen(2-) (85.1 mg, 979.17 μmol). The reaction mixture was stirred at 60° C. for 16 h, cooled to room temperature and filtered through a pad of Celite. The solid cake was washed with DCM (20 mL) and the filtrate was concentrated in vacuo to give tert-butyl N-[3-(2-formyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4,6,8(12)-tetraen-9-yl]cyclobutyl]carbamate (35 mg, 97.92 μmol). 4,12 ]dodeca-2,4,6,8(12)-tetraen-9-yl)cyclobutyl]carbamate (33 mg, 92.85 μmol) was obtained as a yellow oil. LC / MS (ESI + ) [(M+H)+ ]:356.

[0391] Step 6: tert-Butyl N-[3-(2-formyl-1,9-diazatricyclo[6.3.1.0] 4,12 ]dodeca-2,4,6,8(12)-tetraen-9-yl)cyclobutyl]carbamate (15 mg, 42.20 μmol) and tert-butyl N-[(3R)-1-[3-methoxy-4-(methylamino)-5-nitro-benzoyl]-3-piperidyl]carbamate (20 mg, 48.97 μmol) were added to a solution of Na 2 S 2 O 4 (29.4 mg, 168.81 μmol) and water (3 mL) were added. The reaction mixture was stirred at 96° C. for 16 h and concentrated in vacuo. The residue was extracted with DCM (10 mL×3) and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative TLC (DCM / MeOH: 15 / 1, Rf=0.4) to give tert-butyl N-[(3R)-1-[2-[9-[3-(tert-butoxycarbonylamino)cyclobutyl]-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-3-piperidyl]carbamate (10 mg, 14.01 μmol, 33.19% yield) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:714.

[0392] Step 7: tert-Butyl N-[(3R)-1-[2-[9-[3-(tert-butoxycarbonylamino)cyclobutyl]-1,9-diazatricyclo[6.3.1.0 in a 4.0 M solution of hydrogen chloride in dioxane (2 mL) 4,12A mixture of [dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-3-piperidyl]carbamate (10 mg, 14.01 μmol) was stirred at room temperature for 2 h, concentrated in vacuo, and the residue was purified by preparative HPLC to give [2-[9-(3-aminocyclobutyl)-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazol-5-yl]-[(3R)-3-amino-1-piperidyl]methanone (1 mg, 1.95 μmol) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:514.

[0393] Example 33 Preparation of (R)-N-(3-(5-(5-(3-aminopiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)cyclobutyl)acetamide

[0394] [ka]

[0395] [ka]

[0396] Step 1: tert-Butyl N-[3-(2-formyl-1,9-diazatricyclo[6.3.1.0 4,12 To a solution of methyl 3-methoxy-4-(methylamino)-5-nitro-benzoate (15 mg, 62.44 μmol) and 1,2-dihydro-1,3-dimethyl-2,4-dimethyl-2,5-dimethyl-2,6-dimethyl-2,7-dimethyl-2,8-dimethyl-2,9-dimethyl-2,10-dimethyl-2,10-dimethyl-2,2 ...2-dimethyl-2,10-dimethyl-2,2-dimethyl-2,10-dimethyl-2,2-dimethyl-2,10-dimethyl-2,2-dimethyl-2,10-dimethyl-2,2-dimethyl-2,10-dimethyl-2,2-dimethyl-2,10-dimethyl-2 2 S 2 O 4(29.4 mg, 168.81 μmol) and water (3 mL) were added. The reaction mixture was stirred at 96° C. for 16 h and concentrated in vacuo. The residue was extracted with DCM (10 mL×3) and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative TLC (PE / EA: 3 / 1, Rf=0.4) to give 2-[9-[3-(tert-butoxycarbonylamino)cyclobutyl]-1,9-diazatricyclo[6.3.1.0]. 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (10 mg, 18.33 μmol, 43.43% yield) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:546.

[0397] Step 2: Methyl 2-[9-[3-(tert-butoxycarbonylamino)cyclobutyl]-1,9-diazatricyclo[6.3.1.0] in dioxane (2 mL) 4,12 To a solution of 2-[9-(3-aminocyclobutyl)-1,9-diazatricyclo[6.3.1.0]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (10 mg, 18.33 μmol), 4.0 M hydrogen chloride solution was added, stirred at room temperature for 2 hours, and concentrated in vacuo to give crude methyl 2-[9-(3-aminocyclobutyl)-1,9-diazatricyclo[6.3.1.0]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (10 mg, 18.33 μmol). 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (8 mg, 17.96 μmol) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]: 446. The crude product was used in the next step without further purification.

[0398] Step 3: Methyl 2-[9-(3-aminocyclobutyl)-1,9-diazatricyclo[6.3.1.0] in DCM (2 mL) 4,12To a solution of ]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (8 mg, 17.96 μmol), N-ethyl-N-isopropyl-propan-2-amine (74.2 mg, 574.13 μmol, 0.1 mL) and acetyl chloride (10 mg, 127.39 μmol, 7.75 μL) were added at room temperature. The reaction mixture was stirred at room temperature for 1 h and diluted with DCM (20 mL) and water (10 mL). The two phases were separated and the aqueous phase was extracted with DCM (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to give methyl 2-[9-(3-acetamidocyclobutyl)-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (8 mg, 16.41 μmol) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]: 488. This was used in the next step without further purification.

[0399] Step 4: Methyl 2-[9-(3-acetamidocyclobutyl)-1,9-diazatricyclo[6.3.1.0] 4,12 A mixture of ]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (8 mg, 16.41 μmol) and lithium hydroxide hydrate (3.4 mg, 82.04 μmol, 2.28 μL) was stirred at 60° C. for 16 h and concentrated in vacuo. The residue was acidified to about pH 3 with 2N aqueous HCl and extracted with DCM (10 mL×3). The product remained in the aqueous phase, which was lyophilized to provide the crude product, which was used in the next step without purification.

[0400] Step 5: 2-[9-(3-acetamidocyclobutyl)-1,9-diazatricyclo[6.3.1.0] in DMF (2 mL) 4,12To a solution of ]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (5 mg, 10.56 μmol), tert-butyl N-[(3R)-3-piperidyl]carbamate (2.1 mg, 10.56 μmol) and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (4.0 mg, 10.56 μmol), N-ethyl-N-isopropyl-propan-2-amine (6.8 mg, 52.80 μmol, 9.20 μL) was added at room temperature. The reaction mixture was stirred at room temperature for 10 min and purified by preparative HPLC to give tert-butyl N-[(3R)-1-[2-[9-(3-acetamidocyclobutyl)-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-3-piperidyl]carbamate (3 mg, 4.57 μmol) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:656.

[0401] Step 6: tert-Butyl N-[(3R)-1-[2-[9-(3-acetamidocyclobutyl)-1,9-diazatricyclo[6.3.1.0] in a 4.0 M solution of hydrogen chloride in dioxane (2 mL) 4,12 A mixture of N-[3-[2-[5-[(3R)-3-aminopiperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.0]-dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-3-piperidyl]carbamate (3 mg, 4.57 μmol) was stirred at room temperature for 2 h, concentrated in vacuo, and purified with 100% N-[3-[2-[5-[(3R)-3-aminopiperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.0]-methyl- 4,12 ]dodeca-2,4(12),5,7-tetraen-9-yl]cyclobutyl]acetamide (1 mg, 1.80 μmol, 39.34% yield) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H)+ ]:556.

[0402] Example 34: Report of the synthesis of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-((1-ethyl-1H-pyrazol-4-yl)methyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0403] [ka]

[0404] [ka]

[0405] Step 1: A mixture of methyl 4-chloro-3-methoxy-5-nitro-benzoate (245 mg, 997.49 μmol), (1-ethylpyrazol-4-yl)methenamine (137.3 mg, 1.10 mmol) and potassium carbonate (413.6 mg, 2.99 mmol, 180.61 μL) was dissolved in acetonitrile (10 mL). The mixture was stirred at 80 °C for 4 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel (eluted with 0-50% EA / PE) to give 4-[(1-ethylpyrazol-4-yl)methylamino]-3-methoxy-5-nitro-benzoate (300 mg, 897.33 μmol, 89.96% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:334.8.

[0406] Step 2: A mixture of methyl 4-[(1-ethylpyrazol-4-yl)methylamino]-3-methoxy-5-nitro-benzoate (300 mg, 897.33 μmol), tert-butyl 2-formyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (256.9 mg, 897.33 μmol) and sodium hydrosulfite (468.7 mg, 2.69 mmol) was dissolved in ethanol / water (30 mL). The reaction mixture was stirred at 100° C. overnight. After the solvent was removed in vacuo, the residue was purified by flash column chromatography on silica gel (eluted with 0-100% EA / PE) to give tert-butyl 2-[1-[(1-ethylpyrazol-4-yl)methyl]-7-methoxy-5-methoxycarbonyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (300 mg, 525.73 μmol, 78.12% yield) as a liquid oil. LC / MS (ESI) + ) [(M+H) + ]:570.8.

[0407] Step 3: tert-Butyl 2-[1-[(1-ethylpyrazol-4-yl)methyl]-7-methoxy-5-methoxycarbonyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (300 mg, 525.73 μmol) was dissolved in HCl / EA (10 mL). The reaction mixture was stirred at room temperature for 2 h. Some solid appeared. The mixture was filtered and the filtrate was dried in vacuo to give methyl 2-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-1-[(1-ethylpyrazol-4-yl)methyl]-7-methoxy-benzimidazole-5-carboxylate (200 mg, 425.06 μmol, 80.85% yield) as a grey solid. LC / MS (ESI + ) [(M+H) + ]:470.8.

[0408] Step 4: A mixture of 2-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-1-[(1-ethylpyrazol-4-yl)methyl]-7-methoxy-benzimidazole-5-carboxylate (100 mg, 212.53 μmol), 3-bromopropan-1-ol (59.1 mg, 425 μmol, 37.15 μL) and DIPEA (27.5 mg, 37.02 uL) was dissolved in acetonitrile (5 mL). The reaction mixture was stirred at 130° C. for 4 h in a microwave reactor. After the solvent was removed in vacuo, the residue was purified by flash column chromatography on silica gel (eluted with EA / PE 0-100) to give methyl 1-[(1-ethylpyrazol-4-yl)methyl]-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetran-2-yl]-7-methoxy-benzimidazole-5-carboxylate (30 mg, 56.75 μmol) as a liquid oil. LC / MS (ESI) + ) [(M+H) + ]:528.8.

[0409] Step 5: To a solution of methyl 1-[(1-ethylpyrazol-4-yl)methyl]-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylate (30 mg, 56.75 μmol) in THF (1 mL) was added LiOH (aq, 1N) (19.36 μmol, 2 mL). The resulting mixture was stirred at room temperature overnight. The pH of the reaction mixture was adjusted to acidic with 2 mol / L HCl. After removing the solvent in vacuum, the crude product 1-[(1-ethylpyrazol-4-yl)methyl]-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylic acid (25 mg, 48.58 μmol, 85.6% yield) was obtained as a yellow solid. The crude product was used in the next reaction without further purification. LC / MS (ESI + ) [(M+H) + ]:514.8.

[0410] Step 6 A mixture of 1-[(1-ethylpyrazol-4-yl)methyl]-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylic acid (25 mg, 48.58 μmol), tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate (10.6 mg, 48.58 μmol), HATU (18.5 mg, 48.58 μmol) and DIPEA (18.9 mg, 146 μmol, 25.43 μL) was dissolved in DMF (5 mL). The mixture was stirred at 50° C. for 10 min. The desired signal was found by LC / MS. The reaction was diluted with EtOAc (50 ml) and washed with water (25 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (eluted with 0-100% EA / PE) to give tert-butyl N-[(3R,5R)-1-[1-[(1-ethylpyrazol-4-yl)methyl]-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carbonyl]-5-fluoro-3-piperidyl]carbamate (20 mg, 27.98 μmol, 57.59% yield) as a yellow oil. LC / MS (ESI) + ) [(M+H) + ]:714.7.

[0411] Step 7: tert-Butyl N-[(3R,5R)-1-[1-[(1-ethylpyrazol-4-yl)methyl]-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carbonyl]-5-fluoro-3-piperidyl]carbamate (20 mg, 27.98 μmol) was dissolved in HCl / EA (2 mL). The mixture was stirred at room temperature for 30 min. After removal of the solvent in vacuo and purification by pre-HPLC, [(3R,5R)-3-amino-5-fluoro-1-piperidyl]-[1-[(1-ethylpyrazol-4-yl)methyl]-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazol-5-yl]methanone (10 mg, 16.27 μmol, 58.14% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:614.8.

[0412] The following compounds were prepared similarly: Example 35 Synthesis of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(3-hydroxy-3-methylbutyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-benzo[d]imidazol-5-yl)methanone

[0413] [ka]

[0414] Prepared in a similar manner to Example 34. LC / MS (ESI + ) [(M+H) + ]:628.8. 1H NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 7.46 (s, 1H), 7.36 (s, 1H), 7.14 (s, 1H), 7.02 - 6.98 (m, 2H), 6.97 (s, 1H), 6.91 (s, 1H), 6.46 (d, J = 5.4 Hz, 1H), 5.74 (s, 2H), 4.54 (s, 2H), 4.41 (s, 1H), 4.02 (s, 3H), 3.78 (s, 3H), 3.56 (d, J = 6.0 Hz, 5H), 2.73 (s, 1H), 2.39 (s, 1H), 2.06 (d, J = 7.6 Hz, 2H), 1.81 (d, J = 8.2 Hz, 2H), 1.30 (s, 3H), 1.25 (s, 3H).

[0415] Example 36: Report of the synthesis of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-(4-fluorobenzyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0416] [ka]

[0417] Prepared in a similar manner to Example 34. LC / MS (ESI + ) [(M+H) + ]:614.8.

[0418] Example 37: Report of the synthesis of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-(thiophen-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)methanone

[0419] [ka]

[0420] Prepared in a similar manner to Example 34. LC / MS (ESI + ) [(M+H) + ]:602.7.

[0421] Example 38: Report of the synthesis of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-fluoro-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0422] [ka]

[0423] Prepared in a similar manner to Example 34. LC / MS (ESI + ) [(M+H) + ]:602.8.

[0424] Example 39: Report of the synthesis of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-fluoro-2-(1-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0425] [ka]

[0426] Prepared in a similar manner to Example 34. LC / MS (ESI + ) [(M+H) + ]:588.8.

[0427] Example 40: Synthesis report of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-fluoro-1H-benzo[d]imidazol-5-yl)methanone

[0428] [ka]

[0429] Prepared in a similar manner to Example 34. LC / MS (ESI + ) [(M+H) + ]:544.8.

[0430] Example 41: Synthesis report of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-fluoro-2-(1-(3-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0431] [ka]

[0432] Prepared in a similar manner to Example 34. LC / MS (ESI + ) [(M+H) + ]:616.8.

[0433] Example 42: Synthesis report of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-fluoro-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0434] [ka]

[0435] Prepared in a similar manner to Example 34. LC / MS (ESI + ) [(M+H) + ]:596.7.

[0436] Example 43 ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-benzo[d]imidazol-5-yl)methanone

[0437] [ka]

[0438] Prepared in a similar manner to Example 34. LC / MS (ESI+) [(M+H) + ]:600.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.42 (s, 1H), 7.32 (s, 1H), 7.10 (s, 1H), 6.99 - 6.90 (m, 3H), 6.87 (s, 1H), 6.43 (dd, J = 6.2, 2.1 Hz, 1H), 5.70 (s, 2H), 4.50 (t, J = 4.9 Hz, 2H), 3.98 (s, 3H), 3.73 (s, 3H), 3.60 -3.50 (m, 5H), 3.48 - 3.39 (m, 7H), 3.01 (d, J = 10.9 Hz, 1H), 2.18 (s, 1H), 1.81 (p, J = 6.3 Hz, 2H), 1.63 -1.49 (m, 1H).

[0439] Example 44 (R)-(3-aminopiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-benzo[d]imidazol-5-yl)methanone

[0440] [ka]

[0441] Prepared in a similar manner to Example 34. LC / MS (ESI+) [(M+H) + ]:582.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.30 (d, J = 10.1 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.51 - 7.47 (m, 2H), 7.38 (d, J = 1.7 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 1.7 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.96 (d, J= 1.9 Hz, 1H), 6.43 (dd, J = 6.7, 1.6 Hz, 1H), 4.64 (t, J = 5.2 Hz, 2H), 4.22 (d, J = 10.3 Hz, 3H), 4.02 (d, J = 10.6 Hz, 3H), 3.58 - 3.50 (m, 8H), 2.88 (d, J = 5.2 Hz, 1H), 2.42 (s, 1H), 2.30 (s, 2H), 1.80 (dd, J =17.1, 10.0 Hz, 4H), 1.41 (d, J = 5.8 Hz, 2H).

[0442] Example 45 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-benzo[d]imidazol-5-yl)methanone

[0443] [ka]

[0444] Prepared in a similar manner to Example 34. LC / MS (ESI+) [(M+H) + ]:594.8.

[0445] Example 46 ((3S,5S)-3-amino-5-fluoropiperidin-1-yl)(7-fluoro-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-benzo[d]imidazol-5-yl)methanone

[0446] [ka]

[0447] Prepared in a similar manner to Example 34. LC / MS (ESI+) [(M+H) + ]:588.8. 1 H NMR (400 MHz, DMSO-d 6) δ 7.59 - 7.55 (m, 2H), 7.23 (s, 1H), 7.16 (d, J = 11.9 Hz, 1H), 6.97 - 6.92 (m, 3H), 6.44 (dd, J = 5.8, 2.5 Hz, 1H), 5.62 (s, 2H), 4.58 (t, J = 5.2 Hz, 2H), 3.77 (s, 3H), 3.56 (q, J =5.4 Hz, 4H), 3.45 (t, J = 7.4 Hz, 4H), 3.01 (d, J = 11.0 Hz, 3H), 2.17 (s, 2H), 1.81 (p, J = 6.3 Hz, 3H), 1.50 (s, 1H).

[0448] Example 47: Synthesis report of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-fluoro-2-(1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0449] [ka]

[0450] Prepared in a similar manner to Example 34. LC / MS (ESI + ) [(M+H) + ]:626.7. 1 H NMR (400 MHz, DMSO-d 6) δ 8.26 (s, 1H), 7.59 (d, J = 2.3 Hz, 2H), 7.24 (s, 1H), 7.17 (d, J = 11.5 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 3.9 Hz, 2H), 6.63 (d, J = 7.5 Hz, 1H), 5.62 (s, 2H), 4.58 - 4.53 (m, 2H), 4.30 (d, J = 9.7 Hz, 2H), 4.05 (q, J = 7.3 Hz, 2H), 3.75 (t, J = 5.2 Hz, 2H), 2.98 (d, J = 10.8 Hz, 2H), 2.68 (s, 1H), 2.34 (s, 1H), 2.15 (s, 2H), 1.61 - 1.45 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).

[0451] Example 48 Preparation of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-(cyclobutylmethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0452] [ka]

[0453] Prepared in a similar manner as in Example 34. LC-MS: (ESI) m / z 574.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ 8.27 (s, 1H), 7.31 (s, 1H), 6.95 (dd, J = 9.4, 7.5 Hz, 2H), 6.91 (s, 1H), 6.86 (s, 1H), 6.41 (d, J = 6.2 Hz, 1H), 4.72 (d, J = 6.9 Hz, 2H), 4.46 (s, 2H), 4.00 (s, 3H), 3.62 - 3.50 (m,12H), 3.08 (t, J = 10.7 Hz, 1H), 2.65 - 2.57 (m, 1H), 2.21 (s, 1H), 1.78 (dd, J = 16.4, 10.3 Hz, 4H), 1.72 -1.60 (m, 2H), 1.51 (dd, J = 18.5, 8.9 Hz, 2H).

[0454] Example 49 Preparation of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0455] [ka]

[0456] Prepared in a similar manner as in Example 34. LC-MS: (ESI) m / z 544.8 [M+H] + .

