TW202434603A - Substituted bi-and tricyclic hset inhibitors - Google Patents

Abstract

The invention relates to substituted bi- and tricycles of the general formula I,

Description

Substituted bicyclic and tricyclic HSET inhibitors

The present invention relates to substituted bicyclic and tricyclic rings of the general formula I, The invention also relates to the use of the compounds of the invention for treating and/or preventing hyperproliferative diseases and disorders in mammals (especially humans), and pharmaceutical compositions containing such compounds.

DNA replication, followed by chromosome segregation, ensures accurate transmission of genetic information to daughter cells (Hall et al., 2003; Nigg, 2002; Zyss and Gergely, 2009). In most normal and malignant cells, the centrosome serves as the dominant site for the formation of the spindle pole (Meunier and Vernos, 2012). Centrosome duplication is also tightly controlled and occurs simultaneously with DNA replication, ensuring the generation of two functional centrosomes that will form the poles of the mitotic spindle (Sharp et al., 2000). Microtubule (MT) motor proteins play a central role in the assembly of functional mitotic spindles (Cai et al., 2010; Ganem and Compton, 2004). One such protein, HSET (encoded by KIFC1 in humans and Kifc5a in mice), a negative-end MT motor protein, has attracted attention in cancer due to its effects on cell division (Cai et al., 2010; Goshima et al., 2005).

In recent years, the importance of centrosomes, and specifically HSET, for the formation of bipolar spindle bodies has attracted much attention, although the precise role of HSET in this process remains a subject of debate (Mahoney et al., 2006; Tillement et al., 2009). Recent reports have linked centrosome enlargement and high HSET expression to chromosomal misordering and aneuploidy, which are hallmarks of human cancer (Marx et al., 2009). In the fly model, centrosome enlargement disrupts asymmetric cell divisions in neuroblasts and causes tumorigenesis (Basto et al., 2008), and supernumerary centrosomes are also found in most solid tumor types, forming a hallmark of aggressiveness in breast, brain, prostate, cervical, kidney, and bladder cancers (Chan, 2011). Thus, it is increasingly clear that supernumerary centrosomes not only indicate malignancy, but can also drive malignant transformation (Ogden et al., 2013). However, not all cells with enlarged centrosomes undergo multipolar mitosis, and a key mechanism by which cells with extra centrosomes achieve pseudobipolar spindle formation is centrosome clustering (Basto et al., 2008; Ganem et al., 2009).

Although centrosome clustering prevents multipolar mitosis and cell death, it prolongs mitosis and increases the frequency of chromosomal errors as a result of centromeric attachment of the centromeres (Ganem et al., 2009; Kwon et al., 2008; Yang et al., 2008). Based on previous studies, centrosome clustering may prove to be the Achilles' heel of cancer cells with supernumerary centrosomes (Basto et al., 2008), and increasing evidence suggests that inhibition of centrosome clustering may provide a novel therapeutic strategy for tumors with a high incidence of centrosome enlargement (Jordan and Wilson, 2004; Ogden et al., 2012).

The key protein known to be decisive for centrosome clustering is HSET (Ncd on file). HSET is required for clustering of supernumerary centrosomes in tumor cells (Basto et al., 2008; Kwon et al., 2008). HSET is a member of the kinesin 14 family of MT motor proteins, which are mechanolytic enzymes that promote movement along MTs within the cell (Mountain et al., 1999) and which transport organelles, protein complexes and mRNA along tubulin in an ATP-dependent manner. HSET is a minus-end directed motor kinesin that crosslinks and slides tubulin, exerting an inward force (Walczak et al., 1997; Cai et al., 2009; Rath et al., 2012). Although the precise role of HSET in cell division is unclear, previous evidence suggests that it is essential for the survival of cancer cells, but not normal cells (Ganem et al., 2009; Kwon et al., 2008). High HSET expression levels are strongly associated with metastasis of non-small cell lung cancer to the brain, pointing to a link between HSET, centrosome enlargement, and tumorigenesis (Cai et al., 2010; Gordon et al., 2001; Grinberg-Rashi et al., 2009). Knockdown of HSET in normal retinal pigment epidermis 1 (RPE-1) cells or the breast cancer cell line MCF-7 (which do not have a high incidence of centrosome enlargement) does not inhibit bipolar hammer body formation, and the cells undergo normal division (Kleylein-Sohn et al., 2012; Kwon et al., 2008). In contrast, knockdown of HSET in breast cancer and neuroblastoma cell lines MDA-MB-231 and N1E-115, which contain supernumerary centrosomes, each prevents centrosome clustering and induces cell death by the late multipolar stage (Kwon et al., 2008). Therefore, the above findings point to HSET as an interesting target in cancer treatment (Basto et al., 2008; Kraljevic Pavelic et al., 2011; Krämer et al., 2011; Kwon et al., 2008).

Many studies have shown that HSET depletion increases the frequency of cell death and multipolarity in cells with supernumerary centrosomes, but not in cells with a normal number of centrosomes. For example, HSET depletion induces centrosome multipolarity and selectively sensitizes centrosome-enlarged ER- breast cancer cell lines, including triple-negative breast cancer (TNBC), to cell death (Patel et al., 2018). Depletion of HSET has been identified as selective cytotoxic in cancer cells that induce centrosome enlargement (Drosopoulos et al., 2014). Furthermore, HSET overexpression is associated with poor prognosis and resistance to docetaxel in breast cancer (De et al., 2009; Li et al., 2015), observed in ovarian adenocarcinoma patients (Pawar et al., 2014), and in a variety of other cancer types (Pannu et al., 2015). Furthermore, in non-small cell lung cancer (NSCLC), HSET expression was found to be highly predictive of the presence of brain metastases in both early and advanced disease (Grinberg-Rashi et al., 2009).

A wide range of tumors, including those with centrosome enlargement, are treated with cytotoxic tubulin-targeting drugs (e.g., taxol, eribulin). Although inducing temporary remissions, these drugs often display severe side effects and the emergence of drug resistance, leading to early relapses. Recently, agents targeting the kinesin motor protein motorin (e.g., Eg5 inhibitors) have been explored for the treatment of various human tumors, which induce monopolar spindle bodies (the opposite phenotype to HSET inhibition) and target all rapidly dividing cells, including myeloid cells. Therefore, they share dose-limiting toxicity with other anti-mitotic therapies. In contrast, HSET inhibitors are expected to show reduced toxicity by selectively killing cells with enlarged centrosomes, while cells with normal centrosome numbers remain unaffected (Ganem et al., 2009; Patel et al., 2015). Together, these data provide support for the development of agents that selectively inhibit HSET to target centrosome enlarged tumors (Myers and Collins, 2016).

Examples of small molecule HSET inhibitors have been described in the literature. AZ82 is an ADP/ATP competitive inhibitor that showed selectivity against a panel of nine other kinesins, including Eg5 (Wu et al., 2013). AZ82 inhibits tubulin-stimulated HSET ATPase activity in a biochemical assay (IC ₅₀ = 0.3 μM) and induces multipolar spindle formation and mitotic catastrophe in cells with enlarged centrosomes. CW069 is an inhibitor of HSET in a biochemical assay (IC ₅₀ = 75 μM) (Watts et al., 2013). SR31527 also showed biochemical inhibition of HSET (IC ₅₀ = 6.6 μM) (Zhang et al., 2016). More information can be found in WO09155025 and WO15085088.

Therefore, there remains a need for therapies to treat and prevent hyperproliferative diseases and disorders, such as cancer. Therefore, an objective is to discover HSET inhibitors as potential therapeutic agents for the treatment of cancer diseases.

Surprisingly, it has been found that compounds according to the present invention are highly selective and potent inhibitors of HSET and therefore the compounds of the present invention may be useful in the treatment of hyperproliferative diseases and disorders, such as cancer.

The present invention relates to compounds of the general formula I, Where W represents wherein 1 to 4 H atoms may be replaced by D; R ¹ represents Hal, A or OA, R ² represents X represents CH or N, A represents H, F, OH, _NH2 or an unbranched or branched chain alkyl or cycloalkyl group having 1 to 12 C atoms, which may be substituted by ^R4 and wherein two adjacent CH- and/or _CH2- groups may form a double bond or a triple bond and wherein one or two non-adjacent CH- and/or _CH2- groups may be replaced by N-, O- and/or S-atoms and wherein 1 to 7 H atoms may be replaced by D, F or Cl, ^R3 represents H or A, ^R4 represents H or an unbranched or branched chain alkyl group having 1 to 4 C atoms, Hal represents F, Cl, Br or I and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

A preferred embodiment of the present invention is a compound according to formula I, wherein W represents And R ¹ , R ² , R ³ , R ⁴ , X and A have the meanings disclosed above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

A preferred embodiment of the present invention is a compound according to formula I, wherein W represents And R ¹ , R ² , R ³ , R ⁴ , X and A have the meanings disclosed above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

Preferred embodiments of the invention are compounds according to formula I, wherein R ¹ represents OA and W, R ² , R ³ , R ⁴ , X and A have the meanings disclosed above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

Preferred embodiments of the present invention are compounds according to formula I, wherein R ¹ represents OA, wherein A represents an unbranched or branched alkyl group, wherein 1 to 3 H atoms may be replaced by D, F or Cl and W, R ² , R ³ , R ⁴ , X and A have the meanings disclosed above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

A preferred embodiment of the present invention is a compound according to formula I, wherein R ² represents And W, R ¹ , R ³ , R ⁴ , X and A have the meanings disclosed above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

Preferred embodiments of the invention are compounds according to formula I, wherein R ³ represents 5-methyloxadiazole or 2-methyltetrazolyl and W, R ¹ , R ² , R ⁴ , X and A have the meanings disclosed above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

Preferred embodiments of the invention are compounds according to formula I, wherein R ³ represents 5-methyloxadiazole and W, R ¹ , R ² , R ⁴ , X and A have the meanings disclosed above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

Preferred embodiments of the invention are compounds according to formula I, wherein R ⁴ represents methyl and W, R ¹ , R ² , R ³ , X and A have the meanings disclosed above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

The present invention preferably relates to a compound selected from the group consisting of: 1 N-{4-ethoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 2 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-[4-(propan-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propanamide 3 N-{4-cyclobutoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 4 N-[4-(But-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 5 N-[4-(2,2-difluoroethoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 6 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-[4-(2,2,2-trifluoroethoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propanamide 7 N-[4-(3,3-difluorocyclobutoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 8 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-{4-[(1,1,1-trifluoropropan-2-yl)oxy]-[1,3]thiazolo[5,4-c]pyridin-2-yl}propanamide 9 N-{4-ethoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 10 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-propoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}propionamide 11 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[4-(propan-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propionamide 12 N-[4-(But-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 13 N-{4-cyclobutoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 14 N-[4-(3,3-difluorocyclobutoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 15 N-[4-(3-fluoropropoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 16 N-[4-(2,2-difluoropropoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 17 N-[4-(2,2-difluoroethoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 18 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[4-(2,2,2-trifluoroethoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propionamide 19 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-[(1,1,1-trifluoropropan-2-yl)oxy]-[1,3]thiazolo[5,4-c]pyridin-2-yl}propionamide 20 (1s,3s)-N-{4-methoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}cyclobutane-1-carboxamide twenty one (1s,3s)-N-{4-ethoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}cyclobutane-1-carboxamide twenty two (1s,3s)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-propoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}cyclobutane-1-carboxamide twenty three N-{1-ethoxypyrrolo[1,2-a]pyrrol-7-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide twenty four 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{1-propoxypyrrolo[1,2-a]pyrrol-7-yl}propanamide 25 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 26 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 27 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-11-yl](1,1,2,2-2H4)ethyl}benzamide 28 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-11-yl](1,1,2,2-2H4)ethyl}benzamide 29 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}(1,1,2,2-2H4)ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 30 3-(5-methyl-2H-1,2,3,4-tetrazolyl-2-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 31 11-(2-{[7-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 32 11-(2-{[7-(5-methyl-2H-1,2,3,4-tetrazolyl-2-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 33 11-(2-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 34 3-Fluoro-5-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 35 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)(12,12,13,13-2H4)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-11-yl]ethyl}benzamide 36 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)(12,12,13,13-2H4)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 37 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-6-propoxy-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 38 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-(2-{10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-11-yl}ethyl)benzamide 39 1-(Dodeca-11-yn-1-yloxy)-8-(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)-7,8-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrroline-9(6H)-one 40 N-(2-{6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.0^{2,7}]tridec-2,4,6,8-tetraen-11-yl}ethyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide 41 N-{2-[6-(3-fluoropropoxy)-10-oxo-1,5,11-triazatricyclo[7.4.0.0^{2,7}]tridec-2,4,6,8-tetraen-11-yl]ethyl}-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide 42 N-{2-[6-(2,2-difluoroethoxy)-10-oxo-1,5,11-triazatricyclo[7.4.0.0^{2,7}]tridec-2,4,6,8-tetraen-11-yl]ethyl}-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide 43 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.0^{2,7}]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 44 6-(3-Fluoropropoxy)-11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 45 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-(2-{10-oxo-6-[(1,1,2,2,3,3,3-2H7)propoxy]-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-11-yl}ethyl)benzamide 46 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-(2-{10-oxo-6-[2,2,2-trifluoro(1,1-2H2)ethoxy]-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl}ethyl)benzamide 47 N-(2-(1-(Dodeca-11-yn-1-yloxy)-9-oxo-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrrol-8(9H)-yl)ethyl)-3-(2-methyl-2H-tetrazol-5-yl)benzamide 48 11-(3-amino-2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 49 (S)-3-(2-methyl-2H-tetrazol-5-yl)-N-(6-(methylamino)-1-(9-oxo-1-(2,2,2-trifluoroethoxy)-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrrol-8(9H)-yl)hexan-2-yl)benzamide 50 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-[6-(methylamino)-1-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-11-yl]hexan-2-yl]benzamide 51 N-{6-[methyl(prop-2-yn-1-yl)amino]-1-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]hex-2-yl}-3-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)benzamide 52 11-[(2S)-6-[methyl(prop-2-yn-1-yl)amino]-2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}hexyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 53 N-{(S)-4-methylamino-1-[(7-propoxy-benzothiazol-2-ylaminomethyl)-methyl]-butyl}-3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzamide 54 (3S)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-6-(methylamino)-N-(7-propoxy-1,3-benzothiazol-2-yl)hexanamide 55 (3S)-N-(4-Fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-6-(methylamino)hexanamide 56 N-[4-Fluoro-7-(3-fluoropropoxy)-1,3-benzothiazol-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 57 N-[4-Fluoro-7-(2-fluoroethoxy)-1,3-benzothiazol-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 58 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(7-propoxy-benzothiazol-2-yl)-propionamide 59 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (7-propoxy-benzothiazol-2-yl)-amide 60 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (7-methoxy-4-methyl-benzothiazol-2-yl)-amide 61 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (7-methoxy-benzothiazol-2-yl)-amide 62 N-(4-Fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 63 N-(4-chloro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 64 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-propoxypyrazolo[1,5-a]pyridin-2-yl}propionamide 65 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(4-propoxypyrazolo[1,5-a]pyrrolidone-2-yl)-propionamide 66 N-{4-ethoxypyrazolo[1,5-a]pyrrolidone-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 67 N-[4-(3-fluoropropoxy)pyrazolo[1,5-a]pyrrolidone-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 68 N-[4-(2-Fluoroethoxy)pyrazolo[1,5-a]pyrroline-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 69 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[4-(oxacyclobutane-3-yloxy)pyrazolo[1,5-a]pyrrolidone-2-yl]propanamide 70 N-{4-cyclopropoxypyrazolo[1,5-a]pyrrolidone-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 71 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{1-methyl-4-propoxy-1H-pyrrolo[3,2-c]pyridin-2-yl}propionamide 72 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (4-methoxy-pyrazolo[1,5-a]pyridin-2-yl)-amide 73 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(4-methyl-7-propoxy-benzothiazol-2-yl)-propionamide 74 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-N-[2-(4-methyl-7-propoxy-benzothiazol-2-ylaminocarbonyl)-ethyl]-benzamide 75 3-(2-Methyl-2H-tetrazol-5-yl)-N-[2-(7-propoxy-benzothiazol-2-ylaminomethyl)-ethyl]-benzamide 76 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[7-propoxy-4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propionamide 77 (2R)-2-amino-N-(4-fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 78 (S)-2-Hydroxy-3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(7-propoxy-benzothiazol-2-yl)-propionamide 79 N-(7-ethoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 80 (2S)-N-(7-ethoxy-1,3-benzothiazol-2-yl)-2-hydroxy-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 81 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-N-[2-(7-propoxy-benzothiazol-2-ylaminomethyl)-ethyl]-benzamide 82 (2R)-N-(7-ethoxy-1,3-benzothiazol-2-yl)-2-hydroxy-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 83 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(2-{10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-11-yl}ethyl)benzamide 84 2,2-Difluoro-N-(4-fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 85 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-(1-methyl-7-propoxy-1H-1,3-benzodiazol-2-yl)propionamide 86 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-(7-propoxy-1H-1,3-benzodiazol-2-yl)propionamide 87 8-(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl-1,1,2,2-d4)-1-(2,2,2-trifluoroethoxy-1,1-d2)-7,8-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrroline-9(6H)-one-6,6,7,7-d4 88 3-(2-methyl-2H-tetrazol-5-yl)-N-(2-(9-oxo-1-(2,2,2-trifluoroethoxy-1,1-d2)-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrrol-8(9H)-yl-6,6,7,7-d4)ethyl-1,1,2,2-d4)benzamide and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

In addition, the following abbreviations have the following meanings: Boc        tert-butyloxycarbonyl CBZ       benzyloxycarbonyl DNP      2,4-dinitrophenyl FMOC    9-fluorenylmethoxycarbonyl imi-DNP 2,4-dinitrophenyl in the 1-position of the imidazole ring OMe      methyl ester POA     phenoxyacetyl DCCI     dicyclohexylcarbodiimide HOBt     1-hydroxybenzotriazole

The invention further relates to a pharmaceutical preparation comprising one or more compounds according to the invention and/or one of their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios).

The present invention also relates to a pharmaceutical formulation of this type according to the invention, comprising further excipients and/or adjuvants.

Furthermore, the present invention relates to the above pharmaceutical preparations according to the invention, which comprise at least one further pharmaceutically active compound.

Pharmaceutically or physiologically acceptable derivatives are taken to mean, for example, salts of the compounds of the invention, and also so-called prodrug compounds. Prodrug compounds are taken to mean derivatives of the compounds of the invention which have been modified, for example, by means of alkyl or acyl groups (see also amino- and hydroxyl-protecting groups below), sugars or oligopeptides and which are rapidly cleaved or released in the organism to form effective molecules. These also include biodegradable polymer derivatives of the compounds of the invention, as described, for example, in Int. J. Pharm. 115 (1995), 61-67.

The compounds of the present invention can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of the compounds of the present invention in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic bases by procedures known in the art. The pharmaceutically acceptable salt forms of the compounds of the present invention are mostly prepared by known methods. If the compounds of the present invention contain a carboxyl group, one of its suitable salts can be formed by reacting the compounds of the present invention with a suitable base to obtain the corresponding base addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkali earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, such as potassium ethoxide and sodium propoxide; and various organic bases, such as piperidine, diethanolamine and N-methylglutaramide. Aluminum salts of the compounds of the present invention are also included.

In addition, bases of the compounds of the present invention include aluminum salts, ammonium salts, calcium salts, copper salts, iron (III) salts, iron (II) salts, lithium salts, magnesium salts, manganese (III) salts, manganese (II) salts, potassium salts, sodium salts and zinc salts, but this is not intended to represent a limitation.

Among the above-mentioned salts, ammonium, alkaline metal salts of sodium and potassium, and alkaline earth metal salts of calcium and magnesium are preferred. Salts of the compounds of the present invention derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, di- and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins, for example, arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2- -dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperidine, piperidine, polyamine resins, procaine, purine, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine (tromethamine), but this is not intended to represent a limitation.

As mentioned, pharmaceutically acceptable base addition salts of the compounds of the present invention are formed using metals or amines (such as alkali metals and alkaline earth metals or organic amines). Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base addition salts of the compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to cause formation of the salt in a known manner. The free acid can be regenerated by contacting the salt form with the acid and isolating the free acid in a known manner. The free acid forms differ from their corresponding salt forms in certain aspects with respect to certain physical properties (such as solubility in polar solvents); however, for the purposes of the present invention, the salts otherwise correspond to their respective free acid forms.

In view of the above designations, it can be seen that the term "pharmaceutically acceptable salt" in the context of the present invention is intended to include an active compound of the present invention in the form of one of its salts, in particular if this salt form confers improved pharmacokinetic properties on the active compound compared to the free form of the active compound or any other salt form of the active compound used earlier. A pharmaceutically acceptable salt form of an active compound may also provide this active compound for the first time with desirable pharmacokinetic properties that it did not have earlier and may even have a positive effect on the pharmacokinetics of this active compound with respect to its efficacy in vivo.

Solvents of the compounds of the invention are taken to mean adducts of the compounds of the invention with inert solvent molecules, which adducts are formed due to their mutual attractive forces. Solvents are, for example, hydrates, such as monohydrates or dihydrates, or alcoholates, i.e. additions of the compounds with alcohols, such as, for example, methanol or ethanol.

All physiologically acceptable salts, derivatives, solvates and stereoisomers of these compounds (including mixtures thereof in all ratios) are also within the scope of the present invention.

The compounds of the present invention may contain one or more chiral centers, such that all stereoisomers, enantiomers, diastereomers, etc. of the compounds of the present invention are also embraced in the present invention.

The present invention also relates to the optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds.

The compounds of the invention according to the invention may be chiral due to their molecular structure and therefore may appear in various enantiomeric forms. Therefore, they may be in racemic or optically active form. Since the pharmaceutical effects of the racemates or stereoisomers of the compounds according to the invention may be different, it may be desirable to use the enantiomers. In such cases, not only the final products, but even the intermediates may be separated into enantiomeric compounds by chemical or physical measures known to those skilled in the art or originally employed in the synthesis.

Pharmaceutically or physiologically acceptable derivatives are taken to mean, for example, salts of the compounds according to the invention and also so-called prodrug compounds. Prodrug compounds are taken to mean compounds according to the invention which have been modified, for example, with alkyl or acyl groups (see also amino- and hydroxyl-protecting groups below), sugars or oligopeptides and which are rapidly cleaved or released in the organism to form the active compounds according to the invention. These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115 (1995), 61-67.

Suitable acid addition salts are all inorganic or organic salts of physiologically or pharmacologically acceptable acids, for example halides (in particular hydrochlorides or hydrobromides), lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methanesulfonates or p-toluenesulfonates.

Very particularly preferred are the hydrochlorides, trifluoroacetates or bistrifluoroacetates of the compounds according to the invention.

Solvents of the compounds of the invention are taken to mean adducts of inert solvent molecules to the compounds of the invention, which adducts are formed due to their mutual attractive forces. Solvents are, for example, hydrates, such as monohydrates or dihydrates, or alcoholates, i.e. additions of the compounds to alcohols, such as, for example, to methanol or ethanol.

In addition, it is intended that the compounds of the present invention include isotopically labeled forms thereof. Isotopically labeled forms of the compounds of the present invention are identical to such compounds, except that one or more atoms of the compound are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number of the atoms normally occurring in nature. Examples of isotopes that are readily available commercially and can be incorporated into the compounds of the present invention by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, ^2H , ^3H , ^13C , ^14C , ^15N , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F , and ^36Cl , respectively. Any of the compounds of the present invention, their prodrugs, or pharmaceutically acceptable salts containing one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention. Isotopically labeled compounds of the present invention can be used in a number of beneficial ways. For example, isotopically labeled compounds of the present invention that have incorporated, for example, a radioactive isotope such as ³ H or ¹⁴ C are useful in drug and/or substrate tissue distribution analysis. Such radioactive isotopes, i.e., tritium ( ³ H) and carbon-14 ( ¹⁴ C), are particularly preferred due to their ease of preparation and excellent detectability. Incorporation of heavier isotopes (e.g., deuterium ( ² H)) into the compounds of the present invention has therapeutic advantages due to the higher metabolic stability of such isotopically labeled compounds. Higher metabolic stability translates directly into increased in vivo half-life or lower dosage, which in most cases represents a preferred embodiment of the present invention. Isotopically labeled compounds of the present invention can generally be prepared by carrying out the procedures disclosed in the synthetic reaction schemes and the associated descriptions, examples and preparations herein by substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

Deuterium ( ^2H ) may also be incorporated into the compounds of the invention in order to manipulate the oxidative metabolism of the compounds via the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from the exchange of isotopic nuclei, which in turn results from a change in the ground state energy required for covalent bond formation following this isotope exchange. Exchange of heavier isotopes generally results in a decrease in the ground state energy of a chemical bond and thus in a decrease in the rate of rate-limiting bond cleavage. If bond cleavage occurs in or near a saddle point region along the coordinates of a multiproduct reaction, the product distributions may be substantially altered. For interpretation: If deuterium is bonded to a carbon atom in a non-exchangeable position, rate differences of _kM / _kD = 2 to 7 are typical. If this rate difference is successfully applied to a compound of the present invention that is susceptible to oxidation, the in vivo properties of this compound can thereby be drastically modified and lead to improved pharmacokinetic properties.

When discovering and developing therapeutic agents, one skilled in the art seeks to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In vitro liver microsomal analysis currently provides valuable information regarding this type of oxidative metabolic process, which in turn allows the rational design of the deuterated compounds of the invention to have improved stability through resistance to this oxidative metabolism. Significant improvements in the pharmacokinetic profiles of the compounds of the invention are thus achieved and can be quantitatively expressed in terms of increases in in vivo half-life (T1/2), concentration at maximum therapeutic effect ( _Cmax ), area under the dose response curve (AUC), and F; and in terms of material clearance, dose, and cost reduction.

The following is intended to illustrate the above: compounds of the present invention having multiple potential sites for attacking oxidative metabolism (e.g., benzylic hydrogen atoms and hydrogen atoms bonded to nitrogen atoms) are prepared as a series of analogs in which various combinations of hydrogen atoms are replaced by deuterium atoms, such that some, most, or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable an advantageous and accurate determination of the degree of improvement in resistance to oxidative metabolism. In this way, the half-life of the parent compound can be extended by up to 100% due to this type of deuterium-hydrogen exchange.

Replacement of hydrogen in the compounds of the invention with deuterium can also be used to achieve favorable modifications of the metabolite profile of the starting compound in order to reduce or eliminate undesirable toxic metabolites. For example, if a toxic metabolite is generated by oxidative carbon-hydrogen (C-H) bond cleavage, it is reasonable to assume that the deuterated analog will greatly reduce or eliminate the generation of the undesirable metabolite, even if the particular oxidation is not the rate limiting step. Additional information on the state of the art at the time of the patenting of deuterium-hydrogen exchange is provided, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider et al., J. Org. Chem. 52, 3326-3334, 1987; Foster, Adv. Drug Res. 14, 1-40, 1985; Gillette et al., Biochemistry 33(10), 2927-2937, 1994; and Jarman et al., Carcinogenesis 16(4), 683-688, 1993.

The present invention also relates to mixtures of the compounds according to the invention, for example mixtures of two diastereomers (for example in a ratio of 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000). These are particularly preferred mixtures of two stereoisomeric compounds. However, mixtures of two or more compounds according to the invention are also preferred.

Furthermore, the present invention relates to a method for preparing the compound of the present invention, characterized in that a) the base of the compound of the present invention is converted into one of its salts by treating it with an acid, or b) the acid of the compound of the present invention is converted into one of its salts by treating it with an alkali.

It is also possible in each case to carry out stepwise reactions and to modify the order of the coupling reactions of the building blocks by adapting the protecting group concept.

The starting materials or starting compounds are generally known. If they are novel, they can be prepared by methods known per se.

If desired, the starting substances can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds according to the invention.

The compounds of the invention are preferably obtained by solvent decomposition, in particular by hydrolysis or by hydrogenation, by releasing them from their functional derivatives. Preferred starting substances for solvent decomposition or hydrogenation are those containing correspondingly protected amino, carboxyl and/or hydroxyl groups instead of one or more free amino, carboxyl and/or hydroxyl groups, preferably those carrying amino protecting groups instead of H atoms connected to N atoms. In addition, starting substances carrying hydroxyl protecting groups instead of H atoms of hydroxyl groups are preferred. Starting substances carrying protected carboxyl groups instead of free carboxyl groups are also preferred. A plurality of identical or different protected amino, carboxyl and/or hydroxyl groups may also be present in the molecule of the starting substance. If the protecting groups present are different from one another, they can in many cases be selectively cleaved off.

The term "amine-protecting group" is generally known and refers to a group which is suitable for protecting (blocking) an amine group from chemical reactions, but which can be easily removed after the desired chemical reaction elsewhere in the molecule. In particular, typical such groups are unsubstituted or substituted acyl groups, furthermore unsubstituted or substituted aryl groups (e.g., 2,4-dinitrophenyl) or aralkyl groups (e.g., benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amine-protecting groups are removed after the desired reaction or reaction sequence, their type and size are not critical, but preferably they have 1 to 20, in particular 1 to 8, C atoms. The term "acyl group" is to be understood in the broadest sense in conjunction with the process of the invention. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkyloxycarbonyl. Examples of such acyl groups are alkyl groups such as acetyl, propionyl, butyryl; aralkylacyl groups such as phenylacetyl; arylacyl groups such as benzyl or toluyl; aryloxyalkylacyl groups such as phenoxyacetyl; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl groups such as CBZ, 4-methoxybenzyloxycarbonyl or FMOC. Preferred acyl groups are CBZ, FMOC, benzyl and acetyl.

The term "acid protecting group" or "carboxyl protecting group" is likewise generally known and refers to a group which is suitable for protecting the -COOH group from chemical reactions, but which can be easily removed after the desired chemical reaction elsewhere in the molecule. The use of esters instead of free acids, for example, substituted and unsubstituted alkyl esters (such as methyl esters, ethyl esters, tert-butyl esters and substituted derivatives thereof), substituted and unsubstituted benzyl esters or silyl esters is typical. The type and size of the acid protecting group are not critical, but are preferably those having 1 to 20, in particular 1 to 10, C atoms.

The term "hydroxyl-protecting group" is likewise generally known and refers to a group which is suitable for protecting a hydroxyl group from chemical reactions, but which can be easily removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The type and size of the hydroxyl-protecting group are not critical, but are preferably those having 1 to 20, in particular 1 to 10, C atoms. Examples of hydroxyl-protecting groups are especially benzyl, p-nitrobenzyl, p-toluenesulfonyl and acetyl, of which benzyl and acetyl are preferred.

Further typical examples of amino-, acid- and hydroxyl-protecting groups are found, for example, in "Greene's Protective Groups in Organic Synthesis", 4th edition, Wiley-Interscience, 2007.

Functional derivatives of the compounds of the present invention to be used as starting materials can be prepared by known methods of amino acid and peptide synthesis as described, for example, in the standard works and patent applications.

Depending on the protecting group used, the compounds of the invention are released from their functional derivatives, for example, with the aid of strong acids, advantageously using trifluoroacetic acid or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic acids, such as trichloroacetic acid or sulfonic acids, such as benzoylsulfonic acid or p-toluenesulfonic acid. The presence of additional inert solvents and/or catalysts is possible, but generally not necessary.

Depending on the respective synthesis route, the starting substances can optionally be reacted in the presence of an inert solvent.

Suitable inert solvents are, for example, heptane, hexane, petroleum ether, DMSO, benzene, toluene, xylene, trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether (preferably substituted on the indole nitrogen), tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether. , ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitriles such as acetonitrile; esters such as ethyl acetate; carboxylic acids or anhydrides such as, for example, acetic acid or acetic anhydride; nitro compounds such as nitromethane or nitrobenzene, and optionally mixtures of these solvents with each other or with water.

The amount of the solvent is not critical; preferably 10 g to 500 g of the solvent may be added per g of the compound of the present invention to be reacted.

It may be advantageous to add an acid binder, for example an alkali metal or alkali earth metal hydroxide, a carbonate or bicarbonate or another alkali metal salt or alkali earth metal salt of a weak acid, preferably a potassium, sodium or calcium salt, or an organic base such as, for example, triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine component.