[0457] Example 50 Preparation of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-((3,3-difluorocyclobutyl)methyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0458] [ka]

[0459] Prepared in a similar manner as in Example 34. LC-MS: (ESI) m / z 610.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (s, 1H), 7.32 (s, 1H), 6.94 (p, J = 8.2 Hz, 3H), 6.88 (s, 1H), 6.42 (d, J = 5.5 Hz, 1H), 4.85 (d, J = 5.9 Hz, 2H), 4.48 (s, 2H), 4.00 (s, 3H), 3.54 (t, J = 5.9 Hz, 4H), 3.49 - 3.39 (m, 8H), 3.03 (t, J = 10.6 Hz, 1H), 2.57 (d, J = 11.8 Hz, 1H), 2.29 - 2.11 (m, 3H), 1.87 - 1.74 (m, 2H), 1.71 - 1.39 (m, 2H).

[0460] Example 51 Preparation of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-(2,2-difluoroethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0461] [ka]

[0462] Prepared in a similar manner as in Example 34. LC-MS: (ESI) m / z 570.8 [M+H] + .

[0463] Example 52 (1-amino-5-azaspiro[2.4]heptan-5-yl)(1-(cyclopropylmethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0464] [ka]

[0465] [ka]

[0466] Step 1: A mixture of cyclopropylmethanamine (2.2 g, 30.54 mmol, 2.65 mL), methyl 4-chloro-3-methoxy-5-nitro-benzoate (5.0 g, 20.36 mmol), and potassium carbonate (5.6 g, 40.71 mmol, 2.46 mL) was dissolved in acetonitrile (30 mL). The resulting mixture was stirred at 80° C. for 15 h. The desired signal was found by LC / MS. The reaction was diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluted with 0-100% EA / PE) to give methyl 4-(cyclopropylmethylamino)-3-methoxy-5-nitro-benzoate (4.0 g, 14.27 mmol, 70.11% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:280.8.

[0467] Step 2: A mixture of methyl 4-(cyclopropylmethylamino)-3-methoxy-5-nitro-benzoate (4.0 g, 14.27 mmol), tert-butyl 3-formyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (4.5 g, 15.70 mmol) and sodium hydrosulfite (12.4 g, 71.36 mmol) was dissolved in ethanol (15 mL) and H. 2 The resulting mixture was stirred at 80° C. for 15 h. The reaction was diluted with EtOAc (50 ml) and washed with water (25 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give tert-butyl 2-[1-(cyclopropylmethyl)-7-methoxy-5-methoxycarbonyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (5.1 g, 9.87 mmol, 69.18% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:516.8.

[0468] Step 3: tert-Butyl 2-[1-(cyclopropylmethyl)-7-methoxy-5-methoxycarbonyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-carboxylate (5.1 g, 9.87 mmol) was dissolved in HCl (4 M) / dioxane = 1 / 2 (12 mL). The reaction solution was stirred at room temperature for 30 min. After removing the solvent in vacuum, the crude product methyl 1-(cyclopropylmethyl)-2-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-benzimidazole-5-carboxylate (3.8 g, 9.12 mmol, 92.42% yield) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) +]:416.8.

[0469] Step 4: A mixture of methyl 1-(cyclopropylmethyl)-2-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-benzimidazole-5-carboxylate (3.8 g, 9.12 mmol), 3-bromopropan-1-ol (1.9 g, 13.69 mmol, 1.20 mL), and DIPEA (3.5 g, 27.37 mmol, 4.77 mL) was dissolved in acetonitrile (20 mL). The mixture was then heated in a microwave reactor at 120° C. for 15 h. After the solvent was removed in vacuo, the residue was purified by flash column chromatography on silica gel (eluted with EA / PE 0-100) to give methyl 1-(cyclopropylmethyl)-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylate (3.0 g, 6.32 mmol, 69.29% yield) as a liquid oil. LC / MS (ESI + )[(M+H) + ]:474.8.

[0470] Step 5: THF (9 mL) and H 2To a solution of methyl 1-(cyclopropylmethyl)-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylate (1.5 g, 3.16 mmol) in 2H2O (3 mL) was added lithium hydroxide hydrate (265.3 mg, 6.32 mmol, 175.67 μL). The resulting mixture was stirred at 100 °C overnight. The mixture was acidified with 3 mol / L hydrochloric acid. The residue was purified by pre-HPLC to give 1-(cyclopropylmethyl)-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylic acid (900.0 mg, 1.95 mmol, 61.83% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:460.8.

[0471] Step 6: A mixture of tert-butyl N-(5-azaspiro[2.4]heptan-2-yl)carbamate (15.2 mg, 71.66 μmol), 1-(cyclopropylmethyl)-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylic acid (30.0 mg, 65.14 μmol), HATU (29.72 mg, 78.17 μmol), and DIPEA (12.6 mg, 97.71 μmol, 17.02 μL) was dissolved in DMF (2 mL). The resulting solution was stirred at 25° C. for 30 min, diluted with EtOAc (50 mL), and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give tert-butyl N-[5-[1-(cyclopropylmethyl)-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carbonyl]-5-azaspiro[2.4]heptan-2-yl]carbamate (30.0 mg, 45.82 μmol, 70.33% yield) as a yellow solid. LC / MS (ESI) + ) [(M+H) + ]:654.8.

[0472] Step 7: tert-Butyl tert-butyl N-[5-[1-(cyclopropylmethyl)-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carbonyl]-5-azaspiro[2.4]heptan-2-yl]carbamate (30.0 mg, 45.82 μmol) was dissolved in HCl (4 M) / / dioxane=1 / 2 (3 mL). The resulting mixture was stirred at room temperature for 30 minutes. After removing the solvent in vacuo, the residue was purified by pre-HPLC to give (2-amino-5-azaspiro[2.4]heptan-5-yl)-[1-(cyclopropylmethyl)-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazol-5-yl]methanone (20.0 mg, 36.06 μmol, 78.70% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:554.8.

[0473] The following compounds were prepared similarly: Example 53 (3,6-diazabicyclo[3.2.0]heptan-3-yl)(1-(cyclopropylmethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0474] [ka]

[0475] Prepared in a similar manner to Example 52. LC / MS (ESI + ) [(M+H) + ]:540.8

[0476] Example 54 (6-amino-3-azabicyclo[3.1.0]hexan-3-yl)(1-(cyclopropylmethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0477] [ka]

[0478] Prepared in a similar manner to Example 52. LC / MS (ESI + ) [(M+H) + ]:540.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.29 (d, J = 12.0 Hz, 1H), 6.87 - 6.77 (m, 4H), 6.30 (dd, J = 6.4, 1.9 Hz, 1H), 4.44 (d, J = 6.8 Hz, 2H), 4.37 (t, J = 4.9 Hz, 2H), 3.88 (s, 3H), 3.86 - 3.79 (m, 1H), 3.62 (d, J = 12.6 Hz, 2H), 3.47 - 3.40 (m, 5H), 3.35 (d, J = 8.6 Hz, 4H), 1.91 (d, J = 2.2 Hz, 1H), 1.75 - 1.62 (m, 2H), 1.49 (q, J = 5.1 Hz, 1H), 1.41 (s, 1H), 1.03 (tq, J = 8.1, 3.7 Hz, 1H), 0.24 (dt, J = 8.3, 3.0 Hz, 4H).

[0479] Example 55 (1-amino-3-azabicyclo[4.1.0]heptan-3-yl)(1-(cyclopropylmethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0480] [ka]

[0481] Prepared in a similar manner to Example 52. LC / MS (ESI + ) [(M+H) + ]:554.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.18 (s, 1H), 6.89 - 6.70 (m, 4H), 6.30 (dd, J = 6.4, 1.9 Hz, 1H), 4.44 (d, J = 6.8 Hz, 2H), 4.36 (t, J = 4.8 Hz, 2H), 3.88 (s, 3H), 3.42 (t, J = 5.8 Hz, 11H), 2.84 (s, 1H), 1.88 (s, 1H), 1.67 (dt, J = 12.6, 6.2 Hz, 2H), 1.52 (s, 1H), 1.06 - 0.89 (m, 2H), 0.55 (s, 1H), 0.24 (dt, J = 8.3, 3.0Hz, 4H).

[0482] Example 56 (1-amino-6-azaspiro[2.5]octan-6-yl)(1-(cyclopropylmethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0483] [ka]

[0484] Prepared in a similar manner to Example 52. LC / MS (ESI + ) [(M+H) + ]:568.7. 1 H NMR (400 MHz, DMSO-d 6) δ 7.20 (d, J = 1.2 Hz, 1H), 6.86 - 6.75 (m, 4H), 6.30 (dd, J = 6.4, 1.9 Hz, 1H), 4.44 (d, J = 6.8 Hz, 2H), 4.36 (t, J = 4.8 Hz, 2H), 3.89 (s, 3H), 3.44 (s, 3H), 3.41 (s, 4H), 3.32 (t, J = 7.5 Hz, 4H), 2.06 (dd, J = 7.4, 3.9 Hz, 1H), 1.68 (p, J = 6.3 Hz, 2H), 1.60 - 1.41 (m, 2H), 1.33 - 1.11 (m, 2H), 1.07 - 1.00 (m, 1H), 0.40 (dd, J = 7.3, 4.6 Hz, 1H), 0.29 - 0.21 (m, 2H), 0.08 (t, J = 4.3 Hz, 3H).

[0485] Example 57 (1-(cyclopropylmethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0486] [ka]

[0487] Prepared in a similar manner to Example 52. LC / MS (ESI + ) [(M+H) + ]:590.8. 1 H NMR (400 MHz, DMSO-d 6) δ 7.44 (s, 1H), 6.93 - 6.88 (m, 1H), 6.81 (d, J = 6.3 Hz, 3H), 6.29 (dd, J = 6.4, 1.9 Hz, 1H), 4.45 (d, J = 6.8 Hz, 2H), 4.36 (t, J = 4.8 Hz, 2H), 3.90 (s, 3H), 3.59 (s, 2H), 3.41 (t, J = 6.0 Hz, 5H), 3.31 (t, J = 7.4 Hz, 6H), 1.68 (p, J = 6.3 Hz, 2H), 1.06 - 1.00 (m, 1H), 0.24 (dt, J = 8.2, 3.0Hz, 4H).

[0488] Example 58 ((3R,4S)-3-amino-4-fluoropiperidin-1-yl)(1-(cyclopropylmethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0489] [ka]

[0490] Prepared in a similar manner to Example 52. LC / MS (ESI + ) [(M+H) + ]:560.7

[0491] Example 59 ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-(cyclopropylmethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0492] [ka]

[0493] Prepared in a similar manner to Example 52. LC / MS (ESI + ) [(M+H) + ]:560.7.

[0494] Example 60 Preparation of (R)-(7-amino-5-azaspiro[2.4]heptan-5-yl)(1-(cyclopropylmethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0495] [ka]

[0496] Prepared in a similar manner to Example 52. LC / MS (ESI + ) [(M+H) + ]:554.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 7.49 (s, 1H), 7.02 (s, 1H), 6.97 - 6.89 (m, 3H), 6.44 - 6.39 (m, 1H), 4.55 (s, 2H), 4.47 (s, 2H), 4.01 (s, 3H), 3.76 - 3.64 (m, 2H), 3.54 (t, J = 5.7 Hz, 4H), 3.42 (d, J = 7.2 Hz, 4H), 3.14 (s, 1H), 3.06 (s, 1H), 1.81 (dd, J = 14.2, 6.5 Hz, 2H), 1.14 (s, 1H), 0.81 (s, 1H), 0.61 (s, 1H), 0.51 (s, 1H), 0.36 (d, J = 7.5 Hz, 2H), 0.11 (d, J = 4.7 Hz, 2H).

[0497] Example 61 Preparation of (S)-(7-amino-5-azaspiro[2.4]heptan-5-yl)(1-(cyclopropylmethyl)-2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0498] [ka]

[0499] Prepared in a similar manner as in Example 52. LC-MS: (ESI) m / z 554.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 ​​(s, 1H), 7.49 (s, 1H), 7.02 (s, 1H), 6.98 - 6.87 (m, 3H), 6.41 (dd, J = 6.4, 1.7 Hz, 1H), 4.55 (d, J = 5.9 Hz, 2H), 4.47 (s, 2H), 4.01 (s, 3H), 3.79 - 3.63 (m, 2H), 3.54 (t, J = 5.9 Hz, 4H), 3.44 (d, J = 7.8 Hz, 4H), 3.15 (s, 1H), 3.07 (s, 1H), 1.84 - 1.75 (m, 2H), 1.14 (s, 1H), 0.79 (s, 1H), 0.62 (s, 1H), 0.51 (s, 1H), 0.36 (d, J = 7.3 Hz, 2H), 0.11 (d, J = 4.9 Hz, 2H).

[0500] Example 62 Preparation of 3-(5-(5-(5-amino-4,5,6,7-tetrahydro-2H-indazol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)propan-1-ol

[0501] [ka]

[0502] [ka]

[0503] Step 1: EtOH / H 2 To a solution of 4-bromo-2-methoxy-N-methyl-6-nitro-aniline (392.1 mg, 1.50 mmol) and tert-butyl 2-formyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-9-carboxylate (0.43 g, 1.50 mmol) in O (9 mL / 3 mL) was added Na 2 S 2 O 4 (784.43 mg, 4.51 mmol) was added. The mixture was heated under reflux for 3 h. After the reaction was complete, the mixture was concentrated in vacuo and the residue was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and evaporated to give the crude product. The crude product was purified by flash column chromatography on silica gel using 1-40% EtOAc in hexanes to give the title product tert-butyl 2-(5-bromo-7-methoxy-1-methyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (0.65 g, 1.31 mmol, 87.02% yield) as a pale solid. LC / MS (ESI + ) [(M+H) + ]:496.8.

[0504] Step 2: To a stirred solution of tert-butyl 2-(5-bromo-7-methoxy-1-methyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (0.65 g, 1.31 mmol) in MeOH (1 mL) was added 4 M HCl in dioxane (10 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to give the product 2-(5-bromo-7-methoxy-1-methyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene (crude 0.6 g) as an off-white solid. LC / MS (ESI + ) [(M+H) + ]:396.7.

[0505] Step 3: To 2-(5-bromo-7-methoxy-1-methyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene (0.6 g, 1.51 mmol), 3-bromo-1-propanol (1.05 g, 7.55 mmol, 660.12 μL) in acetonitrile (10 mL) was added DIPEA (975.97 mg, 7.55 mmol, 1.32 mL). The resulting mixture was heated at 120° C. for 18 h in a sealed tube. The reaction was cooled to room temperature and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (5-60% ethyl acetate / heptane) to give 3-[2-(5-bromo-7-methoxy-1-methyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]propan-1-ol (250 mg, 549.03 μmol, 36.35% yield) as an off-white solid. LC / MS (ESI + ) [(M+H) + ]:454.8.

[0506] Step 4: 3-[2-(5-bromo-7-methoxy-1-methyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]propan-1-ol (250 mg, 549.03 μmol), diphenylmethanone hydrazone (107.75 mg, 549.03 μmol, 97.95 μL) in dioxane (3 mL). To a microwave tube containing 100 mL of 10 ... 2 The tube was degassed with a gas balloon. The tube was then sealed and heated to 120° C. for 2 h. After completion of the reaction, the mixture was cooled to room temperature and filtered through a pad of Celite, which was washed with ethyl acetate (3×10 mL). The mixture was concentrated in vacuo to give a yellowish solid. The crude product was purified by flash column chromatography on silica gel eluted with (EtOAc / petroleum ether, NA / 100% to 25%, v / v) to give 3-[2-[5-(2-benzhydrylidenehydrazino)-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatrichloro[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]propan-1-ol (160 mg, 280.37 μmol, 51.07% yield) as an off-white solid. LC / MS (ESI + ) [(M+H) + ]:570.8.

[0507] Step 5: To a stirred solution of 3-[2-[5-(2-benzidlylidenehydrazino)-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]propan-1-ol (160 mg, 280.37 μmol) in MeOH (1 mL) was added 4 M HCl in MeOH (8 mL) and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was evaporated to give the product 3-[2-(5-hydrazino-7-methoxy-1-methyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]propan-1-ol (100 mg, crude) as an off-white solid. LC / MS (ESI + ) [(M+H) + ]:406.8.

[0508] Step 6: To a stirred solution of tert-butyl N-[(3Z)-3-(hydroxymethylene)-4-oxo-cyclohexyl]carbamate (71.23 mg, 295.22 μmol) in THF (6 mL) at room temperature was added pTSA (127.09 mg, 738.04 μmol). The reaction mixture was stirred at room temperature for 22 h and upon completion of the reaction, the mixture was diluted with EtOAc (20 mL) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (1–20% MeOH / CH 2 Cl 2 ), then purified by preparative HPLC to give the desired product 3-[2-[5-(5-amino-4,5,6,7-tetrahydroindazol-2-yl)-7-methoxy-1-methyl-benzimidazol-2-yl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-9-yl]propan-1-ol (4.5 mg, 8.80 μmol, 3.58% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:511.8.

[0509] Example 63 Preparation of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1,7-dimethoxy-1H-benzo[d]imidazol-5-yl)methanone

[0510] [ka]

[0511] [ka]

[0512] Step 1: To a solution of methyl 10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylate (5.1 g, 22.15 mmol) in THF (60 mL) was added a solution of lithium hydroxide monohydrate, 98% (2.79 g, 66.46 mmol) in water (20 mL) and the resulting mixture was stirred at 70° C. under nitrogen for 3 h. The reaction crude was concentrated in vacuo, taken up in water (10 mL) and acidified with 2N aqueous hydrochloric acid until no further precipitation was observed. The resulting suspension was stirred for 30 min and filtered through a filter paper. The resulting solid was dried to give 10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylic acid (4.75 g, 21.97 mmol, 99.18% yield) as a brown solid. LC / MS (ESI + ) [(M+H) + ]:216.7.

[0513] Step 2: To a solution of 10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylic acid (4.75 g, 21.97 mmol) and ammonium chloride (3.53 g, 65.91 mmol, 2.30 mL) in DMF (100 mL) at room temperature, HATU (12.53 g, 32.96 mmol) and N,N-diisopropylethylamine (14.20 g, 109.86 mmol, 19.13 mL) were added. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was diluted with H 2 The mixture was quenched with 250 mL of HO (250 mL) and some solid formed and stirring was continued for 0.5 h. The mixture was filtered and dried to give the title product 10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxamide (2.3 g, 10.69 mmol, 48.64% yield) as a wheat solid. LC / MS (ESI + ) [(M+H) + ]:215.8. The intermediate was used directly in the next step without further purification.

[0514] Step 3: To a solution of 10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxamide (2.3 g, 10.69 mmol) in THF (50 mL) was added lithium aluminum hydride (1.09 g, 32.06 mmol) portionwise at 0 °C. The mixture was stirred at 70 °C for 6 h. The reaction mixture was cooled to 0-5 °C and quenched with water (1 mL), followed by 15% NaOH (aqueous) (1 mL), then water (3 mL), and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo to give 1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-ylmethanamine (1.65 g, 8.81 mmol, 82.45% yield) as a brown oil. LC / MS (ESI + ) [(M+H) + ]:187.8.

[0515] Step 4: To a stirred solution of methyl 4-chloro-3-methoxy-5-nitro-benzoate (1.0 g, 4.07 mmol) in acetonitrile (15 mL) was added 1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-ylmethanamine (800.5 mg, 4.27 mmol) and potassium carbonate (844.1 mg, 6.11 mmol) and the mixture was stirred in a sealed tube at 80° C. for 4 hours. The reaction crude was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-60% ethyl acetate / heptane) to give methyl 4-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-ylmethylamino)-3-methoxy-5-nitro-benzoate (0.6 g, 1.51 mmol, 37.18% yield) as a brown solid. LC / MS (ESI + ) [(M+H) + ]:396.8.

[0516] Step 5: To a solution of methyl 4-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-ylmethylamino)-3-methoxy-5-nitro-benzoate (0.6 g, 1.51 mmol) in toluene (12 mL) was added di-tert-butyl dicarbonate (991.1 mg, 4.54 mmol, 1.04 mL). The resulting mixture was stirred at 90° C. for 6 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-20% ethyl acetate / heptane) to give tert-butyl 2-[(2-methoxy-4-methoxycarbonyl-6-nitro-anilino)methyl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (0.26 g, 523.65 μmol, 34.60% yield) as a brown solid. LC / MS (ESI + ) [(M+H) + ]:496.7.