The obtained compound according to the present invention can be separated from the corresponding solution in which it is prepared (for example, by centrifugation and washing) and can be stored in another composition after separation, or it can be directly retained in the prepared solution. The obtained compound according to the present invention can also be dissolved in a desired solvent for a specific purpose.

The duration of the reaction depends on the selected reaction conditions. Generally speaking, the reaction duration is 0.5 hours to 10 days, preferably 1 to 24 hours. When using microwaves, the reaction time can be reduced to values of 1 to 60 minutes.

Furthermore, the compounds according to the invention and also the starting materials for their preparation are prepared by known methods, as described in the literature (e.g. standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), for example under reaction conditions known and suitable for these reactions. It is also possible here to use variants known per se, which are not described in greater detail herein.

Known work-up steps (such as, for example, addition of water to the reaction mixture and extraction) allow the compound to be obtained after removal of the solvent. For further purification of the product, this may be followed by distillation or crystallization or by chromatographic purification.

The acids of the present invention can be converted to alkali addition salts using a base, for example, by reacting equal amounts of acid and base in an inert solvent (such as ethanol) and including evaporation. In particular, suitable bases for this reaction are those that give physiologically acceptable salts. Thus, the acids of the present invention can be converted to the corresponding metal salts, in particular alkali or alkaline earth metal salts or to the corresponding ammonium salts using a base (such as, for example, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate). Organic bases that give physiologically acceptable salts (such as, for example, ethanolamine) are also suitable for this reaction.

On the other hand, the bases of the invention can be converted into the associated acid addition salts using acids, for example, by reaction of equal amounts of base and acid in an inert solvent such as ethanol, followed by evaporation. In particular, suitable acids for this reaction are those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalogen acids (such as hydrochloric acid or hydrobromic acid), phosphoric acids (such as orthophosphoric acid), aminosulfonic acids, and furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polycarboxylic acids, sulfonic acids or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, apple acid, citric acid, gluconic acid, ascorbic acid, niacin, isonicotinic acid, methanesulfonic acid or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxysulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemonosulfonic acid and disulfonic acid or laurylsulfuric acid. Salts with physiologically unacceptable acids (e.g., picric salts) can be used to isolate and/or purify the compounds of the invention.

The compounds of the invention have been found to be well tolerated and to possess valuable pharmacological properties.

Therefore, the present invention furthermore relates to the use of the compounds according to the invention for the preparation of a medicament for the treatment and/or prevention of diseases caused, promoted and/or propagated by HSET.

In particular, the present invention therefore also relates to medicaments comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for the treatment and/or prevention of physiological and/or pathological conditions.

Particularly preferred are physiological and/or pathological conditions associated with HSET.

Physiological and/or pathological conditions refer to medically relevant physiological and/or pathological conditions such as, for example, diseases/illnesses and medical conditions, disorders, symptoms or complications and the like, particularly diseases.

Furthermore, the present invention relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for the treatment and/or prevention of physiological and/or pathological conditions selected from the group consisting of hyperproliferative diseases and disorders.

The invention further relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prevention of physiological and/or pathological conditions selected from the group consisting of hyperproliferative and infectious diseases and disorders, wherein the hyperproliferative disease or disorder is cancer.

Therefore, the present invention particularly preferably relates to a medicament comprising at least one compound according to the present invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios), wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute granulocytic leukemia, adrenocortical cancer, bladder cancer, brain cancer, breast cancer, cervical hyperplasia, cervical cancer, choriocarcinoma, chronic granulocytic leukemia, chronic lymphocytic leukemia, colon cancer, endometrial cancer, esophageal cancer, essential thrombocythemia, genitourinary tract cancer, neuroglioma, neuroglioblastoma, hairy cell leukemia, head and neck cancer, Hodgkin's disease disease), Kaposi's sarcoma, lung cancer, lymphoma, malignant carcinoid tumor, malignant hypercalcemia, malignant melanoma, malignant insulinoma, medullary thyroid carcinoma, melanoma, multiple myeloma, mycosis fungoides, myeloid and lymphocytic leukemia, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, polycythemia vera, primary brain cancer, essential macroglobulinemia, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, skin cancer, small cell lung cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, testicular cancer, thyroid cancer, and Wilms' tumor.

The present invention further preferably relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios) for use in the treatment and/or prevention of a physiological and/or pathological state selected from the group consisting of hyperproliferative and infectious diseases and disorders, wherein the hyperproliferative disease or disorder is selected from the group consisting of age-related macular degeneration, Crohn's disease, disease), cirrhosis, chronic inflammatory-related disorders, proliferative diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, granulomatosis, immune hyperproliferation associated with organ or tissue transplantation, and an immunoproliferative disease or disorder selected from the group consisting of inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), vascular hyperproliferation secondary to retinal hypoxia, and vasculitis.

It is intended that the above disclosed medicaments include the corresponding use of the compounds according to the present invention for the preparation of medicaments for the treatment and/or prevention of the above physiological and/or pathological conditions.

It is further intended that the above disclosed medicaments comprise corresponding methods for the treatment and/or prevention of the above physiological and/or pathological conditions, wherein at least one compound according to the present invention is administered to a patient in need of such treatment.

The compounds according to the present invention preferably exhibit favorable biological activities, which can be easily confirmed in enzyme assays and animal experiments, as described in the Examples. In these enzyme-based assays, the compounds according to the present invention preferably exhibit and cause an inhibitory effect, which is usually recorded by _IC50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.

The compounds according to the present invention can be administered to humans or animals, in particular mammals (such as apes, dogs, cats, rats or mice), and can be used in the therapeutic treatment of the human or animal body and in the alleviation of the above-mentioned diseases. In addition, they can be used as diagnostic agents or reagents.

Furthermore, the compounds according to the invention can be used for the isolation of HSET and the study of the activity or expression of HSET. Furthermore, they are particularly suitable for use in methods for the diagnosis of diseases associated with disturbed HSET activity. Therefore, furthermore, the present invention relates to the use of the compounds according to the invention for the isolation of HSET and the study of the activity or expression of HSET or as binding agents and inhibitors of HSET.

For diagnostic purposes, the compounds according to the invention may, for example, be radiolabeled. Examples of radiolabeling are ³ H, ¹⁴ C, ²³¹ I and ¹²⁵ I. A preferred labeling method is the iodine method (Fraker et al., 1978). Furthermore, the compounds according to the invention may be labeled by enzymes, fluorophores and chromophores. Examples of enzymes are alkaline phosphatases, β-galactosidase and glucose oxidase, examples of fluorophores are fluorescein, examples of chromophores are luminol, and, for example, automated detection systems for fluorescent staining are described in, for example, US 4,125,828 and US 4,207,554.

The invention further relates to pharmaceutical compositions containing the compounds of the invention and their use for the treatment and/or prevention of diseases and disorders in which partial or complete inactivation of HSET may be beneficial.

The compounds of the invention can be used to prepare pharmaceutical preparations, in particular by non-chemical methods. In this case, the compounds of the invention are combined with at least one solid, liquid and/or semi-liquid excipient or adjuvant and, if appropriate, with one or more additional active compounds to form a suitable dosage form.

Therefore, the present invention also relates to pharmaceutical preparations comprising at least one compound according to the invention and/or its physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios. In particular, the present invention also relates to pharmaceutical preparations which additionally comprise excipients and/or adjuvants, and also pharmaceutical preparations which also comprise at least one further pharmaceutically active compound.

In particular, the present invention also relates to a method for preparing a pharmaceutical preparation, characterized in that one of the compounds of the present invention and/or its physiologically acceptable salts, derivatives, solvates and stereoisomers (including mixtures thereof in all ratios) is formulated into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant and, if appropriate, with another pharmaceutically active compound.

The pharmaceutical formulation according to the present invention can be used as a medicament for human or veterinary medicine. The patient or host may belong to any mammalian species, for example, primate species, in particular humans; rodents, including mice, rats and hamsters; rabbits; horses; cows; dogs; cats, etc. Animal models are of interest for experimental research, where they provide models for the treatment of human diseases.

Suitable carrier substances are organic or inorganic substances suitable for enteral (e.g. oral), parenteral or topical administration and which do not react with the novel compound, for example, water, vegetable oils (such as sunflower oil or cod liver oil), benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (such as lactose or starch), magnesium stearate, talc, lanolin or petrolatum. Due to their professional knowledge, those skilled in the art are familiar with adjuvants suitable for the desired pharmaceutical formulation. In addition to solvents (e.g., water), physiological saline solutions or alcohols (such as, for example, ethanol, propanol or glycerol), sugar solutions (such as glucose or mannitol solutions) or mixtures of these solvents, gel formers, tablet adjuvants and other active ingredient carriers, for example, lubricants, stabilizers and/or wetting agents, emulsifiers, salts that influence osmotic pressure, antioxidants, dispersants, defoamers, buffering substances, flavoring agents and/or aroma or flavor correctors, preservatives, solubilizers or dyes may also be used. If desired, the preparations or medicaments according to the invention may contain one or more additional active compounds, for example, one or more vitamins.

If desired, the preparations or medicaments according to the invention may contain one or more additional active compounds and/or one or more action enhancers (adjuvants).

For the purposes of the present invention, the terms "pharmaceutical formulation" and "pharmaceutical preparation" are used synonymously.

As used herein, "pharmaceutically tolerable" refers to agents, precipitating agents, excipients, adjuvants, stabilizers, solvents, and other agents that facilitate administration of the resulting pharmaceutical formulation to a mammal without undesirable physiological side effects, such as, for example, nausea, dizziness, digestive problems, or the like.

In pharmaceutical preparations for parenteral administration, there is a need for isotonicity, normohydration and tolerability and safety (low toxicity) of the formulation, the adjuvants employed and the primary packaging. Surprisingly, the compounds according to the present invention preferably have the advantage that direct use is possible and therefore an additional purification step for removing toxicologically unacceptable reagents (such as, for example, high concentrations of organic solvents or other toxicologically unacceptable adjuvants) is not necessary before using the compounds according to the present invention in pharmaceutical formulations.

The present invention particularly preferably also relates to a pharmaceutical preparation comprising at least one compound according to the invention in precipitated amorphous, precipitated crystalline or dissolved or suspended form and, if appropriate, excipients and/or adjuvants and/or further pharmaceutically active compounds.

The compounds according to the invention preferably allow the preparation of high concentration formulations without the occurrence of undesirable undesired aggregation of the compounds according to the invention. Thus, ready-to-use solutions with a high active ingredient content can be prepared with the aid of the compounds according to the invention using aqueous solvents or in aqueous media.

The compound and/or its physiologically acceptable salt and solvent combination can also be lyophilized and the resulting lyophilized product used, for example, for the preparation of injection preparations.

Aqueous preparations can be prepared by dissolving or suspending the compound according to the present invention in an aqueous solution and optionally adding adjuvants. To this end, a defined volume of a stock solution containing the additional adjuvants at a defined concentration is advantageously added to a solution or suspension of the compound according to the present invention at a defined concentration, and the mixture is diluted with water to a pre-calculated concentration as appropriate. Alternatively, the adjuvant can be added in solid form. The amount of stock solution and/or water necessary in each case can then be added to the aqueous solution or suspension obtained. It is also advantageous to directly dissolve or suspend the compound according to the present invention in a solution containing all additional adjuvants.

Solutions or suspensions comprising the compounds according to the invention and having a pH of 4 to 10, preferably a pH of 5 to 9, and an osmotic pressure of 250 to 350 mosmol/kg can advantageously be prepared. Thus, the pharmaceutical preparation can be administered substantially directly intravenously, intraarterially, intraarticularly, subcutaneously or transcutaneously without pain. Furthermore, the preparation can also be added to infusion solutions such as, for example, glucose solution, isotonic saline solution or Ringer's solution, which can also contain additional active compounds, thus also enabling relatively large amounts of active compounds to be administered.

The pharmaceutical preparations according to the present invention may also comprise a mixture of a plurality of compounds according to the present invention.

The formulation according to the invention is physiologically well tolerated, easy to prepare, accurately dispensed and preferably stable with respect to analysis, decomposition products and aggregates throughout storage and transportation and during multiple freezing and thawing processes. It can preferably be stored in a stable manner at refrigerator temperature (2 to 8°C) and room temperature (23 to 27°C) and 60% relative atmospheric humidity (R.H.) for a period of at least three months to two years.

For example, the compounds according to the invention can be stored in a stable manner by drying and, when necessary to be converted into a ready-to-use pharmaceutical preparation, by dissolving or suspending. Possible drying methods are, for example and without limitation, nitrogen drying, vacuum oven drying, freeze drying, washing with an organic solvent and subsequent air drying, liquid bed drying, fluidized bed drying, spray drying, roller drying, layer drying, air drying at room temperature and other methods.

The term "effective amount" refers to the amount of a pharmaceutical agent or a pharmaceutically active compound that elicits the biological or medical response of a tissue, system, animal or human that is sought or desired, for example, by a researcher or physician.

In addition, the term "therapeutically effective amount" means an amount that has the following results: therapeutic improvement, cure, prevention or elimination of a disease, syndrome, disease state, illness, symptom or prevention of side effects or also a reduction in the progression of a disease, disorder or symptom, compared to a corresponding individual not receiving such amount. The term "therapeutically effective amount" also includes an amount that is effective to increase normal physiological function.

When using the formulation or medicament according to the present invention, the compound according to the present invention and/or its physiologically acceptable salt and solvent complex are generally similar to known commercial formulations, preferably used in a dosage between 0.1 and 500 mg, in particular 5 and 300 mg/use unit. The daily dose is preferably between 0.001 and 250 mg/kg body weight, in particular 0.01 and 100 mg/kg body weight. The formulation can be administered one or more times a day, for example, twice, three times or four times a day. However, the individual dosage for a patient will depend on many individual factors such as, for example, the potency of the particular compound used, body weight, general health status, sex, nutrition, time and method of administration, rate of excretion, combination with other drugs and the severity and duration of the particular disease.

A measure of the uptake of a pharmaceutically active compound in an organism is its bioavailability. If a pharmaceutically active compound is delivered intravenously to an organism in the form of an injectable solution, its absolute bioavailability, i.e., the proportion of the drug that reaches the systemic blood (i.e., the main circulation) in unchanged form, is 100%. In the case of oral administration of a therapeutically active compound, the active compound is generally in solid form in the formulation and must therefore first be dissolved so that it can overcome entry barriers, such as the gastrointestinal tract, oral mucosa, nasal mucosa or skin, in particular the stratum corneum, or can be absorbed by the body. Data on pharmacokinetics, i.e., bioavailability, can be obtained analogously to the method of J. Shaffer et al., J. Pharm. Sciences, 88 (1999), 313-318.

Furthermore, medicaments of this type can be prepared by one of the methods generally known in the pharmaceutical art.

The medicament may be suitable for administration by any desired suitable route, for example, by oral (including buccal or sublingual), rectal, pulmonary, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and in particular intra-articular) routes. This type of medicament can be prepared by all methods known in the pharmaceutical art, for example, by combining the active compound with the excipient(s) or adjuvant(s).

Non-enteral administration is preferably suitable for administering the medicament according to the present invention. In the case of non-enteral administration, intra-articular administration is particularly preferred.

The compounds according to the invention are also suitable for the preparation of medicaments with slow, sustained and/or controlled release of the active compounds to be administered parenterally. Thus, they are also suitable for the preparation of delayed-release formulations, which are advantageous to the patient because administration is only necessary at relatively large time intervals.

Medicaments suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostatic agents and solutes, by which the formulation is allowed to penetrate into the blood or synovial fluid of the recipient to be treated, etc.; and aqueous and non-aqueous sterile suspensions that may contain suspending media and thickening agents. The formulations may be delivered in single-dose or multi-dose containers, such as sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state so that a sterile carrier liquid for injection purposes, such as water, is added only immediately before it must be used. Injection solutions and suspensions prepared according to the formulations may be prepared from sterile powders, granules and tablets.

The compounds according to the invention can also be administered in the form of liposomal delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholine.

The compounds according to the present invention may also be coupled to soluble polymers as targeting agent excipients. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidephenol or palmityl-substituted polyethylene oxide polylysine. In addition, the compounds according to the present invention can be coupled to a class of biodegradable polymers suitable for achieving slow release of pharmaceutical agents, for example, polylactic acid, poly-ε-caprolactone, polyhydroxysuccinic acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, polylactic-co-glycolic acid, polymers such as conjugates between dextran and methacrylate, polyphosphates, various polysaccharides and polyamines and cross-linked or amphiphilic block copolymers of poly-ε-caprolactone, albumin, chitosan, collagen or modified gels and hydrogels.