[0517] Step 6: To a stirred solution of tert-butyl 2-[(2-methoxy-4-methoxycarbonyl-6-nitro-anilino)methyl]-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (0.26 g, 523.65 μmol) in THF (6 mL) was added a 60% dispersion of sodium hydride in mineral oil (37.7 mg, 1.57 mmol) and stirred for 0.5 h. Iodomethane (148.7 mg, 1.05 mmol, 65.20 μL) was added to the mixture and stirred at room temperature for 48 h. After the reaction was complete, the mixture was diluted with H 2 The mixture was quenched with 2,000 (8 mL), diluted with EtOAc (25 mL) and warmed to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc (15 mL x 2). The combined organic phase was washed with brine (30 mL) and anhydrous Na 2 SO 4 The mixture was dried over ice, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (5-50% ethyl acetate / heptane) to give the desired products tert-butyl 2-(1-hydroxy-7-methoxy-5-methoxycarbonyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (80 mg, 167.19 μmol, 31.93% yield), tert-butyl 2-(1,7-dimethoxy-5-methoxycarbonyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (10 mg, 20.30 μmol, 3.88% yield) as white solids. LC / MS (ESI + ) [(M+H) + ]:478.8, 492.8.

[0518] Step 7: To tert-butyl 2-(1-hydroxy-7-methoxy-5-methoxycarbonyl-benzimidazol-2-yl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (80 mg, 167.19 μmol) in MeOH (0.5 mL) was added 4M HCl in dioxane (2 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to give the product methyl 2-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-yl)-1-hydroxy-7-methoxy-benzimidazole-5-carboxylate (70 mg, 185.00 μmol, 110.65% yield) as an off-white solid. LC / MS (ESI + ) [(M+H) + ]:378.8.

[0519] Step 8: To a solution of methyl 2-(1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-1-hydroxy-7-methoxy-benzimidazole-5-carboxylate (80 mg, 192.84 μmol, HC), 3-bromo-1-propanol (134.02 mg, 964.22 μmol, 84.29 μL) in acetonitrile (2 mL) was added N,N-diisopropylethylamine (124.62 mg, 964.22 μmol, 167.95 μL). The resulting mixture was heated to 130° C. for 15 h in a sealed tube. The reaction was cooled to room temperature and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (5-60% ethyl acetate / heptane) to give methyl 1-(3-hydroxypropoxy)-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylate (70 mg, 141.55 μmol, 73.40% yield), methyl 2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-1,7-dimethoxy-benzimidazole-5-carboxylate (8 mg, 17.76 μmol, 9.21% yield) and LC / MS (ESI). + ) [(M+H) + ]:450.8.

[0520] Step 9: Methyl 1-(3-hydroxypropoxy)-2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylate (70 mg, 141.55 μmol), methyl 2-[9-(3-hydroxypropyl)-1, To a solution of 9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-1,7-dimethoxy-benzimidazole-5-carboxylate (8 mg, 17.76 μmol) was added a solution of lithium hydroxide monohydrate, 98% (17.82 mg, 424.64 μmol) in water (0.5 mL) and the resulting mixture was stirred at 60° C. for 5 h. The reaction crude was concentrated in vacuo, taken up in water (5 mL), acidified with 2N aqueous hydrochloric acid, and then extracted with EtOAc (15 mL×2). The organic layer was separated, washed with brine (10 mL) solution and anhydrous NaCl. 2 SO 4 The mixture was dried over ice and evaporated under vacuum to give the product 2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-1,7-dimethoxy-benzimidazole-5-carboxylic acid (20 mg, 45.82 μmol, 32.37% yield). LC / MS (ESI + ) [(M+H) + ]:436.7.

[0521] Step 10: CH at room temperature 2 Cl 2To a solution of 2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-1,7-dimethoxy-benzimidazole-5-carboxylic acid (20 mg, 45.82 μmol) and tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate (10.50 mg, 48.11 μmol) in (3 mL) was added HATU (22.65 mg, 59.57 μmol) and N,N-diisopropylethylamine (17.77 mg, 137.47 μmol, 23.94 μL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, H 2 Quench with O (8 mL) and CH 2 Cl 2 (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate and evaporated to give the crude product. The crude product was purified by elution with CH 2 Cl 2 Purification by flash column chromatography on silica gel using 2-20% MeOH in hexane afforded the title product tert-butyl N-[(3R,5R)-5-fluoro-1-[2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-1,7-dimethoxy-benzimidazole-5-carbonyl]-3-piperidyl]carbamate (15 mg, 23.56 μmol, 51.41% yield) as a pale solid. LC / MS (ESI + ) [(M+H) + ]:636.8.

[0522] Step 11: To a stirred solution of tert-butyl N-[(3R,5R)-5-fluoro-1-[2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-1,7-dimethoxy-benzimidazole-5-carbonyl]-3-piperidyl]carbamate (15 mg, 23.56 μmol) in MeOH (0.5 mL) was added 4 M HCl in dioxane (2 mL) and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was evaporated to give the crude product, which was then purified by preparative HPLC to give [(3R,5R)-3-amino-5-fluoro-1-piperidyl]-[2-[9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-1,7-dimethoxy-benzimidazol-5-yl]methanone (6 mg, 11.18 μmol, 47.46% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:536.8.

[0523] Example 64 Preparation of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(3-hydroxypropyl)-3-methyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0524] [ka]

[0525] [ka]

[0526] Step 1: To a solution of ethyl 7-nitro-1H-indole-2-carboxylate (10.0 g, 42.70 mmol) in ethanol (200 mL) and ethyl acetate (200 mL) was added 10% palladium on carbon (599.6 mg, 4.27 mmol) at room temperature. The reaction mixture was stirred for 1 h at 37 °C for 2 h. 2 The mixture was stirred at room temperature under atmospheric pressure for 16 hours and filtered. The filtrate was concentrated in vacuo to give ethyl 7-amino-1H-indole-2-carboxylate (8.8 g, 43.09 mmol, 100.92% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:204.8.

[0527] Step 2: To a solution of ethyl 7-amino-1H-indole-2-carboxylate (5.1 g, 24.97 mmol) in DCM (50 mL) was added N,N-diisopropylethylamine (9.68 g, 74.92 mmol, 13.05 mL) and 2-bromopropanoyl chloride (12.84 g, 74.92 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h, diluted with DCM (300 mL) and washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (EA / PE: 1 / 3, Rf = 0.55) to give ethyl 7-(2-bromopropanoylamino)-1H-indole-2-carboxylate (7.4 g, 21.82 mmol, 87.36% yield) as a brown oil. LC / MS (ESI + ) [(M+H) + ]:339.8.

[0528] Step 3: To a solution of ethyl 7-(2-bromopropanoylamino)-1H-indole-2-carboxylate (7.4 g, 21.82 mmol) in DMF (140 mL) was added cesium carbonate (21.33 g, 65.45 mmol) at room temperature. The reaction mixture was stirred at 106° C. for 16 h. It was quenched with ice water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic phase was washed with brine (50 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (PE / EA=1 / 0-1 / 1) to give ethyl 11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylate (4.0 g, 15.49 mmol, 70.99% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:258.8.

[0529] Step 4: To a stirred solution of ethyl 11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylate (2.0 g, 7.74 mmol) in THF (20 mL) MeOH (10 mL) was added aqueous LiOH (1.0 M, 23 mL). The mixture was stirred at room temperature for 12 h, acidified to pH 5-6 with 3 M aqueous hydrochloric acid, and extracted with EA (100 × 3 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a white solid 11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylic acid (1.2 g, 5.21 mmol, 67.31% yield). LC / MS (ESI + ) [(M+H) + ]:229.8.

[0530] Step 5: To a solution of 11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylic acid (0.5 g, 2.17 mmol) in DMF (10 mL) was added DIPEA (842.07 mg, 6.52 mmol, 1.13 mL), HATU (1.65 g, 4.34 mmol), and methyl 3-amino-5-methoxy-4-(methylamino)benzoate (913.2 mg, 4.34 mmol). The resulting mixture was stirred at room temperature for 16 h. LC-MS showed that the starting material was consumed and the desired mass was detected. After cooling to room temperature, the mixture was diluted with EA, washed with brine, and dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent in vacuum, the residue was purified by silica gel flash column chromatography (eluted with DCM / MeOH=1:0 to 20:1) to give methyl 3-methoxy-4-(methylamino)-5-[(11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carbonyl)amino]benzoate (0.8 g, 1.89 mmol, 87.20% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:422.8.

[0531] Step 6: CH 3 A solution of methyl 3-methoxy-4-(methylamino)-5-[(11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carbonyl)amino]benzoate (0.8 g, 1.89 mmol) in COOH (8 mL) was stirred at 125° C. for 1 h. The mixture was concentrated in vacuo, diluted with EA (80 mL), washed with aqueous sodium bicarbonate and sodium 2 SO 4After filtration and evaporation of the solvent in vacuum, the residue was purified by silica gel flash column chromatography (eluted with DCM / MeOH=1:0 to 20:1) to give methyl 7-methoxy-1-methyl-2-(11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)benzimidazole-5-carboxylate (320 mg, 791.26 μmol, 41.78% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:403.8.

[0532] Step 7: To a solution of methyl 7-methoxy-1-methyl-2-(11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)benzimidazole-5-carboxylate (320 mg, 791.26 μmol) in anhydrous THF (3 mL) was added borane tetrahydrofuran (272.0 mg, 3.17 mmol, 309.80 μL) slowly at 0 °C. The reaction mixture was stirred at room temperature for 16 h, quenched with MeOH at 0 °C, and concentrated in vacuo. The residue was diluted with 2N aqueous HCl (6 mL), stirred at room temperature for 1 h, and basified to pH 8 with 4N aqueous NaOH. The resulting mixture was extracted with DCM (30 mL × 3) and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (eluted with DCM / MeOH=1:0 to 20:1) to give methyl 7-methoxy-1-methyl-2-(11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)benzimidazole-5-carboxylate (95 mg, 243.32 μmol, 30.75% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:390.8.

[0533] Step 8: Methyl 7-methoxy-1-methyl-2-(11-methyl-1,9-diazatricyclo[6.3.1.0] 4,12 To a solution of 2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4(12),5,7-tetraen-2-yl]benzimidazole-5-carboxylate (65 mg, 166.48 μmol), DIPEA (107.6 mg, 832.41 μmol, 144.99 μL) and 3-bromopropan-1-ol (115.7 mg, 832.41 μmol, 72.77 μL) were added at room temperature. The reaction mixture was stirred at 130 °C in a microwave for 14 h, cooled to room temperature, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluted with DCM / MeOH = 1:0 to 20:1) to give methyl 2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4(12),5,7-tetraen-2-yl]benzimidazole-5-carboxylate (65 mg, 166.48 μmol). 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (20 mg, 44.59 μmol, 26.78% yield) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:448.8.

[0534] Step 9: Methyl 2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.0] in THF (2 mL) MeOH (1.0 mL) 4,12 To a stirred solution of 2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (20 mg, 44.59 μmol) was added aqueous LiOH (1.0 M, 0.2 mL). The mixture was stirred at room temperature for 4 h, acidified to pH 5-6 with 3 M aqueous hydrochloric acid, and extracted with EA (10 × 3 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (20 mg, 44.59 μmol). 4,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (15 mg, 34.52 μmol, 77.42% yield) 2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (15 mg, 34.52 μmol, 77.42% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:434.8.

[0535] Step 10: To a solution of 2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (15 mg, 34.52 μmol) in DMF (2 mL), DIPEA (13.4 mg, 103.57 μmol, 18.04 μL), HATU (26.3 mg, 69.05 μmol), tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate (15.1 mg, 69.05 μmol) were added to the mixture. The resulting mixture was stirred at room temperature for 16 h. After cooling to room temperature, the reaction mixture was diluted with EA, washed with brine, and dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent in vacuum, the residue was purified by silica gel flash column chromatography (eluted with DCM / MeOH=1:0 to 15:1) to give tert-butyl N-[(3R,5R)-5-fluoro-1-[2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-3-piperidyl]carbamate (10 mg, 15.75 μmol, 45.63% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:634.8.

[0536] Step 11: To a solution of tert-butyl N-[(3R,5R)-5-fluoro-1-[2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-3-piperidyl]carbamate (10 mg, 15.75 μmol) in DCM solution (1 mL) was added 4M HCl (dioxane) (1 mL). After completion of the reaction as judged by LC / MS, the mixture was stirred at 25° C. for 3 h. The mixture was concentrated under reduced pressure. The pH of the reaction mixture was adjusted to 100 with saturated NaCl. 2 CO 3 The mixture was adjusted to 8 with solution. The mixture was extracted with DCM (30 mL x 3). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The combined organic layer was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (eluted with DCM / MeOH = 1:0 to 15:1) to give [(3R,5R)-3-amino-5-fluoro-1-piperidyl]-[2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazol-5-yl]methanone (3.1 mg, 5.80 μmol, 36.81% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:534.8. 1 H NMR (400 MHz, DMSO-d 6) δ 7.31 (s, 1H), 6.99 (s, 1H), 6.96 - 6.92 (m, 2H), 6.85 (s, 1H), 6.43 (dd, J =5.8, 2.5 Hz, 1H), 5.37 (d, J = 24.7 Hz, 1H), 4.54 (t, J = 5.0 Hz, 1H), 4.22 (d, J = 6.5 Hz, 3H), 3.99 (s, 3H),3.58 (d, J = 11.3 Hz, 3H), 3.46 (dd, J = 14.3, 6.8 Hz, 2H), 3.38 (d, J = 12.0 Hz, 3H), 3.07 (s, 3H), 2.90 (s, 1H), 2.20 (s, 2H), 2.05 - 1.97 (m, 1H), 1.93 - 1.74 (m, 3H), 1.59 (d, J = 42.8 Hz, 2H), 1.33 (d, J = 14.7 Hz,1H), 0.86 (d, J = 7.0 Hz, 1H).

[0537] Example 65 Preparation of ((R)-3-aminopiperidin-1-yl)(7-methoxy-1-methyl-2-(3-methyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0538] [ka]

[0539] [ka]

[0540] Step 1: Ethyl 11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.0] in anhydrous THF (5 mL) 4,12 ]dodeca-2,4(12),5,7-tetraene-2-carboxylate (25 mg, 96.80 μmol) was added to a solution of LiAlH 4(2.5 M, 154.88 μL) was added at 0° C. The reaction mixture was stirred at room temperature for 2 h, quenched with excess EA (20 mL), stirred at room temperature for 15 min, and filtered. The filtrate was concentrated in vacuo to give crude (11-methyl-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl)methanol (20 mg, 98.89 μmol, 51.08% yield) was obtained. LC / MS (ESI + ) [(M+H) + ]:203.

[0541] Step 2: (11-Methyl-1,9-diazatricyclo[6.3.1.0 in DCM 4,12 To a solution of 20 mg, 98.89 μmol of ]dodeca-2,4(12),5,7-tetraen-2-yl)methanol was added tert-butoxycarbonyl tert-butyl carbonate (2.16 g, 9.89 mmol, 2.27 mL) and N-ethyl-N-isopropyl-propan-2-amine (2.56 g, 19.78 mmol, 3.44 mL). The reaction mixture was stirred at room temperature for 72 h, during which additional DIPEA and Boc were added until the conversion was complete. 2 O was added. The reaction mixture was purified by flash column chromatography on silica gel to give tert-butyl 2-(hydroxymethyl)-11-methyl-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraene-9-carboxylate (10 mg, 33.07 μmol, 33.44% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:303.

[0542] Step 3: tert-Butyl 2-(hydroxymethyl)-11-methyl-1,9-diazatricyclo[6.3.1.0] in chloroform (2.5 mL) 4,12 ]dodeca-2,4(12),5,7-tetraene-9-carboxylate (10 mg, 33.07 μmol) and MnO 2(330.72 μmol) was stirred at 66° C. for 16 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give crude tert-butyl 2-formyl-11-methyl-1,9-diazatricyclo[6.3.1.0 4,12 ] dodeca-2,4(12),5,7-tetraene-9-carboxylate (6 mg, 19.98 μmol, 60.40% yield) was obtained. LC / MS (ESI + ) [(M+H) + ]:301.

[0543] Step 4: EtOH (5 mL) and H 2 tert-Butyl 2-formyl-11-methyl-1,9-diazatricyclo[6.3.1.0 4,12 A mixture of ]dodeca-2,4(12),5,7-tetraene-9-carboxylate (6 mg, 19.98 μmol), tert-butyl N-[(3R)-1-[3-methoxy-4-(methylamino)-5-nitro-benzoyl]-3-piperidyl]carbamate (10 mg, 24.48 μmol) and sodium dithionite (13.9 mg, 79.91 μmol) was stirred at 96° C. for 16 hours, cooled to room temperature and concentrated in vacuo. The residue was extracted with DCM (10 mL×3) and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative TLC (DCM / MeOH:10 / 1) to give tert-butyl 2-[5-[(3R)-3-(tert-butoxycarbonylamino)piperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-11-methyl-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraene-9-carboxylate (2 mg, 3.04 μmol, 15.20% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:659.

[0544] Step 5: tert-Butyl 2-[5-[(3R)-3-(tert-butoxycarbonylamino)piperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-11-methyl-1,9-diazatricyclo[6.3.1.0 4,12 To a mixture of 6.3.1.0 dodeca-2,4(12),5,7-tetraene-9-carboxylate (5 mg, 7.59 μmol) was added 4.0 M hydrogen chloride solution. The resulting mixture was stirred at room temperature for 2 h and concentrated in vacuo to give crude [(3R)-3-amino-1-piperidyl]-[7-methoxy-1-methyl-2-(11-methyl-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl)benzimidazol-5-yl]methanone (3 mg, 6.54 μmol, 86.20% yield) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:459.

[0545] Example 66: Report of the synthesis of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-ethyl-2-(1-(3-hydroxypropyl)-3-methyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0546] [ka]

[0547] [ka]

[0548] Step 1: To a solution of methyl 4-chloro-3-methoxy-5-nitro-benzoate (1.0 g, 4.07 mmol), ethanamine (183.55 mg, 4.07 mmol, 228.58 μL) in THF (10 mL) was added potassium carbonate (1.69 g, 12.21 mmol, 737.17 μL). The resulting mixture was dissolved in THF (10 mL) and stirred at 100° C. for 4 h. After cooling the mixture to room temperature, the reaction mixture was concentrated in vacuo and partitioned between EA (100 mL) and water (10 mL). The organic layer was further washed with water (2×10 ml) and saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange powder, which was purified by flash column chromatography on silica gel (eluted with 0-50% EA / PE) to give methyl 4-(ethylamino)-3-methoxy-5-nitro-benzoate (950 mg, 3.74 mmol, 86.95% yield) as a yellow solid. LC / MS (ESI + )[(M+H) + ]:254.8.

[0549] Step 2: A mixture of methyl 4-(ethylamino)-3-methoxy-5-nitro-benzoate (950 mg, 3.74 mmol) and 10% palladium on carbon (79.5 mg, 747.33 μmol) in THF (20 mL) was diluted with H 2 The mixture was hydrogenated at ambient temperature overnight in air. The mixture was filtered over Celite to remove Pd / C and the solvent was evaporated to give the desired product methyl 3-amino-4-(ethylamino)-5-methoxy-benzoate (800 mg, 3.57 mmol, 95.47% yield) as a colorless solid. LC / MS (ESI + ) [(M+H) + ]:224.8.

[0550] Step 3: A mixture of 11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-2-carboxylic acid (55 mg, 238.90 μmol), methyl 3-amino-4-(ethylamino)-5-methoxy-benzoate (53.6 mg, 238.90 μmol), HATU (90.9 mg, 238.90 μmol), and DIPEA (92.6 mg, 716.71 μmol, 124.83 μL) was dissolved in DMF (5 mL). The resulting mixture was stirred at 50° C. for 10 min, then diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give methyl 4-(ethylamino)-3-methoxy-5-[(11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-2-carbonyl)amino]benzoate (80 mg, 183.29 μmol, 76.72% yield) as a yellow oil. LC / MS (ESI) + ) [(M+H) + ]:436.8.