Particularly suitable for enteral administration (oral or rectal) are tablets, dragees, capsules, syrups, juices, drops or suppositories, and suitable for topical use are ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (e.g., solutions in alcohols (such as ethanol or isopropanol), acetonitrile, DMF, dimethylacetamide, 1,2-propylene glycol or mixtures thereof with each other and/or with water) or powders. Likewise, particularly suitable for topical use are liposomal preparations.

In the case of formulation to give an ointment, the active compound may be employed with a paraffin or water-miscible cream base. Alternatively, the active compound may be formulated into a cream with an oil-in-water cream base or a water-in-oil base.

A pharmaceutical composition adapted for percutaneous administration may be delivered as a separate plaster which is held in close contact with the epidermis of the recipient. Thus, for example, the active compound may be delivered from the plaster by ionotransfer as described in general terms in Pharmaceutical Research, 3 (6), 318 (1986).

It goes without saying that, in addition to the ingredients specifically mentioned above, the medicament according to the present invention may also contain other agents commonly used in the art for a specific type of pharmaceutical formulation.

The present invention also relates to a set consisting of the following individually packaged components: a) an effective amount of a compound of the present invention and/or its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, and b) an effective amount of another pharmaceutically active compound.

The set includes suitable containers, such as boxes or cartons, individual bottles, bags or ampoules. The set may, for example, comprise separate ampoules, each containing an effective amount of a compound of the invention and/or its pharmaceutically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios), and an effective amount of another pharmaceutically active compound in dissolved or lyophilized form.

Furthermore, the medicaments according to the present invention may be used to provide additive or synergistic effects in certain known therapies and/or may be used to restore the efficacy of certain existing therapies.

In addition to the compounds according to the present invention, the pharmaceutical preparations according to the present invention may also contain, for example, other pharmaceutically active compounds for the treatment of cancer, other anti-tumor agents. For the treatment of other diseases mentioned, in addition to the compounds according to the present invention, the pharmaceutical preparations according to the present invention may also contain other pharmaceutically active compounds known to those skilled in the art in their treatment.

In one main embodiment, a method of enhancing the immune response of a host in need thereof is provided. The immune response can be enhanced by reducing T cell tolerance, including by increasing IFN-γ release, by reducing regulatory T cell production or activation, or by increasing antigen-specific memory T cell production in the host. In one embodiment, the method comprises administering a compound of the invention to the host in combination with or alternating with an antibody. In a specific embodiment, the antibody is a therapeutic antibody. In a specific embodiment, a method of enhancing the efficacy of a passive antibody therapy is provided, comprising administering a compound of the invention in combination with or alternating with one or more passive antibodies. This method can enhance the efficacy of antibody therapy for treating abnormal cell proliferative disorders such as cancer or can enhance the efficacy of therapy for treating or preventing infectious diseases. The compounds of the invention can be administered in combination or alternation with an antibody such as, for example, rituximab, herceptin or erbitux.

In another main embodiment, a method of treating or preventing abnormal cell proliferation is provided, which comprises substantially administering a compound of the present invention to a host in need thereof in the absence of another anticancer agent.

In another main embodiment, a method for treating or preventing abnormal cell proliferation in a host in need thereof is provided, comprising substantially administering to the host a first compound of the present invention in combination with a first anticancer agent and subsequently administering to the host a second compound of the present invention, a receptor antagonist. In a sub-embodiment, the second antagonist is substantially administered in the absence of another anticancer agent. In another main embodiment, a method for treating or preventing abnormal cell proliferation in a host in need thereof is provided, comprising substantially administering to the host a compound of the present invention in combination with a first anticancer agent and subsequently administering to the host a second anticancer agent in the absence of an antagonist.

Therefore, the cancer treatments disclosed herein can be performed using the compounds of the invention or in combination with manipulation, irradiation or chemotherapy as a therapy. This type of chemotherapy may include the use of one or more of the following classes of anti-tumor active compounds: (i) anti-proliferative/anti-tumor/DNA damaging active compounds and combinations thereof as used in medical oncology, such as alkylating active compounds (e.g., cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosourea), anti-metabolic agents (e.g., antifolates, such as fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytosine arabinoside, arabinoside, hydroxyurea and gemcitabine), antitumor antibiotics (e.g., anthracyclines such as adriamicin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, actinomycin D dactinomycin and mithramycin), antimitotic compounds (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine, and taxanes such as taxol and taxotere), topoisomerase inhibitors (e.g., epipodophyllotoxin epipodophyllotoxins (such as etoposide and teniposide), amsacrine, topotecan, irinotecan and camptothecin) and cell differentiation active compounds (for example, all trans-retinoic acid, 13-cis-retinoic acid and fenretinide); (ii) compounds with cytostatic activity, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptor modulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin and buserelin), progestins (e.g., megestrol acetate), (iii) active compounds that inhibit cancer invasion, including, for example, metalloproteinase inhibitors, such as marimastat, and urokinase fibrinolytic activator receptor function inhibitors; (iv) growth factor function inhibitors, for example, growth factor antibodies; growth factor receptor antibodies, for example, the anti-erbB2 antibody trastuzumab [Herceptin ^™ ] and the anti-erbB1 antibody cetuximab [C225]); farnesyl transferase inhibitors; tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example, epidermal growth factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example, platelet-derived growth factor family inhibitors and, for example, hepatocyte growth factor family inhibitors; (v) anti-angiogenic active compounds, such as bevacizumab, angiostatin, endostatin, linomide, batimastat, captopril, cartilage-derived inhibitors, genistein, interleukin 12, lavendustin, medroxyprogesterone acetate, recombinant human Platelet factor 4, tecogalan, thrombospondin, TNP-470, anti-VEGF monoclonal antibody, soluble VEGF receptor chimeric protein, anti-VEGF receptor antibody, anti-PDGF receptor, integrin inhibitor, tyrosine kinase inhibitor, serine/threonine kinase inhibitor, antisense oligonucleotide, antisense oligodeoxynucleotide, siRNA, anti-VEGF aptamer, pigment epithelium cell-derived factor and international patent application WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354; (vi) vascular disruptors, such as combretastatin A4 and compounds disclosed in international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapy, for example, those directed to the above-mentioned targets, such as ISIS 2503, anti-Ras antisense; (viii) genetic therapy, including, for example, methods of replacing abnormal modified genes (such as abnormal p53 or abnormal BRCA1 or BRCA2); GDEPT methods (gene-directed enzyme prodrug therapy), such as those using cytosine deaminase, thymidine kinase or bacterial nitroreductase; and methods of increasing a patient's tolerance to chemotherapy or radiation therapy, such as multidrug resistance therapy; and (ix) immunotherapy, including These include, for example, in vitro and in vivo methods for increasing the immunogenicity of a patient's tumor cells, such as transfection with cytokines, such as interleukin 2, interleukin 4, or granulocyte macrophage colony stimulating factor; methods for reducing T cell anergy; methods using transfected immune cells, such as cytokine-transfected dendritic cells; methods using cytokine-transfected tumor cells and methods using anti-idiotypic antibodies; (x) Chemotherapeutic agents, including, for example, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, bleomycin, bortezomib, zomib), busulfan, calusterone, camptothecin, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cinacalcet, cisplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, darbepoetin alpha alfa, daunorubicin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone, epirubicin, epoetin alfa, estramustine, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, and gemcitabine.

Agents from Table 1 can preferably (but not exclusively) be combined with the compounds of the present invention. Table 1 Alkylated active compounds Cyclophosphamide Busulfan Ifosfamide Hexamethylmelamine Thiotepa Chlorambucil Dacarbazine Carmustine Lomustine Procarbazine Altretamine Mechloroethamine Streptozocin Temozolomide Semustine Platinum active compounds Cisplatin Oxaliplatin Spiroplatin Tetraplatin Ormiplatin Iproplatin Carboplatin ZD-0473 (AnorMED) Lobaplatin (Aetema) Satraplatin (Johnson Matthey) BBR-3464 (Hoffrnann-La Roche) SM-11355 (Sumitomo) AP-5280 (Access) Anti-metabolism Azacytidine Gemcitabine Capecitabine 5-Fluorouracil Floxuridine 2-Chlorodeoxyadenosine 6-Hexylpurine 6-Thioguanine Cytarabine 2-Fluorodeoxycytidine Methirine Idatrexate Tomudex Trimetrexate Deoxycoformycin Fludarabine Pentostatin Raltitrexed Decitabine (SuperGen) Clofarabine (Bioenvision) Irofulven (MGI Pharrna) DMDC (Hoffmann-La Roche) Ethynycytidine (Taiho) Topoisomerase inhibitors Amsacrine Epirubicin Etoposide Teniposide or Mitoxantrone Enotecan (CPT-11) 7-Ethyl-10-hydroxycamptothecin Topotecan Dexrazoxane (TopoTarget) Pixantrone (Novuspharrna) Rebeccamycin analog (Exelixis) BBR-3576 (Novuspharrna) Rubitecan (SuperGen) Exatecan (Daiichi) Quinamed (ChemGenex) Gimatecan (Sigma-Tau) Diflomotecan (Beaufour-Ipsen) TAS-103 (Taiho) Elsamitrucin (Spectrum) J-107088 (Merck & Co) BNP-1350 (BioNumerik) CKD-602 (Chong Kun Dang) KW-2170 (Kyowa Hakko) Antitumor antibiotics Actinomycin D (Dactinomycin / Actinomycin D) Doxorubicin (Adriamycin) Deoxyrubicin Valrubicin Daunorubicin (Daunomycin) Therarubicin Rubidazon Plicamycin Porfiromycin Cyanomorpholinyl doxorubicin mitoxantrone (Novantron) Amonafide Azonafide Oxantrazole Losoxantrone Blenoxan Blenoxan Blenoxan Blenoxan Blenoxan C MEN-10755 (Menarini) GPX-100 (Gem Pharmaceuticals) Antimitotic compounds Paclitaxel Docetaxel Colchicine Vinblastine Vinpocetine Vinorelbine Vindesine Dolastatin 10 (NCI) Rhizoxin (Fujisawa) Mivobulin (Warner-Lambert) Cemadotin (BASF) RPR 109881A (Aventis) TXD 258 (Aventis) Epothilone B (Novartis) T 900607 (Tularik) T 138067 (Tularik) Cryptophycin 52 (Eli Lilly) Vinflunine (Fabre) Auristatin PE (Teikoku Hormone) BMS 247550 (BMS) BMS 184476 (BMS) BMS 188797 (BMS) Taxoprexin (Protarga) SB 408075 (GlaxoSmithKline) E7010 (Abbott) PG-TXL (Cell Therapeutics) IDN 5109 (Bayer) A 105972 (Abbott) A 204197 (Abbott) LU 223651 (BASF) D 24851 (ASTA Medica) ER-86526 (Eisai) Combretastatin A4 (BMS) Isohomohalichondrin-B (PharmaMar) ZD 6126 (AstraZeneca) PEG-paclitaxel (Enzon) AZ10992 (Asahi) !DN-5109 (Indena) AVLB (Prescient NeuroPharma) Azaepothilone B (BMS) BNP- 7787 (BioNumerik) CA-4-prodrug (OXiGENE) Dolastatin-10 (NrH) CA-4 (OXiGENE) Aromatase inhibitors Aminoglutethimide Letrozole Anastrozole Formestan Exemestane Atamestan (BioMedicines) YM-511 (Yamanouchi) Thymidylate synthase inhibitors Pemetrexed (Eli Lilly) ZD-9331 (BTG) Nolatrexed (Eximias) CoFactor™ (BioKeys) DNA antagonists Trabectedin (PharmaMar) Glufosfamide (Baxter International) Albumin + 32P (isotope solution) Thymectacin (NewBiotics) Edotreotid (Novartis) Mafosfamide (Baxter International) Apaziquone (Spectrum Pharmaceuticals) O6-Benzylguanine (Paligent) Farnesyl transferase inhibitors Arglabin (NuOncology Labs) Lonafarnib (Schering-Plough) BAY-43-9006 (Bayer) Tipifarnib (Johnson & Johnson) Perillyl alcohol (DOR BioPharma) Pump inhibitors CBT-1 (CBA Pharma) Tariquidar (Xenova) MS-209 (Schering AG) Zosuquidar trihydrochloride (Eli Lilly) Biricodar dicitrate (Vertex) Histone acetyltransferase inhibitors Tacedinaline (Pfizer) SAHA (Aton Pharma) MS-275 (Schering AG) Butyric acid pentyloxymethyl ester (Titan) Depsipeptide (Fujisawa) Metalloproteinase inhibitors Ribonucleoside reductase inhibitors Neovastat (Aeterna Laboratories) Marimastat (British Biotech) Gallium maltate (Titan) Triapin (Vion) CMT-3 (CollaGenex) BMS-275291 (Celltech) Tezacitabine (Aventis) Didox (Molecules for Health) TNF-α agonists/antagonists Virulizin (Lorus Therapeutics) CDC-394 (Celgene) Revimid (Celgene) Endothelin-A receptor antagonists Atrasentan (Abbot) ZD-4054 (AstraZeneca) YM-598 (Yamanouchi) Retinoic acid receptor agonists Fenretinide (Johnson & Johnson) LGD-1550 (ligand) Alitretinoin (Ligand) Immunomodulators Oncophage (Antigenics) GMK (Progenics) Adenocarcinoma Vaccine (Biomira) CTP-37 (AVI BioPharma) JRX-2 (Immuno-Rx) PEP-005 (Peplin Biotech) Synchrovax Vaccine (CTL Immuno) Melanoma Vaccine (CTL Immuno) p21-RAS Vaccine (GemVax) Dexosome therapy (Anosys) Pentrix (Australian Cancer Technology) JSF-154 (Tragen) Cancer vaccine (Intercell) Norelin (Biostar) BLP-25 (Biomira) MGV (Progenics) !3-Alethin (Dovetail) CLL-Thera (Vasogen) Hormonal and anti-hormonal active compounds Estrogen combined with estrogen, ethinyl estradiol, chlorethamide, idenestrol, hydroxyprogesterone caproate, medroxyprogesterone, testosterone, testosterone propionate, testosterone, fluoxymesterone, methyltestosterone, diethylstilbestrol, megestrol, tamoxifen, toremifene, dexamethasone Prednisone Methylprednisolone Prednisolone Aminolamide Leuprolide Goserelin Leuprolide Bicalutamide Flutamide Octreotide Nilutamide Mitotan P-04 (Novogen) 2-Methoxyestradiol (En_treMed) Arzoxifen (Eli Lilly) Photodynamically active compounds Talaporfin (Light Sciences) Theralux (Theratechnologies) Motexafin-gd (Pharmacyclics) Pd Bacterial Magnesium Dechlorophyll (bacteriopheophorbide) (Yeda) Lutetium texaphyrin (Pharmacyclics) Hypericin Tyrosine kinase inhibitors Imatinib (Novartis) Leflunomide (Sugen/Pharmacia) ZD1839 (AstraZeneca) Erlotinib (Oncogene Science) Canertinib (Pfizer) Squalamine (Genaera) SU5416 (Pharmacia) SU6668 (Pharmacia) ZD4190 (AstraZeneca) ZD6474 (AstraZeneca) Vatalanib (Novartis) PKI166 (Novartis) GW2016 (GlaxoSmithKline) EKB-509 (Wyeth) EKB-569 (Wyeth) Kahalide F (PharmaMar) CEP-701 (Cephalon) CEP-751 (Cephalon) MLN518 (Millenium) PKC412 (Novartis) Phenoxodiol O Trastuzumab (Genentech) C225 (ImClone) rhu-Mab (Genentech) MDX-H210 (Medarex) 2C4 (Genentech) MDX-447 (Medarex) ABX-EGF (Abgenix) IMC-1C11 (ImClone) Various other active compounds SR-27897 (CCK-A inhibitor, Sanofi-Synthelabo) Tocladesine (Cyclic AMP agonist, Ribapharm) Alvocidib (CDK inhibitor, Aventis) CV-247 (COX-2 inhibitor, Ivy Medical) P54 (COX-2 inhibitor, Phytopharm) CapCell™ (CYP450 stimulator, Bavarian Nordic) GCS-IOO (gal3 antagonist, GlycoGenesys) G17DT immunogen (gastrin inhibitor, Aphton) Efaproxiral (oxygenator, AlIos Therapeutics) PI-88 (heparinase inhibitor, Progen) Tesmilifen (histamine antagonist, YM BioSciences) Histamine (Histamine H2 receptor agonist, Maxim) Tiazofurin (IMPDH inhibitor, Ribapharm) Cilengitide (integrin antagonist, Merck KGaA) SR-31747 (IL-1 antagonist, Sanofi-Synthelabo) CCI-779 (mTOR kinase inhibitor, Wyeth) Exisulind (PDE-V inhibitor, Cell Pathways) CP-461 (PDE-V inhibitor, Cell Pathways) AG-2037 (GART inhibitor, Pfizer) WX-UK1 (Fibrinolysinogen activator inhibitor, Wilex) PBI-1402 (PMN stimulator, ProMetic LifeSciences) Bortezomib (proteasome inhibitor, Millennium) SRL-172 (T-cell stimulator, SR Pharma) TLK-286 (glutathione-S transferase inhibitor, Telik) PT-100 (growth factor agonist, Point Therapeutics) Midostaurin (PKC inhibitor, Novartis) Bryostatin-1 (PKC stimulator, GPC Biotech) CDA-II (apoptosis promoter, Everlife) SDX-101 (apoptosis promoter, Salmedix) Ceflatonin (apoptosis promoter, ChemGenex) BCX-1777 (PNP inhibitor, BioCryst) Ranpirnase (RNase stimulator, Alfacell) Galarubicin (RNA synthesis inhibitor, Dong-A) Tirapazamine (reducing agent, SRI International) N-acetylcysteine (reducing agent, Zambon) R-Flurbiprofen (NF-κB inhibitor, Encore) 3CPA (NF-κB inhibitor, Active Biotech) Seocalcitol (vitamin D receptor agonist, Leo) 131-I-TM-601 (DNA antagonist, TransMolecular) Eflornithin (ODC inhibitor, ILEX Oncology) Minodronic acid (osteoclast inhibitor, Yamanouchi) Indisulam (p53 stimulator, Eisai) Aplidin (PPT inhibitor, PharmaMar) Rituximab (CD20 antibody, Genentech) Gemtuzumab (CD33 antibody, Wyeth Ayerst) PG2 (hematopoiesis promoter, Pharmagenesis) Immunol™ (triclosan mouthwash, Endo) Triacetyl uridine (uridine prodrug, Welistat) SN-4071 (sarcoma agent, Signature BioScience) TransMID-107™ (immunotoxin, KS Biomedix) PCK-3145 (apoptosis promoter, Procyon) Doranidazole (apoptosis promoter, Pola) CHS-828 (cytotoxic agent, Leo) trans-retinoic acid (differentiation agent, NIH) MX6 (apoptosis promoter, MAXIA) Apomine (apoptosis promoter, ILEX Oncology) Urocidin (apoptosis promoter, Bioniche) Ro-31-7453 (apoptosis promoter, La Roche) Brostallicin (apoptosis promoter, Pharmacia)

Even without further embodiments, it is assumed that those skilled in the art can use the above description in the broadest scope. Therefore, the preferred embodiment should be regarded as a descriptive disclosure only, which is absolutely not limiting in any way.

The following examples are therefore intended to illustrate the invention without limiting it. Unless otherwise specified, the data in % denote % by weight. All temperatures are indicated in degrees Celsius. "Work-up": If necessary, water is added, if necessary, the pH is adjusted to a value between 2 and 10, depending on the composition of the final product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate or magnesium sulfate, filtered and evaporated, and the product is purified by chromatography on silica gel and/or by crystallization.

Rf value on silica gel; mass spectrometry: EI (electron impact ionization): M ⁺ , FAB (fast atom bombardment): (M+H) ⁺ , THF (tetrahydrofuran), NMP (N-methylpyrrolidone), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), MeOH (methanol), EtOH (ethanol), TLC (thin layer chromatography)

List of Abbreviations AUC Area under the plasma drug concentration-time curve C _max Maximum plasma concentration CL Clearance CV Coefficient of variation CYP Cytochrome P450 DMSO Dimethyl sulfoxide F Bioavailability f _a Fraction absorbed iv Intravenous LC-MS/MS Liquid chromatography-tandem mass spectrometry LLOQ Lower limit of quantification NC Not calculated ND Not determined PEG Polyethylene glycol Pgp Permeable glycoprotein PK Pharmacokinetics po Oral rt Room temperature t _1/2 half-life t _max Time to reach maximum plasma concentration of drug UPLC Ultra performance liquid chromatography V _ss Volume of distribution (at steady state) v/v Volume ratio

Methods for Preparation and Analysis of the Compounds of the Invention The present invention relates in particular to the following exemplary compounds and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios.

All solvents used were commercially available and used without further purification. Reactions were typically run under an inert atmosphere of nitrogen or argon using anhydrous solvents. Flash column chromatography was performed using silica gel 60 (0.035 to 0.070 mm particle size). Flash column chromatography was also performed using a Biotage purification system using SNAP KP-Sil cartridges or in reverse phase mode using SNAP Ultra C18 cartridges. Microwave-assisted reactions were performed using a Biotage Initiator microwave system.

^1H NMR spectra were recorded on a Bruker DPX-300, DRX-400, Avance II-400, Avance III HD-400, Avance II+-500, Avance III-500, Avance Neo 600 or Avance III-700 spectrometer using the residual signal of the deuterated solvent as an internal reference. Chemical shifts (δ) are reported in ppm relative to tetramethylsilane (TMS) with reference to the internal deuterated solvent. ^1H NMR data are reported as follows: Chemical shift (multiplicity, coupling constant and number of hydrogens). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quadruplet), sext (sextuple), hept (septuple), m (multiplicity), br (broad).

HPLC/MS spectra of the products were recorded on an Agilent 1100 HPLC system (1100 high pressure gradient pump, 1100 diode array detector, wavelength: 220 nm) connected to an Agilent 1100 mass spectrometer detector (positive mode).

LC-MS analysis was performed on a SHIMADZU LC-MS machine consisting of a UFLC 20-AD system and a LCMS 2020 MS detector.

Details of application conditions for HPLC/MS spectra recorded on a Shimadzu LCMS-2020 system or an Agilent 1100 system:

(A): Column: Kinetex EVO C18, 4.6 x 50 mm, 5.0 µm; Mobile phase A: Water with 0.05% FA, Mobile phase B: ACN with 0.04% FA and 1% water; Gradient: 1% B to 99% B until min 0.8, 99% B to 1% B until min 1.1, stop after 1.50; Flow rate: 3.3 mL/min.

(B): Column: Chromolith HR RP-18e, 4.6 x 50 mm; Mobile phase A: Water with 0.05% FA, Mobile phase B: ACN with 0.04% FA + 1% water; Gradient: 0% B to 100% B until min 2.0, hold until min 2.5, 100% B to 0% B until min 2.51, stop after 2.95; Flow rate: 3.3 mL/min.

(C) Column: Sunfire C18, 3.0 x 100 mm, 5 µm; Mobile phase A: water with 0.05% FA, Mobile phase B: ACN with 0.04% FA and 1% water; Gradient: 1% B to 99% B in 2.0 min, hold until min 2.7, 99% B to 1% B until min 2.71, stop after 3.5; Flow rate: 1.4 mL/min.

(D): Column: Chromolith HR C18, 4.6 x 50 mm; Mobile phase A: Water with 0.1% TFA, Mobile phase B: ACN with 0.1% TFA; Gradient: 1% B to 99% B until min 2.0, hold until min 2.5, 99% B to 1% B until min 2.51, stop after 2.95; Flow rate: 3.3 mL/min.

(E): Column: Kinetex EVO C18, 2.1 x 30 mm, 5.0 µm; Mobile phase A: 0.0375% TFA in water (v/v), Mobile phase B: 0.01875% TFA in acetonitrile (v/v); Gradient: 5% B to 95% B in 0.8 min, 95% B until min 1.2, 5% B until stop after 1.55 min; Flow rate: 1.5 mL/min.

(F): Column: Kinetex EVO C18, 2.1 x 30 mm, 5.0 µm; Mobile phase A: 0.0375% TFA in water (v/v), Mobile phase B: 0.01875% TFA in acetonitrile (v/v); Gradient: 0% B to 60% B in 0.8 min, 60% B until min 1.2, 0% B until stop after 1.55 min; Flow rate: 1.5 mL/min.

(G): Column: Kinetex EVO C18, 2.1 x 30 mm, 5.0 µm; Mobile phase A: 0.025% NH ₃ ·H ₂ O in water (v/v), Mobile phase B: acetonitrile; Gradient: 5% B to 95% B in 0.8 min, 95% B until min 1.2, 5% B until stop after 1.55 min; Flow rate: 1.5 mL/min.

Details of the application conditions for HPLC/MS spectroscopy on an Agilent 1200 series HPLC coupled to a 6210 time-of-flight mass spectrometer with a dual multimode APCI/ESI source and a diode array detector.

(P): Analytical separations were performed at 40 °C on a Merck Chromolith flash column (RP-18e, 25 x 2 mm) using a 2 min gradient at a flow rate of 1.5 mL/min and detection at 254 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient was as follows: 5:95 (A/B) to 100:0 (A/B) over 1.25 min, 100:0 (A/B) for 0.5 min, and then reversed back to 5:95 (A/B) for 0.05 min, and finally 5:95 (A/B) for 0.2 min.

(Q) Analytical separations were performed at 30°C on a Merck Chromolith flash column (RP-18e, 25 x 2 mm) using a 4-minute gradient at a flow rate of 0.75 mL/min and detection at 254 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient was as follows: 5:95 (A/B) to 100:0 (A/B) over 2.5 min, 100:0 (A/B) for 1 min, and then reversed back to 5:95 (A/B) for 0.1 min, and finally 5:95 (A/B) for 0.4 min.

Details of the application conditions for HPLC/MS spectroscopy on a Waters Acquity UPLC coupled to a Waters G2 QtoF mass spectrometer equipped with a multimode ESI/APCI source and a diode array detector.

(R) Analytical separations were performed at 30°C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a 2 min gradient at a flow rate of 0.5 mL/min and detection at 254 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient was as follows: 10:90 (A/B) to 90:10 (A/B) over 1.25 min, 90:10 (A/B) for 0.5 min, and then reversed back to 10:90 (A/B) for 0.15 min, and finally 10:90 (A/B) for 0.1 min.

(S) Analytical separations were performed at 30°C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a 4 min gradient at a flow rate of 0.3 mL/min and detection at 254 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient was as follows: 10:90 (A/B) to 90:10 (A/B) over 3 min, 90:10 (A/B) for 0.5 min, and then reversed back to 10:90 (A/B) for 0.3 min, and finally 10:90 (A/B) for 0.2 min.

(T) Analytical separations were performed at 30°C on an Agilent Poroshell C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a 2 min gradient at a flow rate of 0.5 mL/min and detection at 254 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient was as follows: 10:90 (A/B) to 90:10 (A/B) over 1.25 min, 90:10 (A/B) for 0.5 min, and then reversed back to 10:90 (A/B) for 0.15 min, and finally 10:90 (A/B) for 0.1 min.

(U) Analytical separations were performed at 30°C on an Agilent Poroshell C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a 4 min gradient at a flow rate of 0.3 mL/min and detection at 254 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient was as follows: 10:90 (A/B) to 90:10 (A/B) over 3 min, 90:10 (A/B) for 0.5 min, and then reversed back to 10:90 (A/B) for 0.3 min, and finally 10:90 (A/B) for 0.2 min.

Details of the application conditions for HPLC/MS spectroscopy on an Agilent 1260 Infinity II Series UPLC coupled to a 6530 quadrupole time-of-flight mass spectrometer with an Agilent Jet Stream ESI source and a diode array detector.

(V) Analytical separation was performed at 40 °C on an Agilent Poroshell C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a 2 min gradient elution at a flow rate of 0.6 mL/min and detection at 254, 280 and 214 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient elution was as follows: 10:90 (A/B) to 90:10 (A/B) over 1.25 min, 90:10 (A/B) for 0.5 min, and then reversed back to 10:90 (A/B) for 0.15 min, and finally 10:90 (A/B) for 0.1 min.

(X) Analytical separation was performed at 40 °C on an Agilent Poroshell C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a 4 min gradient elution at a flow rate of 0.4 mL/min and detection at 254, 280 and 214 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient elution was as follows: 10:90 (A/B) to 90:10 (A/B) over 2.5 min, 90:10 (A/B) for 1 min, and then reversed back to 10:90 (A/B) for 0.3 min, and finally 10:90 (A/B) for 0.2 min.

(Y) Analytical separation was performed at 40 °C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a 2 min gradient elution at a flow rate of 0.6 mL/min and detection at 254, 280 and 214 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient elution was as follows: 10:90 (A/B) to 90:10 (A/B) over 1.25 min, 90:10 (A/B) for 0.5 min, and then reversed back to 10:90 (A/B) for 0.15 min, and finally 10:90 (A/B) for 0.1 min.

(Z) Analytical separation was performed at 40 °C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a 4 min gradient elution at a flow rate of 0.4 mL/min and detection at 254, 280 and 214 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient elution was as follows: 10:90 (A/B) to 90:10 (A/B) over 2.5 min, 90:10 (A/B) for 1 min, and then reversed back to 10:90 (A/B) for 0.3 min, and finally 10:90 (A/B) for 0.2 min.

Synthetic intermediate: A1: 5-methyl-3-(2-oxoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole A1.1: Isoquinoline-7-carbonitrile (4.00 g, 25.9 mmol), triethylamine (7.23 mL, 51.9 mmol) and [bmim]OAc (26 mL) were mixed and heated to 80 °C. Hydroxylamine hydrochloride (3.61 g, 51.9 mmol) was added. The reaction mixture was stirred at 80 °C for another 1.5 h. The reaction mixture was cooled to room temperature and mixed thoroughly with EtOAc (250 mL). The emulsion was then mixed with water (750 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with saturated NaCl (3 x 100 mL), dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to give 3.70 g (76%) of N'-hydroxyisoquinoline-7-carboximidamide as an off-white solid. HPLC/MS m/z: 188.0829 [M+H] ⁺ , Rt (S): 0.37 min.

A1.2: Into four individual 20 mL microwave vials was placed one quarter of the following: N'-hydroxyisoquinoline-7-carboximidamide (3.67 g, 19.6 mmol) was mixed with acetonitrile (40 mL) and acetic anhydride (2.2 mL, 23.5 mmol) under an atmosphere of argon. Portions of the reaction mixture were heated at 180 °C for 10 min under microwave irradiation. The combined reaction mixture was evaporated on silica gel and purified by flash chromatography (20 to 80% EtOAc/cyclohexane) to give 3.59 g (87%) of 3-(7-isoquinolinyl)-5-methyl-1,2,4-oxadiazole as an off-white solid. HPLC/MS m/z: 212.1 [M+H] ⁺ , Rt (R): 0.88 min.

A1.3: Under an atmosphere of argon, 3-(7-isoquinolyl)-5-methyl-1,2,4-oxadiazole (3.59 g, 17.0 mmol) was suspended in anhydrous chloroform (57 mL) and cooled in an ice bath. 3-Chloroperoxybenzoic acid (4.57 g, 20.4 mmol) was added. The stirred reaction mixture was allowed to warm to ambient temperature and stirring was continued overnight. Potassium carbonate (9.40 g, 68.0 mmol) was added. The mixture was stirred at room temperature for 4 hours before filtering through a pad of anhydrous MgSO ₄ . The filtrate was concentrated under reduced pressure to obtain 5-methyl-3-(2-oxoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole (3.12 g, 81%) as an off-white powder. HPLC/MS m/z: 228.0713 [M+H] ⁺ , Rt (X): 1.73 min.