[0551] Step 4: Methyl 4-(ethylamino)-3-methoxy-5-[(11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-2-carbonyl)amino]benzoate (80 mg, 183.29 μmol) was dissolved in acetic acid (5 mL) and the reaction mixture was stirred for 2 hours at 100° C. After the reaction was cooled to room temperature, the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel (eluted with 0-50% EA / PE) to give methyl 1-ethyl-7-methoxy-2-(11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)benzimidazole-5-carboxylate (60 mg, 143.39 μmol, 78.23% yield) as a white solid. LC / MS (ESI) +) [(M+H) + ]:418.7.

[0552] Step 5: To a solution of methyl 1-ethyl-7-methoxy-2-(11-methyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)benzimidazole-5-carboxylate (60 mg, 143.39 μmol) in anhydrous THF (2 mL) was added borane-tetrahydrofuran complex (0.5 mL) slowly at 0 °C. The reaction mixture was stirred at room temperature for 1 h, quenched with MeOH at 0 °C, and concentrated in vacuo. The residue was diluted with 1N aqueous HCl (1 mL), stirred at room temperature for 1 h, and basified to pH 8 with 1N aqueous NaOH. The resulting mixture was extracted with DCM (10 mL × 3) and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (eluted with DCM / MeOH=1:0 to 20:1) to give methyl 1-ethyl-7-methoxy-2-(11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)benzimidazole-5-carboxylate (30 mg, 74.17 μmol, 51.73% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:404.8.

[0553] Step 6: A mixture of 1-ethyl-7-methoxy-2-(11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)benzimidazole-5-carboxylate (30 mg, 74.17 μmol), 3-bromopropan-1-ol (51.6 mg, 370.86 μmol, 32.42 μL) and DIPEA (95.86 mg, 741.73 μmol, 129.19 μL) was dissolved in acetonitrile (3 mL). The resulting mixture was stirred at 120 °C for 4 h in a microwave reactor. After removing the solvent in vacuum. The residue was purified by flash column chromatography on silica gel (eluted with EA / PE 0-100) to give methyl 1-ethyl-2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylate (20 mg, 43.24 μmol, 58.30% yield) as a liquid oil. LC / MS (ESI) + )[(M+H) + ]:462.8.

[0554] Step 7: To a solution of methyl 1-ethyl-2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylate (20 mg, 43.24 μmol) in THF (1 mL) was added LiOH (aq, 1N, 2 mL). The resulting mixture was stirred at room temperature overnight. The pH was adjusted to acidic with 2 mol / L HCl. After removing the solvent in vacuum, the crude product 1-ethyl-2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylic acid (15 mg, 33.44 μmol, 77.35% yield) was obtained as a yellow solid. The crude product was used in the next reaction without further purification. LC / MS (ESI + ) [(M+H)+ ]:448.8.

[0555] Step 8: A mixture of 1-ethyl-2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carboxylic acid (15 mg, 33.44 μmol), tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate (7.3 mg, 33.44 μmol), HATU (12.7 mg, 33.44 μmol), and DIPEA (13.0 mg, 100.33 μmol, 17.48 μL) was dissolved in DMF (3 mL). The mixture was stirred at 50° C. for 10 min, diluted with EtOAc (50 mL), and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give tert-butyl N-[(3R,5R)-1-[1-ethyl-2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carbonyl]-5-fluoro-3-piperidyl]carbamate (10 mg, 15.41 μmol, 46.09% yield) as a yellow oil. LC / MS (ESI) + ) [(M+H) + ]:648.7.

[0556] Step 9: tert-Butyl N-[(3R,5R)-1-[1-ethyl-2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazole-5-carbonyl]-5-fluoro-3-piperidyl]carbamate (8 mg, 12.33 μmol) was dissolved in HCl / EA (2 mL). The resulting mixture was stirred at room temperature for 30 min. After removing the solvent in vacuo, the residue was purified by pre-HPLC to give [(3R,5R)-3-amino-5-fluoro-1-piperidyl]-[1-ethyl-2-[9-(3-hydroxypropyl)-11-methyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-benzimidazol-5-yl]methanone (4 mg, 7.29 μmol, 59.12% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:548.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.32 (s, 2H), 7.43 (s, 1H), 7.00 (d, J = 6.2 Hz, 2H), 6.96 (s, 2H), 6.49 (dd, J = 6.3, 2.2 Hz, 1H), 5.35 (s, 1H), 4.69 - 4.65 (m, 2H), 4.07 (s, 3H), 3.62 (dd, J = 6.2, 2.4 Hz, 5H), 3.51 (d, J = 7.0 Hz, 7H), 2.73 (d, J = 2.0 Hz, 1H), 2.07 (d, J = 7.8 Hz, 2H), 1.87 (d, J = 7.2 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H), 1.27 (dd, J = 6.5, 2.3 Hz, 3H).

[0557] The following compounds were prepared similarly: Example 67 Synthesis report of tert-butyl ((1R,4R,7R)-2-(1-ethyl-2-(1-(3-hydroxypropyl)-3-methyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazole-5-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0558] [ka]

[0559] Prepared in a similar manner to Example 66. LC / MS (ESI + ) [(M+H) + ]:642.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.03 (s, 1H), 6.96 (s, 2H), 6.90 (d, J = 2.5 Hz, 1H), 6.43 (dd, J = 6.4, 1.9 Hz, 1H), 4.60 (d, J = 8.5 Hz, 2H), 4.53 (d, J = 5.1 Hz, 1H), 4.17 (d, J = 9.4 Hz, 1H), 4.03 (s, 3H), 3.70 (s, 1H), 3.56 (d, J = 4.7 Hz, 3H), 3.49 - 3.44 (m, 2H), 3.27 - 3.24 (m, 2H), 2.68 (s, 1H), 2.03 - 1.92 (m, 2H), 1.81 (dt, J = 13.8, 6.9 Hz, 4H), 1.51 - 1.30 (m, 14H), 1.21 (dd, J = 15.0, 6.6 Hz, 3H).

[0560] Example 68: Report of the synthesis of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(1-ethyl-2-(1-(3-hydroxypropyl)-3-methyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone

[0561] [ka]

[0562] Prepared in a similar manner to Example 66. LC / MS (ESI + ) [(M+H) + ]:542.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 7.36 (dd, J = 2.6, 1.1 Hz, 1H), 6.98 - 6.93 (m, 3H), 6.90 (d, J = 1.4 Hz, 1H), 6.44 (dd, J = 6.3, 2.0 Hz, 1H), 5.35 - 5.28 (m, 1H), 4.60 (d, J = 7.7 Hz, 2H), 4.02 (d, J = 2.0 Hz, 3H), 3.80 (d, J = 12.1 Hz, 1H), 3.56 (dt, J = 7.2, 3.5 Hz, 3H), 3.47 - 3.43 (m, 2H), 3.39 (s, 1H), 3.19 (s, 1H), 3.08 (d, J = 11.1 Hz, 1H), 2.68 (s, 1H), 2.22 (s, 1H), 1.97 (d, J = 12.9 Hz, 2H), 1.90 - 1.72 (m, 4H), 1.42 (dt, J = 8.4, 4.2 Hz, 4H), 1.21 (dd, J = 9.1, 6.3 Hz, 3H).

[0563] Example 69: Synthesis report of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0564] [ka]

[0565] [ka]

[0566] Step 1: A mixture of ethyl 7-nitro-1H-indole-2-carboxylate (7.0 g, 29.89 mmol) and 10% palladium on carbon (636.0 mg, 6.00 mmol) in methanol (200 mL) was hydrogenated in a H2 atmosphere (balloon) at ambient temperature overnight. The mixture was filtered over Celite to remove Pd / C and the solvent was evaporated to give the desired product 7-amino-1H-indole-2-carboxylate (6.0 g, 29.38 mmol, 98.30% yield) as a colorless solid. LC / MS (ESI + ) [(M+H) + ]:204.8.

[0567] Step 2: A mixture of ethyl 7-amino-1H-indole-2-carboxylate (6 g, 29.38 mmol) and DIPEA (11.39 g, 88.14 mmol, 15.35 mL) was dissolved in THF (100 mL). The mixture was stirred at 0° C. and 2-bromobutanoyl chloride (5.45 g, 29.38 mmol) was added dropwise to the mixture. The mixture was warmed to room temperature, stirred for 1 h, and diluted with water. The aqueous layer was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluted with 0-50% EA / PE) to give ethyl 7-(2-bromobutanoylamino)-1H-indole-2-carboxylate (9.0 g, 25.48 mmol, 86.73% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:354.7.

[0568] Step 3: A suspension of ethyl 7-(2-bromobutanoylamino)-1H-indole-2-carboxylate (3 g, 8.49 mmol) and cesium carbonate (8.30 g, 25.48 mmol) in DMSO (15 mL) was stirred at 100 °C for 1 h in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with (EA:PE 0-50%) to give ethyl 11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-2-carboxylate (2 g, 7.34 mmol, 86.48% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:272.8.

[0569] Step 4: To a solution of ethyl 11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-2-carboxylate (3.0 g, 11.02 mmol) in THF (5 mL) was added LiOH (aq, 1N, 10 mL). The resulting mixture was stirred at room temperature overnight. The pH of the solution was adjusted to acidic with 2 mol / L HCl. The resulting mixture was filtered and the resulting solid was dried in vacuum to obtain the product 11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-2-carboxylic acid (2.3 g, 9.42 mmol, 85.47% yield) as a yellow solid. The crude product was used in the next step reaction without further purification. LC / MS (ESI + ) [(M+H) + ]:244.8.

[0570] Step 5: A mixture of 11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-2-carboxylic acid (200 mg, 818.85 μmol), 5-bromo-3-fluoro-N2-methyl-benzene-1,2-diamine (179.4 mg, 818.85 μmol), HATU (311.4 mg, 818.85 μmol), and DIPEA (317.5 mg, 2.46 mmol, 427.88 μL) was dissolved in DMF (5 mL). The resulting mixture was stirred at 50° C. for 10 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give N-[5-bromo-3-fluoro-2-(methylamino)phenyl]-11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-2-carboxamide (150 mg, 336.86 μmol, 41.14% yield) as a yellow solid. LC / MS (ESI) + ) [(M+H) + ]:446.6.

[0571] Step 6: N-[5-bromo-3-fluoro-2-(methylamino)phenyl]-11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-2-carboxamide (150 mg, 336.86 μmol) was dissolved in acetic acid (10 mL) and stirred at 100° C. for 2 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo, after which the residue was purified by flash column chromatography on silica gel (eluting with 0-50% EA / PE) to give 2-(5-bromo-7-fluoro-1-methyl-benzimidazol-2-yl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-10-one (100 mg, 234.04 μmol, 69.48% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:428.6.

[0572] Step 7: A mixture of 2-(5-bromo-7-fluoro-1-methyl-benzimidazol-2-yl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-10-one (200 mg, 468.09 μmol), dicyanozinc (54.97 mg, 468.09 μmol, 29.68 μL), tris(dibenzylideneacetone)dipalladium(0) (428.64 mg, 468.09 μmol) and 1,1'-bis(diphenylphosphino)ferrocene (259.50 mg, 468.09 μmol) was dissolved in DMSO (5 mL). The reaction mixture was heated at 145 °C in a microwave reactor under nitrogen atmosphere for 3 h. The mixture was purified by flash column chromatography on silica gel (eluted with 0-50% PE / EA) to give 2-(11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-fluoro-1-methyl-benzimidazole-5-carbonitrile (150 mg, 401.73 μmol, 85.82% yield) as a yellow liquid oil. LC / MS [(M+H) + ]:373.8.

[0573] Step 8: To a solution of 2-(11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-fluoro-1-methyl-benzimidazole-5-carbonitrile (150 mg, 401.73 μmol) in anhydrous THF (10 mL) was added borane-tetrahydrofuran complex (10 mL) slowly at 0 °C. The reaction mixture was stirred at room temperature for 1 h, quenched with MeOH at 0 °C, and concentrated in vacuo. The residue was diluted with 1N aqueous HCl (1 mL), stirred at room temperature for 1 h, and basified to about pH 8 with 1N aqueous NaOH. The resulting mixture was extracted with DCM (10 mL × 3) and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (eluted with DCM / MeOH=1:0 to 20:1) to give 2-(11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-fluoro-1-methyl-benzimidazole-5-carbonitrile (100 mg, 278.24 μmol, 69.26% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:359.8.

[0574] Step 9: A mixture of 2-(11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-fluoro-1-methyl-benzimidazole-5-carbonitrile (100 mg, 278.24 μmol), 3-bromopropan-1-ol (116.0 mg, 834.73 μmol, 72.97 μL) and DIPEA (179.8 mg, 1.39 mmol, 242.32 μL) was dissolved in acetonitrile (5 mL). The resulting mixture was stirred at 120 °C for 4 hours using a microwave reactor. After the solvent was removed in vacuum. The residue was purified by flash column chromatography on silica gel (eluted with EA / PE 0-100) to give 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-1-methyl-benzimidazole-5-carbonitrile (80 mg, 191.63 μmol, 68.87% yield) as a liquid oil. LC / MS (ESI) + )[(M+H) + ]:417.8.

[0575] Step 10: A mixture of 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-1-methyl-benzimidazole-5-carbonitrile (80 mg, 191.63 μmol) and KOH (32.8 mg, 575.00 μmol) was dissolved in methanol / water (5 mL) and the resulting mixture was stirred overnight at 80° C. The desired signal was found by LC / MS. The mixture was acidified with 3 mol / L hydrochloric acid and extracted with DCM (10 mL × 3), the organic phase was concentrated under reduced pressure, and the residue was purified by pre-HPLC to give 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-1-methyl-benzimidazole-5-carboxylic acid (50 mg, 114.55 μmol, 59.78% yield) as a yellow solid. LC / MS (ESI + )[(M+H) + ]:436.8.

[0576] Step 11: A mixture of 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-1-methyl-benzimidazole-5-carboxylic acid (30 mg, 68.73 μmol), tert-butyl N-[(1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (PharmaBlock) (14.6 mg, 68.73 μmol), HATU (26.1 mg, 68.73 μmol) and DIPEA (26.7 mg, 206.20 μmol, 35.91 μL) was dissolved in DMF (5 mL). The resulting mixture was stirred at 50° C. for 10 min, diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluted with 0-100% EA / PE) to give tert-butyl N-[(1R,4R,7R)-2-[2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-1-methyl-benzimidazole-5-carbonyl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (20 mg, 31.71 μmol, 46.13% yield) as a yellow oil. LC / MS (ESI) + ) [(M+H) + ]:630.8.

[0577] Step 12: tert-Butyl N-[(1R,4R,7R)-2-[2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-1-methyl-benzimidazole-5-carbonyl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (10 mg, 15.85 μmol) was dissolved in HCl / EA (3 mL). The resulting mixture was stirred at room temperature for 30 min. After removing the solvent in vacuo, the residue was purified by pre-HPLC to give [(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl]-[2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-1-methyl-benzimidazol-5-yl]methanone (5 mg, 9.42 μmol, 59.43% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:530.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (s, 1H), 7.60 (d, J = 4.1 Hz, 1H), 7.21 (d, J = 11.9 Hz, 1H), 7.05 (d, J = 1.3 Hz, 1H), 6.98 - 6.94 (m, 2H), 6.44 (dd, J = 6.2, 2.1 Hz, 1H), 5.26 (s, 1H), 4.54 (s, 1H), 4.17 (d, J = 3.2 Hz, 3H), 3.73 (d, J = 11.7 Hz, 1H), 3.56 (t, J = 2.9 Hz, 4H), 3.48 - 3.43 (m, 2H), 3.21 (s, 1H), 3.09 (d, J = 11.0 Hz, 1H), 2.68 (s, 1H), 2.22 (s, 1H), 1.97 (s, 2H), 1.89 - 1.70 (m, 4H), 1.61 (dt, J = 7.2, 3.7 Hz, 2H), 0.71 (td, J = 7.4, 3.4 Hz, 3H).

[0578] Example 70 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-((R)-3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone and Example 71 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-((S)-3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0579] [ka]

[0580] ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (360 mg, 0.68 mmol) was added to a 100 mL 200 mL 100 mL 100 mL 150 mL 200 mL 100 mL 150 mL 100 mL 150 mL 150 mL 2 Chiral separation was performed by SFC using a column: oz20×250 mm, 10 um (Daicel) (flow rate: 110 g / min) to obtain Synthesis Example 70 (110.0 mg, 30.6%) as an off-white solid (LCMS (ESI) + ) [(M+H) + ]:530.8) 1 H NMR (400 MHz, DMSO - d 6) δ 7.70 - 7.58 (m, 1 H), 7.30 - 7.18 (m, 1 H), 7.04 (d, J=3.3 Hz, 1 H), 6.98 - 6.93 (m, 2 H), 6.43 (dd, J=6.2, 2.2 Hz, 1 H), 5.29 - 5.21 (m, 1 H), 4.57 (t, J=5.1 Hz, 1 H), 4.16 (d, J=3.7 Hz, 3 H), 3.73 (d, J=2.3 Hz, 1 H), 3.54 (q, J=4.3 Hz, 4 H), 3.49 - 3.43 (m, 2 H), 3.39 (s, 1 H), 3.19 (s, 1 H), 3.11 - 3.03 (m, 1 H), 2.23 - 2.10 (m, 1 H), 2.03 - 1.89 (m, 2 H), 1.85 - 1.72 (m, 3 H), 1.64 - 1.58 (m, 2 H), 1.47 - 1.34 (m, 1 H), 0.70 (t, J=7.4 Hz, 3 H), and Example 71 (146.3 mg, 40.6%) was obtained as an off-white solid (LCMS (ESI + ) [(M+H) + :530.8); 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.59 (d, J = 1.2 Hz, 1H), 7.20 (d, J = 11.9 Hz, 1H), 7.04 (s, 1H), 6.95 (d, J = 5.9 Hz, 2H), 6.45 - 6.42 (m, 1H), 4.57 (t, J = 5.0 Hz, 1H), 4.17 (d, J = 2.9 Hz, 3H), 3.71 (s, 1H), 3.55 (s, 4H), 3.48 - 3.43 (m, 2H), 3.20 (s, 2H), 3.08 (d, J = 11.0 Hz, 1H), 2.22 (s, 1H), 2.14 (s, 1H), 1.95 (s, 2H), 1.80 (dd, J = 14.8, 7.3 Hz, 2H), 1.60 (t, J = 7.2 Hz, 2H), 1.24 (s, 2H), 0.69 (t, J = 7.4 Hz, 3H).

[0581] Examples 70 and 71 were tested in a PAD4 biochemical assay. The more potent Example 71 was used for co-crystallization with PAD4 protein and structure determination. The co-crystallization procedure is described in Biological Example 6. The crystal structure of Example 71 and PAD4 protein determined that the ethyl group on the 2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl) ring of Example 71 has an S configuration. It was concluded that the S isomers of other structurally similar compounds are more potent than the corresponding R isomers.

[0582] The following compounds were prepared similarly: Example 72 Preparation of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0583] [ka]

[0584] Prepared in a similar manner to Example 69. LC-MS: (ESI + ) m / z 472.7 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ 8.18 (s, 1H), 7.72 - 7.57 (m, 1H), 7.24 (dd, J = 29.1, 12.1 Hz, 1H), 7.02 (s, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.38 (d, J = 7.1 Hz, 1H), 6.07 (s, 1H), 5.23 (s, 1H), 4.17 (s, 3H), 3.77 (d, J = 12.3 Hz, 1H), 3.64 (s, 1H), 3.36 (d, J = 5.8 Hz, 1H), 3.23 (s, 1H), 3.07 (dd, J = 19.8, 9.9 Hz, 1H), 2.23 (d, J = 23.6 Hz, 1H), 1.96 (s, 2H), 1.75 (t, J = 8.8 Hz, 1H), 1.67 - 1.53 (m, 2H), 1.50 - 1.36 (m, 1H), 0.73 - 0.62 (m, 3H).

[0585] Example 73 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-((R)-3-ethyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone and Example 74 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-((S)-3-ethyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0586] [ka]

[0587] ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (26 mg, 0.55 mmol) was subjected to chiral separation by SFC using a mobile phase (CO2 / (MEOH:ACN (0.2% methanolic ammonia) = 1:1) = 55 / 45) (column: OZ20 x 250 mm, 10 um (Daicel) (flow rate: 110 g / min)) to give Synthesis Example 73 (7 mg, 26.9%) as an off-white solid (LCMS (ESI) + ) [(M+H) + ]: 472.7), affording Example 74 (12 mg, 26.1%) as an off-white solid (LCMS (ESI + ) [(M+H) + ]:472.7).

[0588] Based on the co-crystallization results of Example 71, Example 74, which is more potent than Example 73 in the PAD4 biochemical assay, is believed to have the S configuration.

[0589] Example 75: Report of the synthesis of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0590] [ka]

[0591] Prepared in a similar manner to Example 69. LC / MS (ESI + ) [(M+H) + ]:536.8. 1 H NMR (400 MHz, DMSO-d 6) δ 7.55 (d, J = 1.2 Hz, 1H), 7.15 (d, J = 11.9 Hz, 1H), 7.05 (s, 1H), 6.98 - 6.94 (m, 2H), 6.44 (dd, J = 6.3, 2.1 Hz, 1H), 5.26 (s, 1H), 4.54 (t, J = 5.0 Hz, 1H), 4.18 (s, 3H), 3.56 (d, J = 6.1 Hz, 4H), 3.46 (q, J = 7.3 Hz, 2H), 2.98 (s, 2H), 2.68 (s, 1H), 2.15 (s, 2H), 1.83 (dd, J = 14.6, 7.4 Hz, 2H), 1.62 (d, J = 7.7 Hz, 2H), 0.72 (t, J = 7.4 Hz, 3H).

[0592] Example 76 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-6-(methylamino)-1H-benzo[d]imidazol-5-yl)methanone

[0593] [ka]

[0594] Prepared in a similar manner to Example 69. LC / MS (ESI + ) [(M+H) + ]:559.8.

[0595] Example 77 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(1-(cyclopropylmethyl)-2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1H-benzo[d]imidazol-5-yl)methanone

[0596] [ka]

[0597] Prepared in a similar manner to Example 69. LC / MS (ESI + ) [(M+H) + ]:570.8.

[0598] Example 78 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-6,7-difluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0599] [ka]

[0600] Prepared in a similar manner to Example 69. LC / MS (ESI + ) [(M+H) + ]:548.7.

[0601] Example 79 Preparation of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(3-ethyl-1-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0602] [ka]

[0603] Prepared in a similar manner to Example 69. LC / MS (ESI + ) [(M+H) + ]:534.8. 1 H NMR (400 MHz, DMSO-d 6) δ 7.30 (s, 1H), 6.98 (d, J = 2.8 Hz, 1H), 6.94 (t, J = 4.7 Hz, 2H), 6.84 (s,1H), 6.41 (s, 1H), 5.22 (s, 1H), 4.73 - 4.54 (m, 1H), 4.23 (d, J = 16.6 Hz, 3H), 4.01 (d, J = 15.7 Hz, 4H),3.89 - 3.61 (m, 5H), 3.49 (d, J = 6.1 Hz, 3H), 3.35 (s, 2H), 3.26 (d, J = 5.7 Hz, 3H), 3.01 (s, 2H), 2.16 (s,2H), 1.59 (s, 3H), 1.35 (s, 1H), 0.67 (t, J = 6.5 Hz, 3H).

[0604] Example 80 Preparation of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0605] [ka]

[0606] Prepared in a similar manner to Example 69. LC / MS (ESI + ) [(M+H) + ]:548.8.

[0607] Example 81 and Example 82

[0608] [ka]

[0609] Example 80 [(3R,5R)-3-amino-5-fluoro-1-piperidyl]-[2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazol-5-yl]methanone (12 mg) was separated by SFC under the same preparation conditions as in Example 73 and 74 to obtain Example 81 (3.1 mg, 25.8%) and Example 82 (4.2 mg, 35.0%).

[0610] Based on the co-crystallization results of Example 71, Example 82, which is more potent than Example 81 in the PAD4 biochemical assay, is believed to have the S configuration.

[0611] Example 83 Preparation of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(3-ethyl-1-(3-hydroxy-3-methylbutyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0612] [ka]

[0613] Prepared in a similar manner to Example 69. LC / MS (ESI + ) [(M+H) + ]:576.8. 1 H NMR (400 MHz, DMSO-d 6) δ 7.40 - 7.31 (m, 1H), 6.99 (d, J = 3.2 Hz, 1H), 6.95 (d, J = 3.5 Hz, 2H),6.87 (d, J = 12.7 Hz, 1H), 6.42 (d, J = 3.5 Hz, 1H), 5.24 (s, 1H), 4.37 (s, 1H), 4.22 (s, 3H), 3.99 (s, 3H),3.52 (dd, J = 26.4, 10.6 Hz, 5H), 3.35 (d, J = 6.6 Hz, 2H), 2.25 (d, J = 71.1 Hz, 2H), 1.77 (s, 3H), 1.60 (s,2H), 1.29 (dd, J = 29.2, 10.0 Hz, 2H), 1.21 (s, 6H), 0.68 (dd, J = 8.3, 6.5 Hz, 3H).

[0614] Example 84 Preparation of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(3-ethyl-1-(3-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0615] [ka]

[0616] Prepared in a similar manner to Example 69. LC / MS (ESI + ) [(M+H) + ]:561.8. 1 H NMR (400 MHz, DMSO-d 6) δ 7.30 (s, 1H), 7.02 - 6.91 (m, 3H), 6.84 (s, 1H), 6.42 - 6.38 (m, 1H), 4.21(s, 3H), 3.99 (s, 3H), 3.60 - 3.51 (m, 2H), 3.45 (dt, J = 15.1, 7.5 Hz, 4H), 3.28 (s, 3H), 3.24 (d, J = 15.3Hz, 3H), 2.15 (s, 1H), 2.02 (d, J = 7.6 Hz, 1H), 1.96 - 1.82 (m, 3H), 1.65 - 1.53 (m, 3H), 1.35 (t, J = 15.0Hz, 2H), 0.87 (s, 1H), 0.69 (dd, J = 16.5, 9.1 Hz, 3H).

[0617] Example 85 Preparation of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0618] [ka]

[0619] Prepared in a similar manner to Example 69. LC / MS (ESI + ) [(M+H) + ]:542.8.

[0620] Example 86 and Example 87

[0621] [ka]

[0622] Example 85 [(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl]-[2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazol-5-yl]methanone (61.1 mg) was separated by SFC under the same preparation conditions as in Example 73 and 74 to obtain Example 86 (18 mg, 29.4%) and Example 87 (20 mg, 32.7%).

[0623] Based on the co-crystallization results of Example 71, Example 87, which is more potent than Example 86 in the PAD4 biochemical assay, is believed to have the S configuration.

[0624] Example 88 Preparation of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxy-3-methylbutyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0625] [ka]

[0626] Prepared in a similar manner to Example 69. LC / MS (ESI + ) [(M+H) + ]:558.8. 1 H NMR (400 MHz, DMSO-d 6) δ 8.21 (s, 0.35H), 7.60 (d, J = 4.3 Hz, 1H), 7.25 (dd, J = 28.3, 12.1 Hz, 1H), 7.05 (s, 1H), 6.98 - 6.92 (m, 2H), 6.43 (dd, J = 4.9, 3.3 Hz, 1H), 5.26 (s, 1H), 4.39 (s, 1H), 4.18 (s, 3H), 3.74 (d, J = 12.4 Hz, 1H), 3.54 (d dd, J = 11.8, 8.0, 3.2 Hz, 4H), 3.45 (dd, J = 14.2, 5.4 Hz, 1H), 3.21 (s, 1H), 3.12 - 3.05 (m, 1H), 2.23 (s, 1H), 1.97 (s, 2H), 1.84 - 1.67 (m, 3H), 1.65 - 1.56 (m, 2H), 1.42 (dd, J = 22.7, 10.4 Hz, 1H), 1.23 (d, J = 15.7 Hz, 6H), 0.71 (td, J = 7.4, 3.8 Hz, 3H).

[0627] Example 89 Preparation of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxy-2,2-dimethylpropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0628] [ka]

[0629] Prepared in a similar manner to Example 69. LC-MS (ESI + ): m / z 558.7 [M+H] + .

[0630] Example 90 Preparation of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0631] [ka]

[0632] Prepared in a similar manner to Example 69. LC-MS: (ESI + ) m / z 566.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 0.45H), 7.37 (d, J = 3.9 Hz, 1H), 7.09 (s, 1H), 7.01 - 6.91 (m, 3H), 6.43 (d, J = 6.6 Hz, 1H), 5.49 (d, J = 17.9 Hz, 1H), 5.33 (d, J = 18.2 Hz, 1H), 5.24 (s, 1H), 4.01 (s, 3H), 3.79 (d, J = 11.6 Hz, 1H), 3.54 (d, J = 3.9 Hz, 3H), 3.51 (d, J = 2.1 Hz, 2H), 3.46 (d, J = 7.0 Hz, 2H), 3.19 (s, 1H), 3.07 (d, J = 11.0 Hz, 1H), 2.20 (d, J = 30.2 Hz, 1H), 1.95 (dd, J = 23.1, 11.4 Hz, 2H), 1.81(d dd, J = 29.8, 14.1, 7.0 Hz, 3H), 1.64 - 1.52 (m, 2H), 1.43 (dd, J = 22.9, 14.7 Hz, 1H), 1.24 (s, 1H), 0.67(td, J = 7.3, 3.5 Hz, 3H).

[0633] Example 91 Preparation of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0634] [ka]

[0635] Prepared in a similar manner to Example 69. LC-MS: (ESI + ) m / z 554.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.70 (s, 1H), 8.42 (s, 2H), 8.27 (d, J = 31.4 Hz, 2H), 7.54 - 7.37 (m, 2H), 7.15 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 7.7 Hz, 1H), 5.48 (s, 1H), 4.61 (s, 1H), 4.26 (s, 1H), 3.87 (s, 1H), 3.73 - 3.61 (m, 3H), 3.61 - 3.52 (m, 5H), 3.26 (s, 1H), 2.80 (s, 2H), 2.67 (d, J = 31.2 Hz, 1H), 2.11 - 1.94 (m, 3H), 1.84(t dd, J = 19.6, 13.2, 6.4 Hz, 4H), 1.67 (s, 1H), 1.23 (s, 1H), 0.98 (t, J = 7.4 Hz, 3H).

[0636] Example 92 Preparation of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-(oxetan-3-ylmethyl)-1H-benzo[d]imidazol-5-yl)methanone

[0637] [ka]

[0638] Prepared in a similar manner to Example 69. LC-MS (ESI + ): m / z 586.8 [M+H] + .

[0639] Example 93 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-(furan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)methanone

[0640] [ka]

[0641] Prepared in a similar manner to Example 69. LC-MS: (ESI + ) m / z 597.1 [M+H] + .

[0642] Example 94 Preparation of 3-(5-(5-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-3-ethyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)propanamide

[0643] [ka]

[0644] [ka]

[0645] Step 1: To a solution of 2-(11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazole-5-carboxylate (200 mg, 494.49 μmol) in anhydrous ACN (3 mL) was added DIPEA (319.54 mg, 2.47 mmol, 430.64 μL) and 3-bromopropanamide (375.78 mg, 2.47 mmol) at room temperature. The reaction mixture was stirred at 130° C. for 12 h in a microwave, cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluted with DCM / MeOH=1:0 to 20:1) to give methyl 2-[9-(3-amino-3-oxo-propyl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (42 mg, 88.32 μmol, 17.86% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:475.6.

[0646] Step 2: To a stirred solution of methyl 2-[9-(3-amino-3-oxo-propyl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylate (42 mg, 88.32 μmol) in THF (1 mL), MeOH (0.5 mL) was added aqueous LiOH (1.0 M, 0.26 mL). The mixture was stirred at room temperature for 4 h, acidified to pH 5-6 with 3 M aqueous hydrochloric acid, and extracted with EA (10 × 3 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 2-[9-(3-amino-3-oxo-propyl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (30 mg, 65.00 μmol, 73.60% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:461.5.

[0647] Step 3: To a solution of 2-[9-(3-amino-3-oxo-propyl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (30.0 mg, 65.00 μmol) in DMF (2 mL), DIPEA (25.20 mg, 195.01 μmol, 33.97 μL), HATU (49.43 mg, 130.01 μmol), tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate (17.03 mg, 78.00 μmol) were added to the mixture and the mixture was stirred at room temperature for 16 h. LC-MS showed that the starting material was consumed and the desired mass was detected. After cooling to room temperature, the mixture was diluted with EA, washed with brine and added Na 2 SO 4After filtration and evaporation of the solvent in vacuum, the residue was purified by silica gel flash column chromatography (eluted with DCM / MeOH=1:0 to 15:1) to give tert-butyl N-[(3R,5R)-1-[2-[9-(3-amino-3-oxo-propyl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-5-fluoro-3-piperidyl]carbamate (25 mg, 37.78 μmol, 58.12% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:662.8.

[0648] Step 4: To a solution of tert-butyl N-[(3R,5R)-1-[2-[9-(3-amino-3-oxo-propyl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-5-fluoro-3-piperidyl]carbamate (25 mg, 37.78 μmol) in DCM (1 mL). The mixture was stirred at 25° C. for 3 h. After completion of the reaction as judged by LC / MS. The mixture was concentrated under reduced pressure. The reaction mixture was diluted with saturated Na 2 CO 3 The pH was adjusted to 8 with solution, and the mixture was extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate. The combined organic layer was concentrated in vacuum, and the residue was purified by silica gel flash column chromatography (eluted with DCM / MeOH = 1:0 to 10:1) to give 3-[2-[5-[(3R,5R)-3-amino-5-fluoro-piperidine-1-carbonyl]-7-methoxy-1-methyl-benzimidazol-2-yl]-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetrean-9-yl]propanamide (6.0 mg, 10.68 μmol) as a white solid. LC / MS (ESI + ) [(M+H) +]:561.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (s, 2H), 7.36 (s, 1H), 7.01 (s, 1H), 6.98 - 6.93 (m, 2H), 6.88 (s, 1H), 6.44 (d, J = 4.8 Hz, 1H), 5.22 (s, 1H), 5.01 (d, J = 45.9 Hz, 1H), 4.22 (s, 3H), 4.00 (s, 3H), 3.72 - 3.50 (m, 6H), 2.47 - 2.33 (m, 6H), 1.90 (d, J = 41.6 Hz, 3H), 1.58 (d, J = 7.2 Hz, 3H), 1.33 (d, J = 14.7 Hz, 1H), 0.67 (t, J = 7.3 Hz, 3H).

[0649] Example 95 Preparation of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-5-yl)methanone

[0650] [ka]

[0651] [ka]

[0652] Step 1: A mixture of ethyl 11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylate (2.4 g, 8.81 mmol) and 1 M borane tetrahydrofuran (17.62 mmol, 17.6 mL) was dissolved in N 2 The reaction mixture was stirred under atmospheric pressure for 2 hours. After the reaction was complete, the reaction mixture was 2The mixture was quenched with 20 mL of HO (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and evaporated to give the crude product. The crude material was purified by flash column chromatography on silica gel (5-40% ethyl acetate / heptane) to give ethyl 11-ethyl-1,9-diazatrichloro[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylate (1.1 g, 4.26 mmol, 48.34% yield). LC / MS (ESI + ) [(M+H) + ]:258.8.

[0653] Step 2: To a solution of ethyl 11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylate (1.1 g, 4.26 mmol), 3-bromo-1-propanol (2.96 g, 21.29 mmol, 1.86 mL) in anhydrous acetonitrile 99.8+% (10 mL) was added N,N-diisopropylethylamine (2.75 g, 21.29 mmol, 3.71 mL). The resulting mixture was heated at 130° C. for 18 h in a sealed tube. The reaction was cooled to room temperature and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (5-60% ethyl acetate / heptane) to give ethyl 11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylate (1.0 g, 3.16 mmol, 74.22% yield). LC / MS (ESI + ) [(M+H) + ]:316.8.

[0654] Step 3: To a solution of ethyl 11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylate (1.0 g, 3.16 mmol) in THF (6 mL), MeOH (2 mL) was added an aqueous solution of lithium hydroxide monohydrate (397.86 mg, 9.48 mmol) in water (2 mL) and the resulting mixture was stirred at 60° C. for 5 h. The reaction crude was concentrated in vacuo, taken up in water (8 mL) and acidified with 2N aqueous hydrochloric acid until no further precipitation was observed. The resulting suspension was stirred for 30 min and filtered through a filter paper. The resulting solid was dried to give 11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4 (12),5,7-tetraene-2-carboxylic acid (900 mg, 3.12 mmol, 98.76% yield) as a greenish-gray solid. LC / MS (ESI + ) [(M+H) + ]:288.8.

[0655] Step 4: To a stirred solution of methyl 4-chloro-3-methoxy-5-nitro-benzoate (2.0 g, 8.14 mmol) in anhydrous acetonitrile 99.8+% (12 mL) was added phenylmethanamine (1.75 g, 16.29 mmol) and potassium carbonate (1.69 g, 12.21 mmol). The mixture was stirred at 80° C. under nitrogen for 18 h, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-40% ethyl acetate / heptane) to give methyl 4-(benzylamino)-3-methoxy-5-nitro-benzoate (2.5 g, 7.90 mmol, 97.06% yield) as an orange-red solid. LC / MS (ESI + ) [(M+H) + ]:316.8.

[0656] Step 5: To a flask containing methyl 4-(benzylamino)-3-methoxy-5-nitro-benzoate (2.5 g, 7.90 mmol) in MeOH (50 mL) was added 10% Pd / C (0.25 g, 50% Wt). The solution was degassed with a H2 gas balloon. The mixture was stirred for 18 h. The reaction was completed and filtered through a pad of Celite, which was washed with MeOH (3 x 10 mL). The combined solution was concentrated in vacuo to give methyl 3,4-diamino-5-methoxy-benzoate (1.5 g, 7.65 mmol, 96.73% yield) as a brown solid. LC / MS (ESI + ) [(M+H) + ]:196.8.

[0657] Step 6: To a solution of methyl 3,4-diamino-5-methoxy-benzoate (0.67 g, 3.41 mmol) in acetone (10 mL) was added potassium carbonate (471.96 mg, 3.41 mmol), followed by 3-bromopropyne (507.79 mg, 3.41 mmol, 80% purity). The mixture was stirred at 50 °C for 24 h, cooled to room temperature, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-40% ethyl acetate / heptane) to give methyl 3-amino-5-methoxy-4-(prop-2-ynylamino)benzoate (200 mg, 853.79 μmol, 25.00% yield) as a brown solid. LC / MS (ESI + ) [(M+H) + ]:234.8.

[0658] Step 7: To a solution of methyl 3-amino-5-methoxy-4-(prop-2-ynylamino)benzoate (200 mg, 853.79 μmol) and 11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylic acid (246.18 mg, 853.79 μmol) in DMF (5 mL) at room temperature, HATU (422.03 mg, 1.11 mmol) and N,N-diisopropylethylamine (331.03 mg, 2.56 mmol, 446.13 μL) were added. The reaction mixture was stirred at room temperature for 2 h and then heated to 100° C. for 15 h. After the reaction was complete, H 2 Quench with O (15 mL) and CH 2 Cl 2 (30 mL×2). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate and evaporated to give the crude product. The crude product was purified by elution with CH 2 Cl 2 Purification by flash column chromatography on silica gel using 2-20% MeOH in hexane afforded the title product methyl 3-[[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carbonyl]amino]-5-methoxy-4-(prop-2-ynylamino)benzoate (65 mg, 128.82 μmol, 15.09% yield) as a pale solid. LC / MS (ESI + ) [(M+H) + ]:504.8.