A2: 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole A2.1: Nitrogen was bubbled through a mixture of 7-bromoisoquinolin-1-ol (0.500 g, 2.23 mmol) and zinc cyanide (0.341 g, 2.90 mmol) in DMF (12.4 mL) for 15 min. Palladium tetrakis(triphenylphosphine) (0.155 g, 0.13 mmol) was added and the mixture was heated in a sealed vial at 100 °C for 16 h. The reaction mixture was diluted with brine (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (2 x 50 mL). The aqueous layer, which contained some precipitated product, was re-extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, pre-adsorbed onto silica gel and purified by column chromatography (solvent: methanol/dichloromethane = 0 to 10% gradient) to give 0.314 g (83%) of 1-hydroxyisoquinoline-7-carbonitrile. HPLC/MS m/z: 171.05 [M+H] ⁺ , Rt (R): 0.84 min. ¹ H NMR (500 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.53-8.47 (m, 1H), 8.03 (dd, J = 8.3, 1.8 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 7.1 Hz, 1H), 6.65 (d, J = 7.2 Hz, 1H).

A2.2: 1-Butyl-3-methylimidazolium acetate (1.3 mL) containing 1-hydroxyisoquinoline-7-carbonitrile (0.215 g, 1.26 mmol) and hydroxylamine hydrochloride (0.176 g, 2.52 mmol) was heated at 80°C for 30 minutes. Water (50 mL) was added and the resulting precipitate was filtered, washed with water (50 mL) and dried to give 0.235 g (92%) of N',1-dihydroxyisoquinoline-7-carboximidamide. HPLC/MS m/z: 204.07 [M+H] ⁺ , Rt (R): 0.36 min.

A2.3: N',1-dihydroxyisoquinoline-7-carboximidamide (0.235 g, 1.16 mmol) and acetic anhydride (0.13 mL, 1.39 mmol) in acetonitrile (4.6 mL) were heated at 180 °C for 10 min by microwave irradiation. Water (25 mL) was added, and the resulting precipitate was filtered, washed with water (25 mL), diethyl ether (2 x 10 mL) and dried to give 0.180 g (68%) of 7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-ol. HPLC/MS m/z: 228.08 [M+H] ⁺ , Rt (R): 1.07 min.

A2.4: Heat 7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-ol (50 mg, 0.22 mmol) in phosphonyl chloride (2 mL) at 100 °C for 1 hour. The mixture was concentrated to give 0.054 g (100%) of 3-(1-chloro-7-isoquinolinyl)-5-methyl-1,2,4-oxadiazole. HPLC/MS m/z: 246/248 Cl splitting [M+H] ⁺ , Rt (R): 1.32 min.

B1: 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionic acid B1.1: 3-(5-Methyl-1,2,4-oxadiazol-3-yl)benzoic acid (147.0 mg, 0.720 mmol) and methyl 3-aminopropionate dichloride (126.7 mg, 0.720 mmol) were dissolved in DMF (2.3 mL). HATU (260.1 mg, 0.684 mmol) and N-ethyldiisopropylamine (489,7 µl, 2.880 mmol) were added and the clear yellow solution was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and the residue was purified by RP flash chromatography. The fractions were combined, diluted with saturated aqueous NaHCO ₃ solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 206 mg (99%) of methyl 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propanoate as a colorless solid. HPLC/MS m/z: 289.9 [M+H] ⁺ , Rt (A): 0.83 min.

B1.2: Methyl 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propanoate (413.0 mg, 1.428 mmol) was dissolved in THF (18.0 mL) and water (9.0 mL). While stirring, lithium hydroxide (85.5 mg, 3.569 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, acidified to pH 3-4 with 0.1 N HCl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by RP flash chromatography to give 390 mg (99%) of 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propanoic acid as a colorless solid. HPLC/MS m/z: 275.9 [M+H] ⁺ , Rt (A): 0.77 min.

B2: 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionic acid B2.1: 1-Chloro-7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinoline [intermediate A2] (243.0 mg, 0.989 mmol) and tert-butyl 3-aminopropanoate (861.8 mg, 5.935 mmol) were dissolved in NMP (17.0 mL) in a microwave vessel. N-Ethyldiisopropylamine (420.5 µl, 2.473 mmol) was added and the mixture was stirred at 150 °C for 20 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by RP flash chromatography, the product fractions were combined, diluted with saturated aqueous NaHCO ₃ solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 192 mg (55%) of tert-butyl 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propanoate as an orange solid. HPLC/MS m/z: 354.9 [M+H] ⁺ , Rt (A): 0.74 min.

B2.2.: To a solution of tert-butyl 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propanoate (192.0 mg, 0.542 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (788.5 µl, 10.235 mmol) and the yellow solution was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue (165 mg) was used in the next step without further purification. HPLC/MS m/z: 289.9 [M+H] ⁺ , Rt (A): 0.65 min.

B3: (1S,3S)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}cyclobutane-1-carboxylic acid B3.1: Under an argon atmosphere, 7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-2-ium-2-olate [Intermediate A1] (500.0 mg, 2.201 mmol) and cis-3-aminocyclobutanecarboxylic acid methyl ester hydrochloride (355.3 mg, 2.751 mmol) were dissolved in anhydrous dichloromethane (11.0 mL). N-ethyldiisopropylamine (1.78 mL, 10.452 mmol) and PyBroP (1.33 g, 2.853 mmol) were added, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography to give 392 mg (56%) of methyl (1s,3s)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}cyclobutane-1-carboxylate as a colorless solid. HPLC/MS m/z: 339.1 [M+H] ⁺ , Rt (D): 1.22 min.

B3.2: Intermediate B3.1 (417.0 mg, 1.232 mmol) was dissolved in methanol (4.0 mL), THF (9.0 mL) and water (6 mL) at room temperature. Lithium hydroxide (59 mg, 2.465 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by RP flash chromatography to give 355 mg (89%) of (1s,3s)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}cyclobutane-1-carboxylic acid as a colorless solid. HPLC/MS m/z: 325.1 [M+H] ⁺ , Rt (D): 1.12 min.

B4: (2S)-2-Hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionic acid B4.1: To a solution of (2S)-3-amino-2-hydroxy-propionic acid methyl ester hydrochloride (342.36 mg, 2.2005 mmol) in anhydrous DCM was added DIPEA (1.30 mL, 7.4817 mmol) followed by 5-methyl-3-(2-oxoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Intermediate A1] (1.76 mL, 1.7604 mmol) followed by bromotris(pyrrolidinyl)phosphonium hexafluorophosphate (1066.87 mg, 2.2885 mmol). The mixture was stirred for 42 hours. The mixture was diluted in water and extracted with DCM (2 x 70 mL). The organic phase was dried _{over Na2SO4} . Purification by NP silica gel column chromatography (solvent: 25 to 100% EtOAc/cyclohexane) gave methyl (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoate (230 mg). HPLC/MS m/z: 329.126 [M+H] ⁺ , Rt (T): 0.79 min.

B4.2: Methyl (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoate (215.00 mg, 0.6548 mmol) was dissolved in a 3:1 mixture of MeOH and _H2O (1.06 mL). Lithium hydroxide monohydrate (56.28 mg, 1.3097 mmol) was added. The solution was stirred and then diluted with water (2 mL) and acidified with 1M HCl (pH = 1). The product precipitated to give (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoic acid (100 mg, 49%, 0.3182 mmol). HPLC/MS m/z: 315.111 [M+H] ⁺ , Rt (T): 0.80 min.

Example Example 1 : N-{4- ethoxy- [1,3] thiazolo [5,4-c] pyridin -2- yl }-3-{[3-(5 -methyl -1,2,4- oxadiazol -3- yl ) phenyl ] formamido } propionamide Example 1.1: 4-Amino-2-chloropyridine (1.96 g, 15.246 mmol) and sodium hydroxide (3.17 g, 79.279 mmol) were dissolved in absolute ethanol (15.0 mL) in a microwave tube. The reaction mixture was heated to 150 °C in a microwave reactor for 7 hours. The reaction mixture was cooled to room temperature, diluted with water (40 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to give 1.76 g (84%) of 2-ethoxypyridin-4-amine as a colorless solid. HPLC/MS m/z: 139.1 [M+H] ⁺ , Rt (B): 0.74 min.

Example 1.2: A solution of 2-ethoxypyridin-4-amine (548.0 mg, 3.966 mmol) in dichloromethane (12.7 mL) was cooled to 0 °C. At this temperature NBS (777.0 g, 4.366 mmol) was added and after 5 minutes the reaction mixture was allowed to warm up to room temperature and stirred for 45 minutes. The reaction was quenched with water (50 mL) and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 789 mg (92%) of 3-bromo-2-ethoxypyridin-4-amine as a light brown oil. HPLC/MS m/z: 216.9/218.9 [M+H] ⁺ , Rt (B): 1.09 min.

Example 1.3: A solution of 3-bromo-2-ethoxypyridin-4-amine (789.0 mg, 3.635 mmol) and benzyl isothiocyanate (1.78 g, 10.907 mmol) in acetone (4.0 mL) was stirred at room temperature overnight. A yellow precipitate formed, which was filtered by suction, washed with heptane and dried to give 1.23 g (89%) of 1-benzyl-3-(3-bromo-2-ethoxypyridin-4-yl)thiourea as a yellow solid. HPLC/MS m/z: 379.7/381.7 [M+H] ⁺ , Rt (B): 1.09 min.

Example 1.4: Intermediate 1.3 (1.23 g, 3.235 mmol) was dissolved in methanol (5.0 mL). Sodium hydroxide (360.0 mg, 9.001 mmol) was dissolved in water (1.5 mL) and added to the reaction mixture. The reaction mixture was refluxed for 2 h, cooled down to room temperature and treated with saturated aqueous NH ₄ Cl solution until a precipitate formed. The precipitate was filtered off by suction, washed with water and dichloromethane and dried to give 870 mg (97%) of (3-bromo-2-ethoxypyridin-4-yl)thiourea as a colorless solid. HPLC/MS m/z: 275.8/277.8 [M+H] ⁺ , Rt (B): 1.27 min.

Example 1.5: Intermediate 1.4 (2.42 g, 8.763 mmol), DL-proline (302.9 mg, 2.631 mmol), cesium carbonate (5.71 g, 17.526 mmol) and copper (I) iodide (501.1 mg, 2.631 mmol) were suspended in anhydrous DMSO (7.5 mL). The reaction mixture was heated to 70 ° C under an argon atmosphere and stirred overnight, cooled to room temperature, and stirred for 2 days. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The crude product was purified by RP flash chromatography to give 688 mg (33%) of ammonium 4-ethoxy-[1,3]thiazolo[5,4-c]pyridine-2-carboxylate as a light green solid. HPLC/MS m/z: 195.9 [M+H] ⁺ , Rt (B): 1.13 min.

Example 1.6: Intermediate B1 (36.6 mg, 0.144 mmol) was dissolved in DMF (1.1 mL). 1-Methylimidazole (68.5 mg, 0.834 mmol), intermediate 1.5 (43.4 mg, 0.180 mmol) and chloro-N,N,N′,N′-tetramethylformamidine hexafluorophosphate (68.0 mg, 0.230 mmol) were added and the reaction was stirred at room temperature for 1 hour, heated to 60°C and stirred for 5 hours. The reaction mixture was cooled down to room temperature and diluted with water (5 mL). A precipitate was formed, which was filtered by suction, rinsed thoroughly with water and dried. The crude product was purified by flash chromatography to give 38 mg (58%) of N-{4-ethoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propanamide as a colorless solid. HPLC/MS m/z: 452.8 [M+H] ⁺ , Rt (C): 2.31 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.74 (s, 1H), 8.89 (t, J = 5.6 Hz, 1H), 8.47-8.46 (m, 1H), 8.14-8.12 (m, 1H), 8.09 (d, J = 5.7 Hz, 1H), 8.05-8 .03 (m, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 5.6 Hz, 1H), 4.49 (q, J = 7.0 Hz, 2H), 3.64 (q, J = 6.6 Hz, 2H), 2.86 (t, J = 6.8 Hz, 2H), 2. 68 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H).

The following examples were prepared in a similar manner.

Example 2: 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-[4-(propan-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propanamide 29 mg colorless solid. HPLC/MS m/z: 466.8 [M+H] ⁺ , Rt (C): 2.40 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.76-12.74 (m, 1H), 8.91 (t, J = 5.5 Hz, 1H), 8.47-8.46 (m, 1H), 8.14-8.12 (m, 1H), 8.08 (d, J = 5.6 Hz, 1H), 8.06-8.03 (m, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 5.7 Hz, 1H), 5.46-5.40 (m, 1H), 3.64 (q, J = 6.9 Hz, 2H), 2.87 (t, J = 6.9 Hz, 2H), 2.68 (s, 3H), 1.36 (d, J = 6.2 Hz, 6H).

Example 3 : N-{4 -cyclobutoxy- [1,3] thiazolo [5,4-c] pyridin - 2- yl }-3-{[3-(5 -methyl -1,2,4- oxadiazol -3- yl ) phenyl ] formamido } propionamide 17 mg colorless solid. HPLC/MS m/z: 478.8 [M+H] ⁺ , Rt (A): 0.96 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.83-12.60 (m, 1H), 8.88 (t, J = 5.4 Hz, 1H), 8.48-8.46 (m, 1H), 8.15-8.10 (m, 1H), 8.07-8.02 (m, 1H), 7.99 (d, J = 5.7 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 5.7 Hz, 1H), 5.32 (quint, J = 7.5 Hz, 1H), 3.63 (q, J = 6.5 Hz, 2H), 2.79 (t, J = 6.9 Hz, 2H), 2.68 (s, 3H), 2.48-2.39 (m, 2H), 2.18-2.07 (m, 2H), 1.86-1.75 (m, 1H), 1.73-1.59 (m, 1H).

Example 4 : N-[4-( But -2 -yloxy )-[1,3] thiazolo [5,4-c] pyridin -2- yl ]-3-{[3-(5- methyl -1,2,4- oxadiazol -3- yl ) phenyl ] formamido } propionamide 56 mg colorless solid. HPLC/MS m/z: 480.8 [M+H] ⁺ , Rt (C): 2.50 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.73 (s, 1H), 8.88 (t, J = 5.5 Hz, 1H), 8.47-8.46 (m, 1H), 8.14-8.12 (m, 1H), 8.08 (d, J = 5.7 Hz, 1H), 8.04-8 .02 (m, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H), 5.30-5.25 (m, 1H), 3.66-3.62 (m, 2H), 2.86 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H ), 1.77-1.65 (m, 2H), 1.33 (d, J = 6.2 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H).

Example 5 : N-[4-(2,2 -difluoroethoxy )-[1,3] thiazolo [5,4-c] pyridin -2- yl ]-3-{[3-(5- methyl -1,2,4- oxadiazol -3- yl ) phenyl ] formamido } propionamide 34 mg colorless solid. HPLC/MS m/z: 488.8 [M+H] ⁺ , Rt (C): 2.33 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.82 (s, 1H), 8.90 (t, J = 5.5 Hz, 1H), 8.48-8.46 (m, 1H), 8.14-8.12 (m, 1H), 8.13 (d, J = 5.7 Hz, 1H), 8.05-8 .02 (m, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 5.6 Hz, 1H), 6.55-6.38 (m, 1H), 4.77 (td, J = 15.0, 3.6 Hz, 2H), 3.64 (q, J = 6.7 Hz, 2H), 2.88 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H).

Example 6 : 3-{[3-(5- methyl -1,2,4- oxadiazol - 3 -yl ) phenyl ] formamido }-N-[4-(2,2,2 -trifluoroethoxy )[1,3] thiazolo [5,4-c] pyridin -2- yl ] propanamide 14 mg colorless solid. HPLC/MS m/z: 506.7 [M+H] ⁺ , Rt (A): 0.95 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.87 (s, 1H), 8.89 (t, J = 5.5 Hz, 1H), 8.47-8.46 (m, 1H), 8.14 (d, J = 5.7 Hz, 1H), 8.14-8.12 (m, 1H), 8.04-8 .02 (m, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.47 (d, J = 5.7 Hz, 1H), 5.20 (q, J = 9.0 Hz, 2H), 3.66-3.62 (m, 2H), 2.88 (t, J = 6.8 Hz, 2H), 2.68 (s , 3H).

Example 7 : N-[4-(3,3 -difluorocyclobutoxy )-[1,3] thiazolo [5,4-c] pyridin -2- yl ]-3-{[3-(5- methyl -1,2,4- oxadiazol -3- yl ) phenyl ] formamido } propionamide 31.5 mg colorless solid. HPLC/MS m/z: 514.7 [M+H] ⁺ , Rt (C): 2.43 min. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 12.78 (s, 1H), 8.88 (t, J = 5.5 Hz, 1H), 8.46 (t, J = 1.8 Hz, 1H), 8.14-8.11 (m, 1H), 8.10 (d, J = 5.7 Hz, 1H), 8. 05-8.02 (m, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 5.7 Hz, 1H), 5.35-5.27 (m, 1H), 3.64 (q, J = 6.4 Hz, 2H), 3.24-3.15 (m, 2H), 2.87 (t , J = 6.8 Hz, 2H), 2.87-2.77 (m, 2H), 2.68 (s, 3H).