[0659] Step 8: A mixture of methyl 3-[[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carbonyl]amino]-5-methoxy-4-(prop-2-ynylamino)benzoate (65 mg, 128.82 μmol) and acetic acid (3 mL) was heated under N 2 The mixture was stirred at 100° C. for 3 hours under atmospheric pressure. The reaction mixture was concentrated in vacuo and diluted with EtOAc (10 mL), NaHCO3 (aq) (6 mL) and extracted with EtOAc (10 mL x 2). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and evaporated to give the crude product. The crude product was purified by flash column chromatography on silica gel using 1-70% EtOAc in hexanes to give the title product methyl 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodec-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-prop-2-ynyl-benzimidazole-5-carboxylate (10 mg, 20.55 μmol, 15.95% yield). LC-MS (ESI): m / z 486.8 [M+H] + .

[0660] Step 9: To a solution of methyl 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-prop-2-ynyl-benzimidazole-5-carboxylate (10 mg, 20.55 μmol) in THF (2.0 mL) was added a solution of lithium hydroxide monohydrate (2.59 mg, 61.66 μmol) in water (0.5 mL) and the resulting mixture was stirred at room temperature for 15 h. The reaction crude was concentrated in vacuo, taken up in water (5 mL), acidified with 2N aqueous hydrochloric acid, and diluted with MeOH / CH 2 Cl 2 (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to give the product 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodec-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-prop-2-ynyl-benzimidazole-5-carboxylic acid (5 mg, 10.58 μmol, 51.48% yield) as an off-white solid. LC / MS (ESI + ) [(M+H) + ]:472.8.

[0661] Step 10: CH at room temperature 2 Cl 2 To a solution of 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-prop-2-ynyl-benzimidazole-5-carboxylic acid (5 mg, 10.58 μmol) and tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate (2.77 mg, 12.70 μmol) in 1 mL of 10 ... 2 Quench with O (8 mL) and CH 2 Cl 2 (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate and evaporated to give the crude product. The crude product was purified by elution with CH 2 Cl 2 Purification by flash column chromatography on silica gel using 2-20% MeOH in hexane afforded the title product tert-butyl N-[(3R,5R)-1-[2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-prop-2-ynyl-benzimidazole-5-carbonyl]-5-fluoro-3-piperidyl]carbamate (5.0 mg, 7.43 μmol, 70.24% yield) as a pale solid. LC / MS (ESI + ) [(M+H) + ]:672.8.

[0662] Step 11: To a stirred solution of tert-butyl N-[(3R,5R)-1-[2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-prop-2-ynyl-benzimidazole-5-carbonyl]-5-fluoro-3-piperidyl]carbamate (5.0 mg, 7.43 μmol) in MeOH (0.5 mL) was added 4 M HCl in EtOAc (2 mL). The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was evaporated to give the crude product, which was then purified by pre-HPLC to give [(3R,5R)-3-amino-5-fluoro-1-piperidyl]-[2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-methoxy-1-prop-2-ynyl-benzimidazol-5-yl]methanone (2.5 mg, 4.37 μmol, 58.74% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:572.8.

[0663] Example 96 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(1-ethyl-2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1H-benzo[d]imidazol-5-yl)methanone

[0664] [ka]

[0665] [ka]

[0666] Step 1: A mixture of ethanamine (1.4 g, 31.51 mmol, 1.77 mL), 5-bromo-1,2-difluoro-3-nitro-benzene (5.0 g, 21.01 mmol), and potassium carbonate (2.9 g, 21.01 mmol, 1.27 mL) was dissolved in acetonitrile (28.8 mL). This was stirred at 80° C. for 15 h. The reaction was diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluted with 0-100% EA / PE) to give 4-bromo-N-ethyl-2-fluoro-6-nitro-aniline (4.0 g, 15.21 mmol, 72.37% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:262.8.

[0667] Step 2: 4-Bromo-N-ethyl-2-fluoro-6-nitro-aniline (4.0 g, 15.21 mmol) in methanol (30 mL) and H 2 The mixture (balloon) was hydrogenated over 10% palladium on carbon (413.6 mg, 3.90 mmol) at ambient temperature overnight. The mixture was filtered over Celite to remove the Pd / C and the solvent was evaporated to give the desired product 5-bromo-N2-ethyl-3-fluoro-benzene-1,2-diamine (3.0 g, 12.87 mmol, 84.65% yield) as a colorless solid. LC / MS (ESI + ) [(M+H) + ]:232.8.

[0668] Step 3: A mixture of 5-bromo-N2-ethyl-3-fluoro-benzene-1,2-diamine (2.9 g, 12.61 mmol), 11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxylic acid (2.8 g, 11.46 mmol), HATU (6.5 g, 17.20 mmol), and DIPEA (2.9 g, 22.93 mmol, 3.99 mL) was dissolved in DMF (7.43 mL). The resulting mixture was stirred at 80° C. for 4 h. The reaction was diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give N-[5-bromo-2-(ethylamino)-3-fluoro-phenyl]-11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxamide (3.0 g, 6.53 mmol, 56.97% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:440.8.

[0669] Step 4: N-[5-Bromo-2-(ethylamino)-3-fluoro-phenyl]-11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxamide (3.0 g, 6.53 mmol) was dissolved in acetic acid (15 mL) and stirred at 120 °C for 2 h. The reaction was cooled to room temperature and the solvent was removed in vacuo, after which the residue was purified by flash column chromatography on silica gel (eluting with 0-50% EA / PE) to give 2-(5-bromo-1-ethyl-7-fluoro-benzimidazol-2-yl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-10-one (2.6 g, 5.89 mmol, 90.20% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:440.8.

[0670] Step 5: A mixture of dicyanozinc (276.1 mg, 2.35 mmol, 149.09 μL), N-[5-bromo-2-(ethylamino)-3-fluoro-phenyl]-11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-2-carboxamide (3.0 g, 6.53 mmol), 1,1'-bis(diphenylphosphino)ferrocene (724.2 mg, 1.31 mmol) and tris(dibenzylideneacetone)dipalladium(0) (598.1 mg, 653.15 μmol) was dissolved in DMSO (30 mL). The resulting mixture was stirred at 140 °C for 2 h in a microwave reactor under nitrogen atmosphere. The mixture was purified by flash column chromatography on silica gel (eluted with 0-50% PE / EA) to give 2-(5-bromo-1-ethyl-7-fluoro-benzimidazol-2-yl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-10-one (2.0 g, 4.53 mmol, 69.39% yield) as a yellow liquid oil. LC / MS (ESI + ) [(M+H) + ]:387.8.

[0671] Step 6: To a solution of 1-ethyl-2-(11-ethyl-10-oxo-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-fluoro-benzimidazole-5-carbonitrile (1.7 g, 4.53 mmol) in anhydrous THF (10 mL) was added borane-tetrahydrofuran complex slowly at 0 °C. The reaction mixture was stirred at room temperature for 30 min, quenched with MeOH at 0 °C, and concentrated in vacuo. The residue was diluted with 1N aqueous HCl (1 mL), stirred at room temperature for 1 h, and basified to about pH 8 with 1N aqueous NaOH. The resulting mixture was extracted with DCM (10 mL × 3) and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (eluted with DCM / MeOH=1:0 to 20:1) to give 1-ethyl-2-(11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-fluoro-benzimidazole-5-carbonitrile (1.4 g, 3.75 mmol, 82.72% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:373.8.

[0672] Step 7: A mixture of 3-bromopropan-1-ol (2.6 g, 18.75 mmol, 1.64 mL), 1-ethyl-2-(11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-fluoro-benzimidazole-5-carbonitrile (1.4 g, 3.75 mmol), and DIPEA (2.9 g, 22.49 mmol, 3.92 mL) was dissolved in acetonitrile (15 mL). The resulting mixture was stirred at 120° C. for 15 h in a microwave reactor. After the solvent was removed in vacuo, the residue was purified by flash column chromatography on silica gel (eluted with EA / PE 0-100) to give 1-ethyl-2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carbonitrile (1.2 g, 2.78 mmol, 74.18% yield) as a liquid oil. LC / MS (ESI + ) [(M+H) + ]:431.8.

[0673] Step 8: A mixture of 1-ethyl-2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carbonitrile (1.2 g, 2.78 mmol) and potassium hydroxide (467.2 mg, 8.34 mmol) was dissolved in methanol / water=1 / 1 (10 mL). The resulting mixture was stirred at 100° C. overnight. The desired signal was found by LC / MS. The mixture was acidified with 3 mol / L hydrochloric acid and purified by pre-HPLC to give 1-ethyl-2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carboxylic acid (800.0 mg, 1.78 mmol, 63.0% yield) as a yellow solid. LC / MS (ESI + ) [(M+H)+ ]:450.8.

[0674] Step 9: A mixture of 1-ethyl-2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carboxylic acid (50 mg, 110.99 μmol), tert-butyl N-[(1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (PharmaBlock) (25.9 mg, 122.09 μmol), DIPEA (28.7 mg, 221.97 μmol, 38.66 μL) and HATU (63.3 mg, 166.48 μmol) was dissolved in DMF (2 mL). The resulting mixture was stirred at 50° C. for 10 minutes. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluted with 0-100% EA / PE) to give tert-butyl N-[(1R,4R,7R)-2-[1-ethyl-2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carbonyl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (30.0 mg, 46.53 μmol, 41.92% yield) as a yellow oil. LC / MS (ESI + ) [(M+H) + ]:644.8.

[0675] Step 10: tert-Butyl N-[(1R,4R,7R)-2-[1-ethyl-2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carbonyl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (30.0 mg, 46.53 μmol) was dissolved in HCl (4M) / diane=1 / 2 (3 mL). The resulting mixture was stirred at room temperature for 30 minutes. After removal of the solvent in vacuo and purification by pre-HPLC, [(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl]-[1-ethyl-2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazol-5-yl]methanone (14.0 mg, 25.70 μmol, 55.24% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:544.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.62 (dd, J = 4.5, 1.2 Hz, 1H), 7.23 (d, J = 11.9 Hz, 1H), 7.01 - 6.91 (m, 3H), 6.44 (dd, J = 6.8, 1.5 Hz, 1H), 5.22 (s, 1H), 4.57 (dq, J = 14.6, 7.3 Hz, 2H), 3.75 (d, J = 11.7 Hz, 1H), 3.60 - 3.53 (m, 4H), 3.52 - 3.40 (m, 3H), 3.21 (s, 1H), 3.09 (d, J = 11.0 Hz, 1H), 2.22 (s, 1H), 2.00 - 1.72 (m, 5H), 1.72 - 1.48 (m, 6H), 1.44 (t, J = 9.7 Hz, 1H), 0.70 (td, J = 7.5, 3.5 Hz, 3H).

[0676] Example 97 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(1-ethyl-2-((R)-3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1H-benzo[d]imidazol-5-yl)methanone and Example 98 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(1-ethyl-2-((S)-3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1H-benzo[d]imidazol-5-yl)methanone

[0677] [ka]

[0678] ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(1-ethyl-2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1H-benzo[d]imidazol-5-yl)methanone (200 mg, 0.37 mmol) was added to the mobile phase (CO 2 / MEOH (0.2% methanol ammonia) = 45 / 55) (column: OZ4.6 × 100 mm 5 um) (flow rate: 120 g / min) was used to perform chiral separation by SFC to obtain Synthesis Example 97 (60 mg, 11.03%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 7.61 (s, 1H), 7.24 (d, J=11.8 Hz, 1H), 7.01 - 6.90 (m, 3H), 6.44 (dd, J=6.8, 1.5 Hz, 1H), 5.22 (t, J=6.7 Hz, 1H), 4.60 - 4.53 (m, 2H), 3.77 (s, 1H), 3.55 (h, J=2.3 Hz, 4H), 3.50 - 3.44 (m, 3H), 3.23 (s, 1H), 3.10 - 3.04 (m, 1H), 2.26 (s, 1H), 1.99 - 1.74 (m, 5H), 1.62 - 1.43 (m, 6H), 1.24 (d, J=3.8 Hz, 1H), 0.68 (t, J=7.4 Hz, 3H). Also obtained was Example 98 (50 mg, 9.19%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.23 (d, J = 11.9 Hz, 1H), 7.00 - 6.91 (m, 3H), 6.44 (dd, J = 6.8, 1.6 Hz, 1H), 5.21 (q, J = 5.0 Hz, 1H), 4.56 (dq, J = 14.6, 7.5 Hz, 2H), 3.77 (s, 1H), 3.55 (td, J = 6.0, 2.1 Hz, 4H), 3.46 (t, J = 7.2 Hz, 3H), 3.21 (s, 1H), 3.08 (d, J = 10.7 Hz, 1H), 2.23 (s, 1H), 1.99 - 1.70 (m, 5H), 1.61 - 1.39 (m, 6H), 1.24 (d, J = 3.5 Hz, 1H), 0.69 (t, J = 7.5 Hz, 3H).

[0679] Based on the co-crystallization results of Example 71, Example 98, which is more potent than Example 97 in the PAD4 biochemical assay, is believed to have the S configuration.

[0680] Example 99 ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(1-ethyl-2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1H-benzo[d]imidazol-5-yl)methanone

[0681] [ka]

[0682] Prepared in a similar manner to Example 96. LC / MS (ESI + ) [(M+H) + ]:550.8.

[0683] Example 100 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(1-ethyl-2-(3-ethyl-1-(3-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1H-benzo[d]imidazol-5-yl)methanone

[0684] [ka]

[0685] [ka]

[0686] Step 1: 1-Ethyl-2-(3-ethyl-1-(3-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1H-benzo[d]imidazole-5-carbonitrile To a solution of 1-ethyl-2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carbonitrile (50.0 mg, 115.87 μmol) in THF (2 mL) was added iodomethane (24.7 mg, 173.81 μmol, 10 μL). The resulting mixture was stirred at 25° C. for 5 h. The desired signal was found by LC / MS. The mixture was acidified with 3 mol / L hydrochloric acid. The mixture was purified by pre-HPLC to give 1-ethyl-2-[11-ethyl-9-(3-methoxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carbonitrile (40.0 mg, 89.78 μmol, 77.48% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:445.8

[0687] Step 2: 1-Ethyl-2-(3-ethyl-1-(3-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1H-benzo[d]imidazole-5-carboxylic acid A mixture of 1-ethyl-2-[11-ethyl-9-(3-methoxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carbonitrile (40.0 mg, 89.78 μmol) and potassium hydroxide (10.0 mg, 179.56 μmol) was dissolved in methanol / water=1 / 1 (2 mL) and stirred at 100° C. overnight. The desired signal was found by LC / MS. The mixture was acidified with 3 mol / L hydrochloric acid. The mixture was purified by pre-HPLC to give 1-ethyl-2-[11-ethyl-9-(3-methoxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carboxylic acid (30.0 mg, 64.58 μmol, 71.93% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:464.8

[0688] Step 3: tert-Butyl ((1R,4R,7R)-2-(1-ethyl-2-(3-ethyl-1-(3-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1H-benzo[d]imidazole-5-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate A mixture of 1-ethyl-2-[11-ethyl-9-(3-methoxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carboxylic acid (30.0 mg, 64.58 μmol), tert-butyl N-[(1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (16.4 mg, 77.50 μmol), DIPEA (16.7 mg, 129.16 μmol, 22.50 μL), and HATU (36.8 mg, 96.87 μmol) was dissolved in DMF (2 mL). The resulting mixture was stirred at 25° C. for 10 min. The desired signal was found by LC / MS and SM was consumed. The reaction was diluted with EtOAc (50 ml) and washed with water (25 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give tert-butyl N-[(1R,4R,7R)-2-[1-ethyl-2-[11-ethyl-9-(3-methoxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carbonyl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (20.0 mg, 30.36 μmol, 47.01% yield) as a yellow oil. LC / MS (ESI + ) [(M+H) + ]:658.8

[0689] Step 4: ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(1-ethyl-2-(3-ethyl-1-(3-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1H-benzo[d]imidazol-5-yl)methanone tert-Butyl N-[(1R,4R,7R)-2-[1-ethyl-2-[11-ethyl-9-(3-methoxypropyl)-1,9-diazatrichloro[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazole-5-carbonyl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (20.0 mg, 30.36 μmol) was dissolved in HCl (4M) / diane=1 / 2 (3 mL). The resulting mixture was stirred at room temperature for 30 minutes. After removing the solvent in vacuo, the residue was purified by pre-HPLC to give [(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl]-[1-ethyl-2-[11-ethyl-9-(3-methoxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-benzimidazol-5-yl]methanone (8.0 mg, 14.32 μmol, 47.17% yield) as an off-white solid. LC / MS (ESI + ) [(M+H) + ]:558.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.62 (d, J = 4.4 Hz, 1H), 7.30 - 7.19 (m, 1H), 7.02 - 6.91 (m, 3H), 6.45 - 6.39 (m, 1H), 5.22 (s, 1H), 4.58 (s, 2H), 3.75 (d, J = 11.7 Hz, 1H), 3.55 (d, J = 7.6 Hz, 2H), 3.46 (td, J = 6.4, 3.1 Hz, 5H), 3.28 (s, 3H), 3.20 (s, 1H), 3.11 - 3.02 (m, 2H), 2.21 (d, J = 8.0 Hz, 1H), 1.99 - 1.84 (m, 4H), 1.72 (d, J = 8.1 Hz, 1H), 1.62 - 1.49 (m, 5H), 0.69 (td, J = 7.5, 3.4 Hz, 3H).

[0690] Example 101 Preparation of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-4-fluoro-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-6-yl)methanone

[0691] [ka]

[0692] Step 1: To a solution of 4-bromo-2-fluoro-6-nitro-aniline (2.5 g, 10.64 mmol) in DMF (20 mL) was added copper(I) cyanide (1.91 g, 21.28 mmol, 652.55 μL). After stirring at 165 °C for 22 h, the reaction mixture was cooled to room temperature, poured into water (75 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (80 mL) and saturated aqueous sodium chloride solution (80 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-20% ethyl acetate / heptane) to give 4-amino-3-fluoro-5-nitro-benzonitrile (1.2 g, 6.63 mmol, 62.28% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:181.8.

[0693] Step 2: A mixture of 4-amino-3-fluoro-5-nitro-benzonitrile (0.6 g, 3.31 mmol) and 10% palladium on carbon (60.0 mg) in methanol (10 mL) was heated at 50 °C for 2 h under H 2 (balloon). The mixture was filtered over Celite to remove Pd / C and the solvent was evaporated to give the desired product 3,4-diamino-5-fluoro-benzonitrile (500 mg, 3.31 mmol, 99.86% yield) as a colorless solid. LC / MS (ESI +) [(M+H) + ]:151.8.

[0694] Step 3: To a solution of 3,4-diamino-5-fluoro-benzonitrile (0.5 g, 3.31 mmol), 3-bromopropyne (472.25 mg, 3.97 mmol) in DMSO (6 mL) was added potassium iodide (54.92 mg, 330.82 μmol) followed by DIPEA (855.10 mg, 6.62 mmol, 1.15 mL). After stirring at 120° C. for 4 h, the reaction mixture was cooled to room temperature, poured into water (15 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (30 mL) and saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% ethyl acetate / heptane) to give 4-amino-3-fluoro-5-(prop-2-ynylamino)benzonitrile (0.3 g, 1.59 mmol, 47.93% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:189.8.

[0695] Step 4: EtOH / H 2To a solution of 4-amino-3-fluoro-5-(prop-2-ynylamino)benzonitrile (0.3 g, 1.59 mmol) and tert-butyl 11-ethyl-2-formyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (498.51 mg, 1.59 mmol) in O (8 mL / 4 mL) was added disodium hydrosulfite (828.27 mg, 4.76 mmol) and the mixture was heated at reflux for 18 h. After completion of the reaction, the mixture was concentrated in vacuo and the residue was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (40 mL), dried over sodium sulfate and evaporated to give the crude product. The crude product was purified by flash column chromatography using 15-30% EtOAc in hexanes to give the title product tert-butyl 2-(6-cyano-4-fluoro-1-prop-2-ynyl-benzimidazol-2-yl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (0.22 g, 454.98 μmol, 28.69% yield) as a pale solid. LC / MS (ESI) + ) [(M+H) + ]:483.8.

[0696] Step 5: To a stirred solution of tert-butyl 2-(6-cyano-4-fluoro-1-prop-2-ynyl-benzimidazol-2-yl)-11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraene-9-carboxylate (220 mg, 454.98 μmol) in MeOH (2 mL) was added 4 M HCl in dioxane (5 mL) and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was evaporated to give the crude product 2-(11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodec-2,4(12),5,7-tetraen-2-yl)-7-fluoro-3-prop-2-ynyl-benzimidazole-5-carbonitrile (190 mg, 452.51 μmol, 99.46% yield, HC) as a brown solid. LC / MS (ESI+ ) [(M+H) + ]:383.8.

[0697] Step 6: To a solution of 2-(11-ethyl-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl)-7-fluoro-3-prop-2-ynyl-benzimidazole-5-carbonitrile (190 mg, 452.51 μmol, HC), 3-bromo-1-propanol (314.47 mg, 2.26 mmol, 197.78 μL) in acetonitrile (3.0 mL) was added N,N-diisopropylethylamine (292.41 mg, 2.26 mmol, 394.09 μL). The resulting mixture was heated at 130° C. for 18 h in a sealed tube. The reaction was cooled to room temperature and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (5-50% ethyl acetate / heptane) to give 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-3-prop-2-ynyl-benzimidazole-5-carbonitrile (70 mg, 158.55 μmol, 35.04% yield) as a pale yellow oil. LC / MS (ESI) + ) [(M+H) + ]:441.7.

[0698] Step 7: To a solution of 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-3-prop-2-ynyl-benzimidazole-5-carbonitrile (70 mg, 158.55 μmol) in MeOH (2 mL), water (2 mL) was added KOH (71.17 mg, 1.27 mmol). The mixture was stirred at 100 °C for 18 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, taken up in water (2 mL), acidified with 2N aqueous hydrochloric acid to pH approx. 2-3, and diluted with MeOH / CH 2 Cl 2(2×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to give the product 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-3-prop-2-ynyl-benzimidazole-5-carboxylic acid (35 mg, 76.00 μmol, 47.94% yield) as a pale oil. LC / MS (ESI + ) [(M+H) + ]:460.7.

[0699] Step 8: CH at room temperature 2 Cl 2 To a solution of 2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-3-prop-2-ynyl-benzimidazole-5-carboxylic acid (35 mg, 76.00 μmol) and tert-butyl N-[(1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (16.13 mg, 76.00 μmol) in (5 mL) was added HATU (37.57 mg, 98.81 μmol) and N,N-diisopropylethylamine (29.47 mg, 228.01 μmol, 39.71 μL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was subjected to H 2 Quench with O (6 mL) and CH 2 Cl 2 (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate and evaporated to give the crude product. The crude product was purified by elution with CH 2 Cl 2Purification by flash column chromatography on silica gel using 2-20% MeOH in hexane afforded the title product tert-butyl N-[(1R,4R,7R)-2-[2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodec-2,4(12),5,7-tetraen-2-yl]-7-fluoro-3-prop-2-ynyl-benzimidazole-5-carbonyl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (25 mg, 38.18 μmol, 50.24% yield) as a pale solid. LC / MS (ESI + ) [(M+H) + ]:654.8.

[0700] Step 9: To a stirred solution of tert-butyl N-[(1R,4R,7R)-2-[2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-3-prop-2-ynyl-benzimidazole-5-carbonyl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (25.00 mg, 38.18 μmol) in MeOH (1 mL) was added 4 M HCl in dioxane (3 mL) and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was evaporated to give the crude product, which was then purified by preparative HPLC to give [(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl]-[2-[11-ethyl-9-(3-hydroxypropyl)-1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-7-fluoro-3-prop-2-ynyl-benzimidazol-5-yl]methanone (12.5 mg, 22.54 μmol, 59.03% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:554.8.

[0701] Example 102: Synthesis report of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-ethyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0702] [ka]

[0703] [ka]

[0704] Step 1: Methyl 2-(11-ethyl-1,9-diazatricyclo[6.3.1.0]dihydrochloride) in THF (2.0 mL), MeOH (1.0 mL) 4,12 To a stirred solution of 72-(11-ethyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazole-5-carboxylate (100 mg, 247.24 μmol) was added aqueous LiOH (1.0 M, 0.74 mL). The mixture was stirred at room temperature for 16 h, acidified to pH 5-6 with 3 M aqueous hydrochloric acid, and extracted with EA (20 × 3 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 72-(11-ethyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazole-5-carboxylate (100 mg, 247.24 μmol). 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (90 mg, 230.51 μmol, 93.23% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:390.8.

[0705] Step 2: 2-(11-ethyl-1,9-diazatricyclo[6.3.1.0] 4,12To a solution of ]dodeca-2,4(12),5,7-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazole-5-carboxylic acid (90 mg, 230.51 μmol), DIPEA (89.37 mg, 691.54 μmol, 120.45 μL), HATU (131.47 mg, 345.77 μmol), tert-butyl N-[(1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (48.94 mg, 230.51 μmol) were added to the mixture and the mixture was stirred at room temperature for 2 h. LC-MS showed that the starting material was consumed and the desired mass was detected, which was diluted with EA, washed with brine and dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent in vacuum, the residue was purified by flash column chromatography on silica gel (eluted with DCM / MeOH=1:0 to 12:1) to give tert-butyl N-[(1R,4R,7R)-2-[2-(11-ethyl-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (80 mg, 136.82 μmol, 59.35% yield) was obtained as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:584.7.

[0706] Step 3: tert-Butyl N-[(1R,4R,7R)-2-[2-(11-ethyl-1,9-diazatricyclo[6.3.1.0 4,12 To a solution of ]dodeca-2,4,6,8(12)-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazole-5-carbonyl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (80 mg, 136.82 μmol) was added 4M HCl (dioxane) (2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the reaction mixture was washed with saturated Na 2 CO 3The pH was adjusted to 8 with solution, and the mixture was extracted with DCM (30 mL × 3). The organic layer was dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent in vacuum, the residue was purified by flash column chromatography on silica gel (eluted with DCM / MeOH = 1:0 to 10:1) to give [(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl]-[2-(11-ethyl-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl)-7-methoxy-1-methyl-benzimidazol-5-yl]methanone (55 mg, 113.50 μmol, 82.95% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:484.7. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.51 - 7.31 (m, 1H), 7.00 - 6.89 (m, 3H), 6.85 (t, J = 7.6 Hz, 1H), 6.36 (d, J = 7.0 Hz, 1H), 6.05 (s, 1H), 5.22 (s, 1H), 4.21 (s, 3H), 3.99 (s, 3H), 3.85 (d, J = 12.5 Hz, 1H), 3.59 - 3.48 (m, 3H), 3.23 (s, 1H), 3.08 (d, J = 11.0 Hz, 1H), 2.29 (s, 1H), 1.97 (s, 2H), 1.56 (dd, J = 12.4, 5.4 Hz, 2H), 1.51 - 1.41 (m, 1H), 1.32 (d, J = 15.4 Hz, 1H), 1.25 (dd, J = 9.6, 3.6 Hz, 2H), 0.67 - 0.56 (m, 3H).

[0707] Example 103 Preparation of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(7-fluoro-2-(1-(3-hydroxypropyl)-3-isopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0708] [ka]

[0709] [ka]

[0710] Step 1: To a solution of ethyl 7-amino-1H-indole-2-carboxylate (4 g, 19.59 mmol) and 2-bromo-3-methylbutanoic acid (3.55 g, 19.59 mmol) in DMF (60 mL) at room temperature, DIPEA (7.59 g, 58.76 mmol, 10.23 mL) and HATU (11.17 g, 29.38 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. LC-MS showed that the starting material was consumed and the desired mass was detected, the reaction mixture was diluted with EA, washed with brine and dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent in vacuum, the residue was purified by flash column chromatography on silica gel (eluted with PE / EA=1:0 to 5:1) to give ethyl 7-(2-bromo-3-methylbutanamido)-1H-indole-2-carboxylate (5.1 g, 13.89 mmol, 70.90% yield) as a pale solid. LC / MS (ESI + ) [(M+H) + ]:367.8.

[0711] Step 2: To a solution of ethyl 7-[(2-bromo-3-methyl-butanoyl)amino]-1H-indole-2-carboxylate (5.1 g, 13.89 mmol) in DMSO (50 mL) was added cesium carbonate (13.57 g, 41.66 mmol) at room temperature. The reaction mixture was stirred at 106° C. for 2 h, cooled to room temperature, and washed with ice H 2 The mixture was quenched with 20 mL of HO (20 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (50 mL x 4), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (PE / EA=1 / 0 to 2 / 1) to give ethyl 3-isopropyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-5-carboxylate (3.1 g, 10.83 mmol, 77.96% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:286.8.

[0712] Step 3: Ethyl 11-isopropyl-10-oxo-1,9-diazatricyclo[6.3.1.0] in THF (20 mL) 4,12 To a solution of 1.0 g of 1,2,4,6,8(12)-dodeca-2,4,6,8(12)-tetraene-2-carboxylate (3.49 mmol) was added lithium aluminum hydride (473.9 mg, 13.97 mmol) in a batch over 10 min at 0° C. After 10 min, the bath was removed and the solution was stirred at room temperature for 16 h. The reaction mixture was quenched with ice (0.5 g) and diluted with 0.5 mL of 15% saturated NaOH and 1.0 mL of H 2 O was added at 0° C. The solution was stirred at room temperature for 15 min and poured into a mixture of ethyl acetate (100 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent in vacuum, the residue was purified by flash column chromatography on silica gel (PE / EA=1 / 0 to 1 / 1) to give (11-isopropyl-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl)methanol was obtained as a white solid. LC / MS (ESI+ )[(M+H) + ]:230.8.

[0713] Step 4: (11-isopropyl-1,9-diazatricyclo[6.3.1.0 4,12 To a solution of 5-(hydroxymethyl)-3-isopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-1-carboxylate (320 mg, 968.46 μmol, 74.35% yield) was added di-tert-butyl dicarbonate (568.6 mg, 2.61 mmol, 597.89 μL). The mixture was stirred at 95 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with EA, washed with brine, and dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent in vacuum, the residue was purified by flash column chromatography on silica gel (eluted with PE / EA = 1:0 to 5:1) to give tert-butyl 5-(hydroxymethyl)-3-isopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-1-carboxylate (320 mg, 968.46 μmol, 74.35% yield) as a brown solid. LC / MS (ESI + ) [(M+H) + ]:330.8.

[0714] Step 5: CHCl 3 tert-Butyl 2-(hydroxymethyl)-11-isopropyl-1,9-diazatricyclo[6.3.1.0 4,12 A mixture of tert-butyl 2-formyl-11-isopropyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4,6,8(12)-tetraene-9-carboxylate (320 mg, 968.46 μmol) and manganese dioxide (344.6 mg, 3.87 mmol) was stirred at 66° C. for 16 hours, cooled to room temperature, and filtered. The filtrate was concentrated in vacuo to give tert-butyl 2-formyl-11-isopropyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4,6,8(12)-tetraene-9-carboxylate (320 mg, 968.46 μmol) and manganese dioxide (344.6 mg, 3.87 mmol). 4,12 ] dodeca-2,4,6,8(12)-tetraene-9-carboxylate (310 mg, 943.96 μmol, 97.47% yield). + ) [(M+H) + ]:328.8.

[0715] Step 6: EtOH (10 mL) and H 2 tert-Butyl 2-formyl-11-isopropyl-1,9-diazatricyclo[6.3.1.0 4,12 A mixture of ]dodeca-2,4,6,8(12)-tetraene-9-carboxylate (310 mg, 943.96 μmol), methyl 3-fluoro-4-(methylamino)-5-nitrobenzoate (236.93 mg, 1.04 mmol) and sodium dithionite (986.11 mg, 5.66 mmol) was stirred at 96° C. for 16 hours, cooled to room temperature and concentrated in vacuo. The residue was extracted with DCM (10 mL×3) and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluted with PE / EA=1:0 to 10:1) to give tert-butyl 5-(7-fluoro-5-(methoxycarbonyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-3-isopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-1-carboxylate (300 mg, 592.22 μmol, 62.74% yield) as a white solid. LC / MS (ESI + ) [(M+H) + ]:506.8.

[0716] Step 7: tert-Butyl 2-(7-fluoro-5-methoxycarbonyl-1-methyl-benzimidazol-2-yl)-11-isopropyl-1,9-diazatricyclo[6.3.1.0] in MeOH (3 mL) 4,12 To a solution of ]dodeca-2,4,6,8(12)-tetraene-9-carboxylate (300 mg, 592.22 μmol) was added 4M HCl (dioxane) (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the reaction mixture was washed with saturated Na 2 CO 3The pH was adjusted to 8 with solution. The mixture was extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent in vacuum, the residue was purified by silica gel flash column chromatography (eluted with DCM / MeOH = 1:0 to 20:1) to give 7-fluoro-2-(11-isopropyl-1,9-diazatricyclo[6.3.1.0]. 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl)-1-methyl-benzimidazole-5-carboxylate (220 mg, 541.27 μmol, 91.40% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:406.8.

[0717] Step 8: Methyl 7-fluoro-2-(11-isopropyl-1,9-diazatricyclo[6.3.1.0]phenyl)acetate in anhydrous ACN (3 mL) 4,12 To a solution of ]dodeca-2,4,6,8(12)-tetraen-2-yl)-1-methyl-benzimidazole-5-carboxylate (100 mg, 246.03 μmol), DIPEA (159.0 mg, 1.23 mmol, 214.27 μL) and 3-bromopropan-1-ol (171.0 mg, 1.23 mmol, 107.54 μL) were added at room temperature. The reaction mixture was heated at 130° C. for 14 h in a microwave, cooled to room temperature, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluted with DCM / MeOH=1:0 to 20:1) to give methyl 7-fluoro-2-(1-(3-hydroxypropyl)-3-isopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylate (25 mg, 53.82 μmol, 21.87% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:464.8.

[0718] Step 9: Methyl 7-fluoro-2-[9-(3-hydroxypropyl)-11-isopropyl-1,9-diazatricyclo[6.3.1.0] in THF (1.00 mL), MeOH (0.5 mL) 4,12 To a stirred solution of 7-fluoro-2-[9-(3-hydroxypropyl)-11-isopropyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4,6,8(12)-tetraen-2-yl]-1-methyl-benzimidazole-5-carboxylate (25 mg, 53.82 μmol) was added aqueous LiOH (1.0 M, 0.5 mL). The mixture was stirred at room temperature for 2 h, acidified to pH 5-6 with 3 M aqueous hydrochloric acid, and extracted with EA (20 × 3 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 7-fluoro-2-[9-(3-hydroxypropyl)-11-isopropyl-1,9-diazatricyclo[6.3.1.0]dodeca-2,4,6,8(12)-tetraen-2-yl]-1-methyl-benzimidazole-5-carboxylate (25 mg, 53.82 μmol). 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl]-1-methyl-benzimidazole-5-carboxylic acid (20 mg, 44.39 μmol, 82.49% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:450.8.

[0719] Step 10: 7-Fluoro-2-[9-(3-hydroxypropyl)-11-isopropyl-1,9-diazatricyclo[6.3.1.0] in DMF (2 mL) 4,12To a solution of ]dodeca-2,4,6,8(12)-tetraen-2-yl]-1-methyl-benzimidazole-5-carboxylic acid (20 mg, 44.39 μmol), DIPEA (17.21 mg, 133.18 μmol, 23.20 μL), HATU (25.3 mg, 66.59 μmol), tert-butyl N-[(1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (PharmaBlock) (9.4 mg, 44.39 μmol) were added to the mixture and the mixture was stirred at room temperature for 2 h. LC-MS showed that the starting material was consumed and the desired mass was detected, which was diluted with EA, washed with brine and dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent in vacuum, the residue was purified by flash column chromatography on silica gel (eluted with DCM / MeOH=1:0 to 15:1) to give tert-butyl ((1R,4R,7R)-2-(7-fluoro-2-(1-(3-hydroxypropyl)-3-isopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate (15 mg, 23.26 μmol, 52.40% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:644.8.

[0720] Step 11: To a solution of tert-butyl ((1R,4R,7R)-2-(7-fluoro-2-(1-(3-hydroxypropyl)-3-isopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate (15 mg, 23.26 μmol) in MeOH (2 mL) was added 4M HCl (dioxane) (2 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the reaction mixture was diluted with saturated Na 2 CO 3The pH was adjusted to 8 with solution, and the mixture was extracted with DCM (30 mL × 3). The organic layer was dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent in vacuum, the residue was purified by flash column chromatography on silica gel (eluted with DCM / MeOH = 1:0 to 10:1) to give [(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl]-[7-fluoro-2-[9-(3-hydroxypropyl)-11-isopropyl-1,9-diazatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl]-1-methyl-benzimidazol-5-yl]methanone (8.6 mg, 15.79 μmol, 67.87% yield) was obtained as a white solid. LC / MS (ESI + ) [(M+H) + ]:544.8.

[0721] Example 104 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(7-fluoro-2-(3-isopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0722] [ka]

[0723] Prepared in a similar manner to Example 103. LC / MS (ESI + ) [(M+H) + ]:486.7. 1 H NMR (400 MHz, DMSO-d 6) δ 7.66 (dd, J= 45.7, 4.3 Hz, 1H), 7.24 (dd, J = 30.3, 12.0 Hz, 1H), 6.99 (s, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.39 (d, J = 7.1 Hz, 1H), 6.07 (s, 1H), 5.10 (d, J = 7.1 Hz, 1H), 4.17 (s, 3H), 3.72 (dd, J = 27.9, 12.4 Hz, 2H), 3.51 (dd, J = 12.0, 3.0 Hz, 2H), 3.23 (s, 2H), 3.11 - 3.04 (m, 1H), 2.21 (d, J = 24.7 Hz, 1H), 2.03 - 1.82 (m, 3H), 1.75 (d, J = 8.4 Hz, 1H), 1.42 (dd, J = 29.7, 19.9 Hz, 1H), 1.28 - 1.21 (m, 1H), 0.78 (d, J = 6.7 Hz, 3H), 0.43 - 0.34 (m, 3H).

[0724] Example 105 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(7-fluoro-2-((R)-3-isopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone and Example 106 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(7-fluoro-2-((S)-3-isopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0725] [ka]

[0726] ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(7-fluoro-2-(3-isopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (302 mg, 0.62 mmol) was subjected to chiral separation by SFC using a mobile phase (CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 60 / 40) (AD 20 x 250 mm, 10 um (Daicel) (flow rate: 100 g / min)) to give Synthesis Example 105 (80 mg, 16.4%) as an off-white solid (LCMS (ESI + ) [(M+H) + ]:486.7, H NMR (400 MHz, DMSO-d 6 ) δ 7.61 (s, 1H), 7.35 - 7.17 (m, 1H), 6.99 (d, J=2.9 Hz, 1H), 6.93 (d, J =8.0 Hz, 1H), 6.87 (t, J=7.6 Hz, 1H), 6.38 (d, J=7.1 Hz, 1H), 6.09 (d, J=3.1 Hz, 1H), 5.10 (d, J=8.1Hz, 1H), 4.16 (d, J=3.2 Hz, 3H), 3.72 (d, J=15.5 Hz, 1H), 3.69 - 3.59 (m, 1H), 3.54 - 3.48 (m, 2H),3.19 (s, 1H), 3.06 (t, J=9.4 Hz, 1H), 2.20 (d, J=3.9 Hz, 1H), 2.04 - 1.82 (m, 4H), 1.76 - 1.65 (m, 1H),1.46 - 1.33 (m, 1H), 1.26 - 1.21 (m, 1H), 0.78 (d, J=6.6 Hz, 3H), 0.38 (dd, J=7.0, 4.1 Hz, 3H), and Example 106 (100 mg, 20.5%) was obtained as an off-white solid (LCMS (ESI + ) [(M+H) + ]:486.7, 1 H NMR (400 MHz, DMSO-d 6) δ 7.38 (s, 1H), 7.10 - 6.96 (m, 1H), 6.78 (s, 1H), 6.72 (d, J = 7.9 Hz, 1H),6.66 (t, J = 7.6 Hz, 1H), 6.17 (d, J = 7.1 Hz, 1H), 5.88 (d, J = 3.1 Hz, 1H), 4.92 - 4.85 (m, 1H), 3.95 (d, J= 3.0 Hz, 3H), 3.51 - 3.41 (m, 2H), 3.34 - 3.25 (m, 2H), 2.97 (s, 1H), 2.89 - 2.76 (m, 1H), 1.99 (s, 1H),1.79 - 1.63 (m, 3H), 1.56 - 1.49 (m, 1H), 1.26 - 1.14 (m, 1H), 1.02 (d, J = 3.4 Hz, 1H), 0.57 (dd, J = 6.8,2.0 Hz, 3H), 0.17 (d, J = 7.2 Hz, 3H).