Example 8 : 3-{[3-(5 -methyl -1,2,4- oxadiazol -3- yl ) phenyl ] formamido }-N-{4-[(1,1,1- trifluoropropan -2- yl ) oxy ]-[1,3] thiazolo [5,4-c] pyridin -2- yl } propanamide 36 mg colorless solid. HPLC/MS m/z: 520.7 [M+H] ⁺ , Rt (C): 2.52 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.88-12.81 (m, 1H), 8.89 (t, J = 5.6 Hz, 1H), 8.47-8.45 (m, 1H), 8.14-8.13 (m, 1H), 8.13-8.11 (m, 1H), 8.05 -8.02 (m, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 5.7 Hz, 1H), 6.09-6.02 (m, 1H), 3.64 (q, J = 6.5 Hz, 2H), 2.86 (t, J = 6.8 Hz, 2H), (s, 3H), 1.53 (d, J = 6.5 Hz, 3H).

Example 9 : N-{4- ethoxy- [1,3] thiazolo [5,4-c] pyridin -2- yl }-3-{[7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ] amino } propionamide Intermediate B2 (170.0 mg, 0.570 mmol) was dissolved in anhydrous DMF (4.4 mL) and treated with intermediate 1.5 (206.3 mg, 0.855 mmol) and triethylamine (576.7 mg, 5.699 mmol). T3P (50 wt. % in ethyl acetate; 847.4 μl, 1.425 mmol) was added and the reaction mixture was heated to 60 °C under nitrogen atmosphere and stirred for 1 day. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was triturated with DMSO and filtered by suction. The additional product was separated from the filtrate by RP flash chromatography to give 139 mg (51%) of the title compound as a light yellow solid. HPLC/MS m/z: 475.8 [M+H] ⁺ , Rt (C): 1.84 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.79-12.75 (m, 1H), 8.89-8.88 (m, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.08 (d, J = 5.7 Hz, 1H), 8.06 (t, J = 5.4 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 5.7 Hz, 1H), 6.98 (d, J = 5.7 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 3.85 q, J = 6.4 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H).

The following examples were prepared in a similar manner.

Example 10: 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-propoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}propionamide 15 mg colorless solid. HPLC/MS m/z: 490.1 [M+H] ⁺ , Rt (D): 1.47 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.91-8.85 (m, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 8.06-7.95 (m, 3H), 7.84 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 5.7 Hz , 1H), 7.00-6.92 (m, 1H), 4.38 (t, J = 6.6 Hz, 2H), 3.84 (q, J = 6.5 Hz, 2H), 2.90 (t, J = 6.9 Hz, 2H), 2.69 (s, 3H), 1.84-1.70 (m, 2H), 0. 99 (t, J = 7.4 Hz, 3H).

Example 11 : 3-{[7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1- yl ] amino }-N-[4-( propan -2 -yloxy )-[1,3] thiazolo [5,4-c] pyridin -2- yl ] propionamide 19 mg colorless solid. HPLC/MS m/z: 489.8 [M+H] ⁺ , Rt (C): 1.90 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.78-12.72 (m, 1H), 8.90-8.88 (m, 1H), 8.15 (dd, J = 8.4, 1.5 Hz, 1H), 8.07 (d, J = 5.7 Hz, 1H), 8.05 (t, J = 5.4 Hz, 1H), 7.97 (d, J = 5.6 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 5.6 Hz, 1H), 6.97 (d, J = 5.7 Hz, 1H), 5.46-5.40 (m, 1H), 3.85 (td, J = 6.9, 5.4 Hz, 2H), 2.96 (t, J = 6.9 Hz, 2H), 2.69 (s, 3H), 1.36 (d, J = 6.2 Hz, 6H).

Example 12 : N-[4-( But -2 -yloxy )-[1,3] thiazolo [5,4-c] pyridin -2- yl ]-3-{[7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ] amino } propionamide 112 mg of colorless foam. HPLC/MS m/z: 503.8 [M+H] ⁺ , Rt (C): 1.96 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.76 (s, 1H), 8.89-8.88 (m, 1H), 8.15 (dd, J = 8.4, 1.5 Hz, 1H), 8.08 (d, J = 5.6 Hz, 1H), 8.05 (t, J = 5.5 Hz, 1H ), 7.97 (d, J = 5.7 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 5.6 Hz, 1H), 6.98 (d, J = 5.7 Hz, 1H), 5.30-5.25 (m, 1H), 3.85 (q, J = 6.6 Hz , 2H), 2.97 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 1.77-1.71 (m, 1H), 1.71-1.65 (m, 1H), 1.34 (d, J = 6.2 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H).

Example 13 : N-{4 -cyclobutoxy- [1,3] thiazolo [5,4-c] pyridin - 2- yl }-3-{[7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ] amino } propionamide 33 mg colorless solid. HPLC/MS m/z: 501.8 [M+H] ⁺ , Rt (A): 0.79 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.77 (s, 1H), 8.90-8.88 (m, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.06 (d, J = 5.7 Hz, 1H), 8.08-8.04 (m, 1H), 7 .97 (d, J = 5.7 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 5.7 Hz, 1H), 6.98 (d, J = 5.7 Hz, 1H), 5.36-5.31 (m, 1H), 3.85 (q, J = 6.5 Hz, 2H ), 2.97 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.47-2.42 (m, 2H), 2.17-2.10 (m, 2H), 1.84-1.78 (m, 1H), 1.71-1.63 (m, 1H).

Example 14 : N-[4-(3,3 -difluorocyclobutoxy )-[1,3] thiazolo [5,4-c] pyridin -2- yl ]-3-{[7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ] amino } propionamide 23 mg colorless solid. HPLC/MS m/z: 537.8 [M+H] ⁺ , Rt (C): 1.95 min. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 12.82 (s, 1H), 8.89 (s, 1H), 8.15 (dd, J = 8.4, 1.6 Hz, 1H), 8.10 (d, J = 5.7 Hz, 1H), 8.05 (t, J = 5.5 Hz, 1H), 7. 97 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 5.7 Hz, 1H), 6.97 (d, J = 5.8 Hz, 1H), 5.35-5.27 (m, 1H), 3.85 (q, J = 6.4 Hz, 2H) , 3.25-3.15 (m, 2H), 2.98 (t, J = 6.7 Hz, 2H), 2.89-2.77 (m, 2H), 2.69 (s, 3H).

Example 15 : N-[4-(3 -fluoropropoxy )-[1,3] thiazolo [5,4-c] pyridin -2- yl ]-3-{[7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1 -yl ] amino } propionamide 13 mg colorless solid. HPLC/MS m/z: 507.8 [M+H] ⁺ , Rt (A): 0.76 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.81-12.77 (m, 1H), 8.90-8.88 (m, 1H ) , 8.15 (dd, J = 8.4, 1.5 Hz, 1H), 8.09 (d , J = 5.7 Hz, 1H), 8.05 (t, J = 5.5 ( t, J = 5.8 Hz, 1H), 4.55 (t, J = 6.4 Hz, 2H), 3.85 (q, J = 6.6 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.19 (quint, J = 6.2 Hz, 1H), 2.15 (quint, J = 6 .1 Hz, 1H).

Example 16 : N-[4-(2,2 -difluoropropoxy )-[1,3] thiazolo [5,4-c] pyridin -2- yl ]-3-{[7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ] amino } propionamide 6 mg brown solid. HPLC/MS m/z: 525.9 [M+H] ⁺ , Rt (A): 0.78 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.87-12.84 (m, 1H), 8.89-8.88 (m, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.12 (d, J = 5.6 Hz, 1H), 8.05 (t, J = 5.5 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 5.6 Hz, 1H), 6.97 (d, J = 5.9 Hz, 1H), 4.76 (t, J = 13.1 Hz, 2H), 3.85 (q, J = 6.5 Hz, 2H), 2.98 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 1.76 (t, J = 19.1 Hz, 3H).

Example 17 : N-[4-(2,2 -difluoroethoxy )-[1,3] thiazolo [5,4-c] pyridin -2- yl ]-3-{[7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ] amino } propionamide 46 mg colorless solid. HPLC/MS m/z: 511.7 [M+H] ⁺ , Rt (A): 0.77 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.88 (s, 1H), 8.97-8.92 (m, 1H), 8.52-8.02 (m, 1H), 8.20 (s, 1H), 8.12 (d, J = 5.7 Hz, 1H), 7.94 (d, J = 5.8 Hz , 1H), 7.93-7.88 (m, 1H), 7.43 (d, J = 5.7 Hz, 1H), 7.08-7.00 (m, 1H), 6.56-6.38 (m, 1H), 4.77 (td, J = 14.9, 3.5 Hz, 2H), 3.87 (q, J = 6. 4 Hz, 2H), 3.01 (t, J = 6.7 Hz, 2H), 2.69 (s, 3H).

Example 18 : 3-{[7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1- yl ] amino }-N-[4-(2,2,2 -trifluoroethoxy )-[1,3] thiazolo [5,4-c] pyridin -2- yl ] propionamide 15 mg light yellow solid. HPLC/MS m/z: 529.7 [M+H] ⁺ , Rt (A): 0.80 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.90 (s, 1H), 8.90-8.88 (m, 1H), 8.17-8.15 (m, 1H), 8.14 (d, J = 5.7 Hz, 1H), 8.10-8.03 (m, 1H), 7.97 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 5.6 Hz, 1H), 6.98 (d, J = 5.6 Hz, 1H), 5.20 (q, J = 9.0 Hz, 2H), 3.86 (q, J = 6.4 Hz, 2H), 2. 99 (t, J = 6.7 Hz, 2H), 2.69 (s, 3H).

Example 19 : 3-{[7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1- yl ] amino }-N-{4-[(1,1,1- trifluoropropan -2- yl ) oxy ]-[1,3] thiazolo [5,4-c] pyridin -2- yl } propionamide 34 mg colorless solid. HPLC/MS m/z: 543.7 [M+H] ⁺ , Rt (A): 0.81 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.88 (s, 1H), 8.89-8.87 (m, 1H), 8.15 (dd, J = 8.4, 1.5 Hz, 1H), 8.14 (d, J = 5.7 Hz, 1H), 8.05 (t, J = 5.4 Hz, 1H ), 7.97 (d, J = 5.7 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 5.7 Hz, 1H), 6.97 (d, J = 5.6 Hz, 1H), 6.10-6.03 (m, 1H), 3.85 (q, J = 6.5 Hz , 2H), 2.98 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 1.54 (d, J = 6.5 Hz, 3H).

Example 20 : (1s,3s)-N-{4 -methoxy- [1,3] thiazolo [5,4-c] pyridin -2- yl }-3-{[7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1 -yl ] amino } cyclobutane -1- carboxamide Intermediate B3 (25.0 mg, 0.077 mmol) was dissolved in anhydrous DMF (1.0 mL) and treated with HATU (64.5 mg, 0.170 mmol) and N-ethyldiisopropylamine (59.8 mg, 0.463 mmol). 4-Methoxy-[1,3]thiazolo[5,4-c]pyridin-2-amine (14.6 mg, 0.077 mmol) was added, and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 10 mg (27%) of the title compound as a colorless solid. HPLC/MS m/z: 488.2 [M+H] ⁺ , Rt (D): 1.39 min. ¹ H NMR (700 MHz, methanol- _{d 4} ): δ 9.34-9.31 (m, 1H), 8.55-8.52 (m, 1H), 8.09 (d, J = 5.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 6.8 Hz, 1H) , 7.34 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 6.8 Hz, 1H), 4.56-4.51 (m, 1H), 4.11 (s, 3H), 3.39-3.34 (m, 1H), 3.01-2.96 (m, 2H), 2.81-2.75 (m , 2H), 2.74 (s, 3H).

The following examples were prepared in a similar manner.

Example 21 : (1s,3s)-N-{4- ethoxy- [1,3] thiazolo [5,4-c] pyridin -2- yl }-3-{[7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ] amino } cyclobutane -1- carboxamide 29 mg brown oil. HPLC/MS m/z: 502.2 [M+H] ⁺ , Rt (C): 2.00 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.70 (s, 1H), 9.04 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.22-8.06 (m, 1H), 8.10 (d, J = 5.7 Hz, 1H), 7.96 (d, J = 5 .8 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 5.6 Hz, 1H), 7.02-6.97 (m, 1H), 4.77-4.69 (m, 1H), 4.51 (q, J = 7.0 Hz, 2H), 3.22-3.16 (m , 1H), 2.71 (s, 3H), 2.68-2.62 (m, 2H), 2.51-2.45 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H).

Example 22 : (1s,3s)-3-{[7-(5- methyl -1,2,4- oxadiazol - 3- yl ) isoquinolin -1- yl ] amino }-N-{4 -propoxy- [1,3] thiazolo [5,4-c] pyridin -2- yl } cyclobutane -1- carboxamide 12 mg brown oil. HPLC/MS m/z: 516.2 [M+H] ⁺ , Rt (D): 1.52 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.76-12.64 (m, 1H), 9.03-9.01 (m, 1H), 8.16-8.14 (m, 1H), 8.12 (d, J = 7.2 Hz, 1H), 8.10 (d, J = 5.8 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 5.7 Hz, 1H), 6.98 (d, J = 5.7 Hz, 1H), 4.77-4.70 (m, 1H), 4.41 (t, J = 6.6 Hz, 2 H), 3.22-3.16 (m, 1H), 2.71 (s, 3H), 2.67-2.62 (m, 2H), 2.50-2.45 (m, 2H), 1.83-1.77 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).

Example 23 : N-{1- ethoxypyrrolo [1,2-a] pyrrol - 7- yl }-3-{[7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1- yl ] amino } propionamide Example 23.1: 1-Chloro-7-nitropyrrolo[1,2-a]pyrrolidone (190.0 mg, 0.962 mmol) was dissolved in ethanol (3 mL) and dichloromethane (3 mL), potassium hydroxide (200.0 mg, 3.565 mmol) was added, and the mixture was heated to 50 °C and stirred for 1.5 h. The dark brown solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness to give 172.5 mg (87%) of 1-ethoxy-7-nitropyrrolo[1,2-a]pyrrolidone as a reddish brown solid. HPLC/MS m/z: 208.1 [M+H] ⁺ , Rt (D): 1.54 min.

Example 23.2: 1-Ethoxy-7-nitropyrrolo[1,2-a]pyrrolidone (172.5 mg, 0.833 mmol), zinc powder (272.3 mg, 4.164 mmol) and ammonium acetate (770.4 mg, 9.994 mmol) were suspended in ethanol (5.0 mL), and the mixture was heated to 80 °C and stirred for 2 minutes. The reaction mixture was cooled to room temperature, filtered and the filter cake was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and extracted with water and 2N NaOH. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness to give 145 mg (98%) of 1-ethoxypyrrolo[1,2-a]pyrrolidine-7-amine as a brown gum. HPLC/MS m/z: 178.1 [M+H] ⁺ , Rt (D): 0.82 min.

Example 23.3: 3-{[(tert-Butoxy)carbonyl]amino}propionic acid (63.4 mg, 0.335 mmol), 1-ethoxypyrrolo[1,2-a]pyrrolidine-7-amine (57.7 mg, 0.305 mmol) and HATU (140.5 mg, 0.366 mmol) were suspended in DMF (2.0 mL). N-Ethyldiisopropylamine (104.7 µl, 0.610 mmol) was added and the clear brown solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with 30 ml of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography to give 76.5 mg (72%) of tert-butyl N-[2-({1-ethoxypyrrolo[1,2-a]pyrrol-7-yl}carbamyl)ethyl]carbamate as an off-white solid. HPLC/MS m/z: 349.2 [M+H] ⁺ , Rt (D): 1.28 min.