[0727] Based on the co-crystallization results of Example 71, Example 106, which is more potent than Example 105 in the PAD4 biochemical assay, is believed to have the S configuration.

[0728] Example 107 Preparation of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(7-fluoro-2-(3-isopropyl-1-methyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0729] [ka]

[0730] Prepared in a similar manner to Example 103. LC / MS (ESI + ) [(M+H) + ]:500.8.

[0731] Example 108 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(3-cyclopropyl-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-5-yl)-7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

[0732] [ka]

[0733] [ka]

[0734] Step 1: A mixture of methyl 2-bromo-2-cyclopropyl-acetate (2.0 g, 10.36 mmol), benzene-1,2-diamine (1.34 g, 12.43 mmol, 1.31 mL), and TEA (2.10 g, 20.72 mmol, 2.89 mL) was dissolved in DMF (20 mL). The resulting mixture was stirred at 80 °C for 15 h. The crude material was purified by flash column chromatography on silica gel (0-100% H 2 O / CH 3 The product was purified by LC / MS (eluted with CN) to give 3-cyclopropyl-3,4-dihydro-1H-quinoxalin-2-one (1.5 g, 7.97 mmol, 76.92% yield) as a white solid. + ) [(M+H) + ]:188.8.

[0735] Step 2: A mixture of 3-cyclopropyl-3,4-dihydro-1H-quinoxalin-2-one (1.5 g, 7.97 mmol) and sodium nitrite (659.8 mg, 9.56 mmol, 304.36 μL) was dissolved in CH 3COOH (8 mL). The resulting mixture was stirred at room temperature for 30 min. Filtration afforded 3-cyclopropyl-4-nitroso-1,3-dihydroquinoxalin-2-one (1.2 g, 5.52 mmol, 69.32% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:217.8.

[0736] Step 3: A mixture of 3-cyclopropyl-4-nitroso-1,3-dihydroquinoxalin-2-one (1.2 g, 5.52 mmol), ammonium hydrochloride (2.07 g, 38.67 mmol) and zinc (1.81 g, 27.62 mmol, 252.96 μL) was dissolved in THF:H 2 The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EA / PE) to give 4-amino-3-cyclopropyl-1,3-dihydroquinoxalin-2-one (800.0 mg, 3.94 mmol, 71.25% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:203.8.

[0737] Step 4: A mixture of 4-amino-3-cyclopropyl-1,3-dihydroquinoxalin-2-one (800 mg, 3.94 mmol), methyl 2-oxopropanoate (602.8 mg, 5.90 mmol, 533.42 μL) was dissolved in ethanol (8 mL). The resulting mixture was stirred at room temperature for 3 h and then concentrated in vacuo to give methyl (2E)-2-[(2-cyclopropyl-3-oxo-2,4-dihydroquinoxalin-1-yl)imino]propanoate (1.0 g, 3.48 mmol, 88.42% yield) as a yellow solid. LC / MS (ESI + ) [(M+H) + ]:287.8

[0738] Step 5: A mixture of methyl (2E)-2-[(2-cyclopropyl-3-oxo-2,4-dihyd...

Claims

1. Formula (I0): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein 【Chemistry 2】 is a single or double bond, provided that 【Transformation 3】 is aromatic, R １ teeth, 【Chemistry 4】 is selected from the group consisting of During the ceremony, X is O or S; Ring A is a 4- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl; Ring B is a 3- to 6-membered monocyclic carbocyclyl or a 3- to 6-membered monocyclic heterocyclyl; R ２ is deuterium, halogen, CN, C １～６ Alkyl, C １～６ Alkoxyl, or -NR ａ R ｂ and X １ is N or C, X ２ is N, X ３ is -N(R ３ ) - or -C(R ３ ) = X ４ is N or C, X ５ is N or CH, wherein R ３ is C １～６ Alkyl, C １～６ Alkoxyl, C ２～６ Alkenyl, C ２～６ Alkynyl, —NR ａ R ｂ , -CH ２ -3 to 8-membered cycloalkyl, -CH ２ -3 to 8-membered heterocyclyl, -CH ２ -6 to 10-membered aryl, or -CH ２ - 5 to 10 membered heteroaryl, R ３ or R ３ The C in the group represented by １～６ Alkyl, C １～６ Alkoxyl, C ２～６ Alkenyl, C ２～６ The alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may optionally be selected from the group consisting of halogen, oxo, hydroxyl, C １～６ Alkyl, haloC １～６ Alkyl, hydroxyl C １～６ Alkyl, methoxyl C １～６ Alkyl, C １～６ Alkoxyl, HaloC １～６ Alkoxyl, Hydroxyl C １～６ Alkoxyl, Methoxyl C １～６ Alkoxyl, and -NR ａ R ｂ and is substituted with one or more groups selected from Ring T is 【Transformation 5】 is a tricyclic ring selected from the group consisting of During the ceremony, Z is —O— or —S—; W is -(CH ２ ) ｏ -, -CH(R ｗ )-, -C(=O)-, or -CH ２ -C(=O)-, where o is 1 or 2, and R ｗ is C １～６ is alkyl, V is -N(R ６ )- or -C(=O)-; R ４ is hydrogen, deuterium, a halogen, or CN; R ５ is hydrogen, C １～６ Alkyl, haloC １～６ Alkyl, hydroxyl C １～６ alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R ５ The 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl represented by the formula (I) may optionally be selected from halogen, oxo, hydroxyl, C １～６ Alkyl, haloC １～６ Alkyl, hydroxyl C １～６ Alkyl, methoxyl C １～６ Alkyl, C １～６ Alkoxyl, HaloC １～６ Alkoxyl, Hydroxyl C １～６ Alkoxyl, Methoxyl C １～６ Alkoxyl, and -NR ａ R ｂ and is substituted with one or more groups selected from R ６ is hydrogen, C １～６ Alkyl, C １～６ Alkylene Hydroxyl, C １～６ Alkyleneamine, Benzoyl, Carbonyl C １～６ Alkyl, carbonyl C １～６ Alkylene Hydroxyl, C １～６ Alkylene amides, C １～６ Alkylene carbamates, C １～６ Alkylene urea, 3-8 membered cycloalkyl, —CH ２ -6 to 10-membered aryl, or -CH ２ - 5 to 10 membered heteroaryl, R ６ The C represented by １～６ Alkyl, C １～６ Alkylene Hydroxyl, C １～６ Alkyleneamine, Benzoyl, Carbonyl C １～６ Alkyl, carbonyl C １～６ Alkylene Hydroxyl, C １～６ Alkylene amides, C １～６ Alkylene carbamates, C １～６ Alkylene urea, 3-8 membered cycloalkyl, —CH ２ -6 to 10-membered aryl, or -CH ２ - 5 to 10 membered heteroaryl is optionally selected from halogen, hydroxyl, amino, CN, C １～６ Alkyl, C １～６ Alkylcarbonyl, C １～６ Alkylene Hydroxyl, C １～６ substituted with one or more groups selected from alkylcarbonylamino, and 3- to 8-membered cycloalkyl; R ７ is deuterium, halogen, cyano, C １～６ Alkyl, C １～６ Alkoxy, C ２～６ Alkenyl, C ２～６ Alkynyl, —NR ａ R ｂ , -S(=O) ２ C １～６ alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R ７ The C represented by １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkenyl, C １～６ the alkynyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more groups selected from halogen and hydroxyl; Y １ is C or N, and Y １ If is C, then 【Transformation 6】 is a double bond, and Y １ If is N, then 【Transformation 7】 is a single bond, Y ２ is -O-, -S-, -S(=O)-, -N(R ｄ )-, -C(=O)-, -C(R ｄ ) ２ -, or -C(R ｅ ) = Y ３ is -CH ２ -, -CH ２ -CH ２ -, -HC=, -NH-, -N=, -C(=O)-, or -N(R ｆ )-CH ２ - and Y ４ is -NH-, -CH ２ - or -N=, wherein R ｄ is hydrogen or C １～６ is alkyl, R ｅ is hydrogen, halogen, or C １～６ is alkyl, R ｆ is hydrogen, C １～６ Alkyl, —C(═O)C １～６ alkyl, or 3- to 6-membered cycloalkyl; R １１ is -CH ２ - 3 to 8 membered cycloalkyl; R ８ is halogen, CN, C １～６ Alkyl, haloC １～６ Alkyl, C １～６ Alkoxy, —NR ａ R ｂ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)OR ｂ , -NR ａ C(=O)NR ｂ , -NR ａ SO ２ R ｂ , -NR ａ S(=O)(=NR ｂ ) R ｃ , 3- to 8-membered carbocyclyl, or 3- to 8-membered heterocyclyl, or two R ８ groups, together with the atoms to which they are attached, form a 3- to 8-membered carbocyclyl or a 3- to 8-membered heterocyclyl; R ９ and R １０ are independently hydrogen, deuterium, halogen, C １～６ alkyl, １～６ The alkyl is optionally substituted with one or more groups selected from halogen, hydroxyl, and methoxyl; R ａ , R ｂ , and R ｃ are each independently hydrogen, deuterium, or C １～６ selected from the group consisting of alkyl, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; m and n are independently 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, or 6; A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein said heterocyclyl contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and said heteroaryl contains 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur.

2. The compound has the formula (I): 【Transformation 8】 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: W is -(CH ２ ) ｏ -, -C(=O)-, or -CH ２ -C(=O)-, where o is 1 or 2; R ７ is deuterium, halogen, cyano, C １～６ Alkyl, C １～６ Alkoxy, C ２～６ Alkenyl, C ２～６ Alkynyl, —NR ａ R ｂ , 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R ７ The C represented by １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkenyl, C １～６ The alkynyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more groups selected from halogen and hydroxyl; 2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

3. R １ but, 【Chemistry 9】 is; or R １ but, 【Chemistry 10】 and Ring B is a 3-4 membered monocyclic heterocyclyl, preferably Ring B is oxetanyl; or R １ but, 【Chemistry 11】 and R ９ and R １０ are independently hydrogen, halo, or haloC １～６ is alkyl; 3. The compound of claim 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

4. W is -CH ２ - and / or R ４ The compound of claim 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein is hydrogen.

5. Ring A is a 4- to 6-membered monocyclic heterocyclyl, a 6- to 9-membered fused heterocyclyl, a 6- to 9-membered bridged heterocyclyl, or a 6- to 9-membered spiroheterocyclyl; and / or R ８ But halogen, C １～６ Alkyl, haloC １～６ Alkyl, —NR ａ R ｂ , -NR ａ (C=O)R ｂ , or -NR ａ C(=O)OR ｂ and p is 0, 1, 2, or 3; and / or R ２ But halogen, CN, C １～６ Alkyl, or C １～６ alkoxyl, and m is 0, 1, or 2; and / or R ３ But C １～４ Alkyl, C １～４ Alkoxyl, C ２～４ Alkynyl, —CH ２ -3 to 5-membered cycloalkyl, -CH ２ -3 to 5-membered heterocyclyl, -CH ２ -phenyl, or -CH ２ - 5- to 6-membered heteroaryl, R ３ or R ３ The C in the group represented by １～４ Alkyl, C １～４ Alkoxyl, C １～４ The alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl may optionally be selected from the group consisting of halogen, C １～４ Alkyl, hydroxyl, and C １～４ substituted with 1 to 3 groups selected from alkoxyl; and / or R ５ But hydrogen, C １～４ alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R ５ The 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl represented by the formula (I) may optionally be selected from halogen, hydroxyl, C １～４ Alkyl, haloC １～４ Alkyl, hydroxyl C １～４ Alkyl, methoxyl C １～６ Alkyl, C １～６ Alkoxyl, HaloC １～６ Alkoxyl, Hydroxyl C １～６ Alkoxyl, Methoxyl C １～６ Alkoxyl, and -NR ａ R ｂ and / or is substituted with 1 to 3 groups selected from R ６ But hydrogen, C １～４ Alkyl, C １～４ Alkylene Hydroxyl, C １～４ Alkyleneamine, Benzoyl, Carbonyl C １～４ Alkyl, carbonyl C １～４ Alkylene Hydroxyl, C １～４ Alkylene amides, C １～４ Alkylene carbamates, C １～４ Alkylene urea, 3-6 membered cycloalkyl, —CH ２ -6-membered aryl, or -CH ２ - 5 to 8 membered heteroaryl, R ６ The C represented by １～４ Alkyl, C １～４ Alkylene Hydroxyl, C １～４ Alkyleneamine, Benzoyl, Carbonyl C １～４ Alkyl, carbonyl C １～４ Alkylene Hydroxyl, C １～４ Alkylene amides, C １～４ Alkylene carbamates, C １～４ Alkylene urea, 3-6 membered cycloalkyl, —CH ２ -6-membered aryl, or -CH ２ 5- to 8-membered heteroaryl is optionally selected from halogen, hydroxyl, amino, CN, C １～４ Alkyl, C １～５ Alkylcarbonyl, C １～４ Alkylene Hydroxyl, C １～４ substituted with one or more groups selected from alkylcarbonylamino, and 3- to 6-membered cycloalkyl; and / or R ７ But halogen, cyano, C １～４ alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 7-membered heteroaryl; R ７ The C represented by １～４ The alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 7-membered heteroaryl is optionally substituted with one or more halogens, and n is 0 or 1; 5. The compound of claim 4, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

6. Ring A is 【Chemistry 12】 is selected from the group consisting of R ８ But halogen, NH ２ , or C １～３ alkyl, and p is 0, 1, or 2; R ２ is -F or -OCH ３ and m is 1; R ３ But C １～２ Alkyl, C ２～３ Alkynyl, —CH ２ -3 to 4-membered cycloalkyl, -CH ２ -3- to 4-membered heterocyclyl, -CH ２ -phenyl, or -CH ２ -5-membered heteroaryl, R ３ or R ３ The C in the group represented by １～２ Alkyl, C ２～３ The alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl may optionally be selected from the group consisting of halogen, C １～２ Alkyl, and C １～２ substituted with 1 to 3 groups selected from alkoxyl; R ５ But hydrogen, C １～３ alkyl, or 3- to 4-membered cycloalkyl; R ６ But hydrogen, C １～３ Alkyl, C １～３ Alkylene Hydroxyl, C １～３ Alkyleneamine, Benzoyl, Carbonyl C １～３ Alkyl, carbonyl C １～３ Alkylene Hydroxyl, C １～３ Alkylene amides, C １～３ Alkylene carbamates, C １～３ Alkylene urea, 3-5 membered cycloalkyl, —CH ２ -6-membered aryl, or -CH ２ -5-membered heteroaryl, R ６ The hydrogen represented by １～３ Alkyl, C １～３ Alkylene Hydroxyl, C １～３ Alkyleneamine, Benzoyl, Carbonyl C １～３ Alkyl, carbonyl C １～３ Alkylene Hydroxyl, C １～３ Alkylene amides, C １～３ Alkylene carbamates, C １～３ Alkylene urea, 3-5 membered cycloalkyl, —CH ２ -6-membered aryl, or -CH ２ 5-membered heteroaryl is optionally fluoro, hydroxyl, amino, CN, C １～３ Alkyl, C １～５ Alkylcarbonyl, C １～３ Alkylene Hydroxyl, C １～３ substituted with 1 to 3 groups selected from alkylcarbonylamino and 3- to 4-membered cycloalkyl; n is 0; 5. The compound of claim 4, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

7. R ３ but, 【Chemistry 13】 and / or R ６ but, 【Chemistry 14】 selected from the group consisting of:

6. The compound of claim 5, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

8. The compound is represented by formula (II) 【Chemistry 15】 The compound according to claim 6, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:

9. R １ but, 【Chemistry 16】 9. The compound of claim 8, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

10. R ａ , R ｂ , and R ｃ are each independently hydrogen or C １～６ 8. The compound of claim 7, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R is alkyl. 【Request Item 11】 【Chemistry 17】 but, [Chemistry 18] wherein the definition of each variable is as defined in claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

12. Ring T is represented by formula (T1) or (T3) 【Chemistry 19】 and the definitions of the remaining variables are as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

13. The compound has the formula (III) 【Chemistry 20】 wherein: Ring A is 【Chemistry 21】 is selected from the group consisting of R ２ is halogen, CN, C １～６ Alkyl, or C １～６ is alkoxyl, R ３ is C １～６ Alkyl, C ２～６ Alkynyl, —CH ２ -3 to 5-membered cycloalkyl, -CH ２ -3 to 5-membered heterocyclyl, -CH ２ -phenyl, or -CH ２ -5-membered heteroaryl, R ３ or R ３ The C in the group represented by １～６ Alkyl, C ２～６ The alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl may optionally be selected from the group consisting of halogen and C １～６ substituted with 1 to 3 groups selected from alkyl; R ５ is hydrogen, C １～３ alkyl, or 3- to 4-membered cycloalkyl; R ６ is hydrogen or C １～６ alkyl, and R ６ The C represented by １～６ The alkyl may optionally be selected from halogen, hydroxyl, and C １～６ substituted with 1 to 3 groups selected from alkoxy; R ７ is halogen, cyano, C １～６ Alkyl, haloC １～６ Alkyl, or -S(=O) ２ C １～３ is alkyl, R ８ is a halogen or NH ２ and p is 0, 1, or 2; 2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein n is 0 or 1.

14. The compound has the formula (IIIA) 【Chemistry 22】 wherein: R ２ is halogen, CN, C １～６ Alkyl, or C １～６ is alkoxyl, R ３ is C １～４ is alkyl, R ５ is hydrogen, C １～３ alkyl, or 3- to 4-membered cycloalkyl; R ６ is hydrogen or C １～６ alkyl, and R ６ The C represented by １～６ the alkyl is optionally substituted with 1 to 3 groups selected from halogen, hydroxyl, and methoxy; R ７ is halogen, cyano, C １～６ Alkyl, haloC １～６ Alkyl, or -S(=O) ２ C １～３ is alkyl, 2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein n is 0 or 1.

15. Ring T is represented by formula (T2) or (T4) 【Chemistry 23】 The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

16. The compound has the formula (IV) 【Chemistry 24】 wherein: R １ teeth, 【Chemistry 25】 2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:

17. The compound is 【Chemistry 26-1】 【Chemistry 26-2】 【Chemistry 26-3】 【Chemistry 26-4】 【Chemistry 26-5】 【Chemistry 26-6】 【Chemistry 26-7】 【Chemistry 26-8】 【Chemistry 26-9】 【Chemistry 26-10】 A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

19. 18. A pharmaceutical composition for treating a disease or condition mediated by PAD4 activity, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

20. 20. A pharmaceutical composition for treating a subject having a disease or condition, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the disease or condition is a bacterial infection, a viral infection, a metabolic disease, an autoimmune disease, an autoinflammatory disease, cancer, or a septic condition.

21. 21. The pharmaceutical composition of claim 20, wherein the disease or condition is a pulmonary infection (e.g., COVID-19), acute lymphocytic leukemia, ankylosing spondylitis, asthma, breast cancer, lung cancer, colon cancer, pancreatic cancer, hematological cancer, neurological cancer, skin cancer, chronic lymphocytic leukemia, cutaneous lupus erythematosus, gout, inflammatory bowel disease (IBD), type 2 diabetes, obesity, type 1 diabetes mellitus (T1DM), cystic fibrosis, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, or vasculitis.

22. 21. The pharmaceutical composition of claim 20, wherein the disease or condition is cancer and the cancer has metastasized.

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