Example 23.4: Intermediate 23.3 (76.5 mg, 0.220 mmol) was dissolved in 1,4-dioxane (1.0 mL) and treated with HCl in 1,4-dioxane (4 M, 1.5 mL). The mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was used in the next step without further purification. Yield: 70.5 mg (100%) of 3-amino-N-{1-ethoxypyrrolo[1,2-a]pyrrol-7-yl}propanamide dihydrochloride as a light orange solid. HPLC/MS m/z: 249.1 [M+H] ⁺ , Rt (D): 0.86 min.

Example 23.5: The amide coupling reaction was carried out as described for intermediate B3.1. Yield: 11 mg (13%) of N-{1-ethoxypyrrolo[1,2-a]pyrrol-7-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propanamide as a colorless solid. HPLC/MS m/z: 458.1 [M+H] ⁺ , Rt (D): 1.26 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 10.30-10.27 (m, 1H), 8.94-8.89 (m, 1H), 8.19-8.14 (m, 1H), 8.09-7.95 (m, 2H), 7.99 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 4.7, 0.8 Hz, 1H), 7.89-7.85 (m, 1H), 7.03 (d, J = 4.7 Hz, 1H), 7.02-6.97 (m, 1H), 6.56-6.55 (m, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.8 1 (q, J = 6.6 Hz, 2H), 2.77 (t, J = 7.0 Hz, 2H), 2.70 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H).

Example 24 : 3-{[7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1- yl ] amino }-N-{1 -propoxypyrrolo [ 1,2 -a] pyrrol- 7- yl } propanamide Prepared as described for Example 23. Yield: 16 mg light yellow solid. HPLC/MS m/z: 472.1 [M+H] ⁺ , Rt (D): 1.33 min. ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 10.26 (s, 1H), 8.90-8.88 (m, 1H), 8.16-8.14 (m, 1H), 8.03-7.99 (m, 1H), 8.00 (d, J = 5.7 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.90 (dd, J = 4.7, 0.9 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 4.8 Hz, 1H), 6.97 (d, J = 5.7 Hz, 1H), 6.58-6.57 (m, 1H), 4 .32 (t, J = 6.6 Hz, 2H), 3.83-3.79 (m, 2H), 2.75 (t, J = 7.0 Hz, 2H), 2.69 (s, 3H), 1.79-1.73 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

Example 25 : 11-[2-[[7-(5 -methyl -1,2,4- oxadiazol-3 - yl )-1- isoquinolinyl ] amino ] ethyl ]-6-(2,2,2- trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] trideca -2,4,6,8 - tetraen -10- one Example 25.1: A suspension of methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (600.00 mg, 2.8487 mmol), 2,2,2-trifluoroethanol (0.37 mL, 4.9853 mmol), cesium carbonate (1600.00 mg, 4.9107 mmol), tBuBrettPhos Pd G3 (97.36 mg, 0.1139 mmol), tBuBrettPhos (110.46 mg, 0.2279 mmol) and 4Å MS (1600 mg) in toluene (4.00 mL, 0.3600 M) and THF (4.00 mL, 0.3600 M) was heated at 80 °C in a sealed vial for 22 h. The reaction mixture was filtered and washed with EtOAc (100 mL). Purification by NP silica gel column chromatography (solvent: 20 to 80% EtOAc/cyclohexane) gave methyl 4-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (658.4 mg, 79%, 2.2571 mmol) as a cream solid. HPLC/MS m/z 275.0579 [M+H] ⁺ , Rt (Y): 1.48 min. ¹ H NMR (600 MHz, chloroform-d): δ 9.14 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.38-7.33 (m, 1H), 7.04 (dd, J = 5.9, 1.0 Hz, 1H), 4.92 (q, J = 8.5 Hz, 2H), 3.96 (s, 3H).

Example 25.2: A solution of methyl 4-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (600.00 mg, 2.0569 mmol), tert-butyl N-hydroxyethylcarbamate (0.57 mL, 3.7024 mmol) and triphenylphosphine (809.25 mg, 3.0853 mmol) in THF (5.14 mL, 0.4000 M) was cooled to 0° C. Diisopropyl azodicarboxylate (0.65 mL, 3.291 mmol) was added dropwise over 20 min, and the resulting mixture was warmed to RT and stirred for 18 h. The crude product was evaporated and subjected to NP silica gel column chromatography (0 to 60% EtOAc/cyclohexane) to give methyl 1-[2-(tert-butoxycarbonylamino)ethyl]-4-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxylate (867.2 mg, 101%, 2.0777 mmol) as a colorless solid. HPLC/MS m/z 418.1587 [M+H] ⁺ , Rt (R): 1.49 min. ¹ H NMR (600 MHz, chloroform-d): δ 7.87 (d, J = 6.1 Hz, 1H), 7.47 (d, J = 0.9 Hz, 1H), 7.09 (d, J = 6.1 Hz, 1H), 4.91 (q, J = 8.6 Hz, 2H), 4.64 (dt, J = 19. 4, 6.1 Hz, 3H), 3.91 (s, 3H), 3.52 (q, J = 6.0 Hz, 2H), 1.39 (s, 9H). ¹³ C NMR (151 MHz, CHLOROFORM-d): δ 162.09, 157.04, 156.10, 145.63, 140.51, 127.04, 124.81, 122.97, 110.88, 109.90, 102.59, 79.80, 62.52, 62.29, 62.05, 61.81, 52.07, 44.99, 41.37, 28.46.

Example 25.3: Methyl 1-[2-(tert-butoxycarbonylamino)ethyl]-4-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxylate (867.20 mg, 2.0777 mmol) was mixed with 4N HCl in dioxane (20.78 mL, 83.109 mmol) and 1,4-dioxane (20.78 mL, 0.1000 M) at RT under nitrogen and stirred for 2 h. The volatiles were removed under reduced pressure. The crude solid was washed with chloroform to obtain methyl 1-(2-aminoethyl)-4-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxylate hydrochloride (724.2 mg, 99%, 2.0474 mmol) as a light yellow solid. HPLC/MS m/z 318.1071 [M+H-HCl] ⁺ , Rt (Y): 1.13 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.40 (d, J = 5.9 Hz, 2H), 7.97 (d, J = 6.1 Hz, 1H), 7.68 (dd, J = 6.2, 0.9 Hz, 1H), 7.31 (d, J = 0.9 Hz, 1H), 5.17 (q, J = 9.1 Hz, 2H), 4.81 (t, J = 6.8 Hz, 2H), 3.88 (s, 3H), 3.18 (sext, J = 6.1 Hz, 2H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 160.92, 155.97, 144.96, 140. 29, 127.48, 126.85, 125.01, 123.17, 121.33, 109.93, 108.19, 103.21, 61.43, 61.20, 60.97, 60.74, 52.18, 52.10, 42.60, 38.87.

Example 25.4: Crude methyl 1-(2-aminoethyl)-4-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxylate hydrochloride was dissolved in EtOH (9.33 mL, 0.2100 M) and triethylamine (1.39 mL, 9.8948 mmol) and the mixture was stirred at 80° C. overnight. The crude mixture was evaporated under reduced pressure, redissolved in DCM and water was added. The water was extracted several times with DCM and the combined organic layers were washed, dried over MgSO ₄ and evaporated under reduced pressure to give 6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (566.4 mg, 100%, 1.9858 mmol) as a white solid. It was used in the next step without further purification. HPLC/MS m/z 286.0760 [M+H] ⁺ , Rt (Y): 1.27 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.28 (t, J = 2.8 Hz, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.33 (dd, J = 6.0, 0.9 Hz, 1H), 7.00 (d, J = 0.9 Hz, 1H), 5.16 (q, J = 9.1 Hz, 2H), 4.34-4.29 (m, 2H), 3.67-3.61 (m, 2H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 159.43, 155.70, 141.63, 138.92, 130.05, 125.07, 123.23, 110.51, 103.03, 101.45, 61.22, 60.99, 60.76 , 60.53, 40.78, 39.44.

Example 25.5: 6-(2,2,2-Trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (600.00 mg, 2.1036 mmol) was dissolved in DMF (30.05 mL, 0.0700 M). The resulting solution was cooled down to 0 °C in an ice bath, followed by the addition of NaH (168.29 mg, 4.2073 mmol). The reaction mixture was stirred at 0 °C for 30 min. N -Boc-2-chloroethylamine (467.50 mg, 2.5244 mmol) dissolved in DMF (2.5 mL) was added dropwise to the reaction mixture and allowed to warm to RT. The reaction mixture was stirred at RT for 2 days. 0.6 eq. of N -Boc-2-chloroethylamine reagent was added to the reaction cooled to 0 °C, followed by another 1 eq. of NaH and the reaction was stirred at RT overnight. Water was added and the reaction was extracted with EtOAc (3x), and the combined organic layers were washed with brine, dried over MgSO ₄ and evaporated under reduced pressure. The crude was subjected to NP chromatography (0 to 100% EtOAc: cyclohexane) to afford tert-butyl N-[2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]ethyl]carbamate (694.7 mg, 77%, 1.6216 mmol). HPLC/MS m/z 429.1699 [M+H] ⁺ , Rt(Y): 1.48 min. ¹ H NMR (600 MHz, chloroform-d): δ 7.88 (d, J = 6.0 Hz, 1H), 7.39-7.36 (m, 1H), 6.90 (dd, J = 6.0, 0.9 Hz, 1H), 4.92 (q, J = 8.5 Hz, 2H), 4.30-4.25 (m, 2H), 3.89-3.84 (m, 2H), 3.73 (t, J = 6.1 Hz, 2H), 3.43 (q, J = 6.1 Hz, 2H), 1.35 (s, 9H).

Example 25.6: tert-Butyl N-[2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-11-yl]ethyl]carbamate (52.00 mg, 0.1214 mmol) was mixed with 4N HCl in 1,4-dioxane (5.60 mL, 22.408 mmol) and 1,4-dioxane (5.60 mL, 0.1000 M) at RT under nitrogen and stirred for 2 h. The volatiles were removed under reduced pressure to give 11-(2-aminoethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one; hydrochloride (199.4 mg). The solid salt was redissolved in MeOH and passed through an SCX-II column, released with 2N _NH3 in methanol to give 11-(2-aminoethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (180 mg, 98%, 0.5483 mmol) as a white solid. HPLC/MS m/z 329.1221 [M+H] ⁺ , Rt (R): 0.84 min.

Example 25.7: DIPEA (0.28 mL, 1.5992 mmol) was added dropwise to a suspension of 11-(2-aminoethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (140.00 mg, 0.4265 mmol), 5-methyl-3-(2-oxoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole (116.28 mg, 0.5117 mmol) and PyBrop (238.56 mg, 0.5117 mmol) in DCM (3.55 mL, 0.1200 M). The tube was sealed and heated to 60 °C in a microwave for 1 hour. The reaction was evaporated in vacuo and subjected to RP column chromatography (10 to 80% MeOH:water + 0.1% formic acid) to give partially pure product. The pure fraction was run through an SCX-II column, liberated with 2N NH ₃ in methanol and evaporated. The second subsequent RP column gave 11-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]ethyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (61.4 mg, 27%, 0.1142 mmol) as a cream-colored powder. HPLC/MS m/z 538.1807 [M+H] ⁺ , Rt (Z): 2.33 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.89-8.86 (m, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.07 (t, J = 5.5 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.88 (d, J = 6 .0 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 6.0, 0.9 Hz, 1H), 7.00 (d, J = 0.9 Hz, 1H), 6.96 (dd, J = 5.8, 0.8 Hz, 1H), 5.15 (q, J = 9.1 Hz , 2H), 4.37-4.32 (m, 2H), 3.88-3.82 (m, 4H), 3.79 (q, J = 5.8 Hz, 2H), 2.67 (s, 3H). ¹³ C NMR (151 MHz, DMSO-d6): δ 177.47, 167.60, 158.33, 155.73, 155.65, 143.49, 141.36, 138.90, 138.42, 130.03, 127.68, 127.34, 123. 33, 122.70, 117.56, 110.71, 109.32, 102.89, 101.56, 60.79, 46.59, 45.57, 40.58, 39.14, 12.03.

The intermediates of the following examples were prepared in a similar manner.

Example 26 : 3-(2 -methyltetrazol - 5- yl )-N-[2-[10 -oxo- 6-(2,2,2 -trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] tridec -2,4,6,8 -tetraen -11 - yl ] ethyl ] benzamide Example 26.1: DIPEA (0.03 mL, 0.1462 mmol) was added to a mixture of 3-(2-methyl-2H-tetrazol-5-yl)-benzoic acid (8.58 mg, 0.0420 mmol), HATU (27.80 mg, 0.0731 mmol) and 11-(2-aminoethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one [Example 25.6] (12.00 mg, 0.0366 mmol) in DCM (0.37 mL, 0.1000 M). This was stirred for 2 h before saturated _aqueous NaHCO3 was added. This was extracted with DCM, dried over MgSO ₄ and evaporated. The compound was subjected to RP column chromatography (10 to 80% MeOH: water + 0.1% formic acid) to give 3-(2-methyltetrazol-5-yl)-N-[2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]ethyl]benzamide (11.9 mg, 63%, 0.0231 mmol) as a white solid. HPLC/MS m/z 515.1753 [M+H] ⁺ , Rt (Z): 2.54 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.87 (t, J = 5.8 Hz, 1H), 8.50 (t, J = 1.8 Hz, 1H), 8.18 (dt, J = 7.7, 1.4 Hz, 1H), 7.95 (dt, J = 7.8, 1.5 Hz, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.32 (dd, J = 6.0, 0.9 Hz, 1H), 7.01 (d, J = 0.9 Hz, 1H), 5.15 (q, J = 9.2 Hz, 2H), 4.44 (s, 3 H), 4.40 (dd, J = 6.9, 4.7 Hz, 2H), 3.93-3.88 (m, 2H), 3.74 (t, J = 6.0 Hz, 2H), 3.58 (q, J = 5.9 Hz, 2H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 166.30, 164.14, 158.90, 156.12, 141.84, 139.41, 135.93, 130.35, 129.89, 129.55, 129.25, 127.54, 125 .54, 123.68, 111.17, 103.37, 102.14, 61.48, 61.26, 61.03, 46.58, 46.20, 41.10, 40.17, 37.90.

Example 27 : 3-(2 -methyltetrazol - 5- yl )-N-[1,1,2,2 -tetradeutero -2-[10 -oxo- 6-(2,2,2 -trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] trideca -2(7),3,5,8- tetraen - 11 - yl ] ethyl ] benzamide Example 27.1: To a stirred suspension of 6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (700.00 mg, 2.4542 mmol) in DMF (35.06 mL, 0.0700 M) was added NaH (60% dispersion in mineral oil) (215.97 mg, 5.3993 mmol) portionwise at RT and then stirred at 60° C. for 30 min. The reaction was cooled to RT and to this solution was added 1,2-dibromoethane- d ₄ (1.06 mL, 12.271 mmol) and stirred at RT overnight. The reaction mixture was poured into water, and the precipitated solid was collected by filtration to give 11-(2-bromo-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (249.8 mg, 26%, 0.6305 mmol) as a white solid. HPLC/MS m/z 396.0402 [M+H, ⁷⁹ Br] ⁺ , Rt (Y): 1.42 min. ¹ H NMR (600 MHz, chloroform-d): δ 7.90 (d, J = 6.0 Hz, 1H), 7.41 (d, J = 0.9 Hz, 1H), 6.93 (dd, J = 6.0, 0.9 Hz, 1H), 4.92 (q, J = 8.6 Hz, 2H), 4.36-4.30 (m, 2H), 4.01-3.95 (m, 2H). Water and ethyl acetate were then added. The organic layer was separated and dried over anhydrous MgSO ₄ . After filtration, the solvent was removed under reduced pressure to give 11-(1,1,2,2-tetradeutero-2-hydroxy-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (398.8 mg, 49%, 1.1965 mmol) as a pure white solid. HPLC/MS m/z 334.1234 [M+H] ⁺ , Rt (Y): 1.22 min. ¹ H NMR (600 MHz, chloroform-d): δ 7.85 (dd, J = 10.3, 6.0 Hz, 1H), 7.31 (d, J = 0.9 Hz, 1H), 6.88 (ddd, J = 17.1, 6.0, 0.9 Hz, 1H), 4.88 (dq, J = 23.7, 8 .5 Hz, 2H), 4.29-4.23 (m, 2H), 3.96-3.90 (m, 2H).

Example 27.2: To a stirred solution of sodium azide (43.32 mg, 0.6663 mmol) in DMF (4.04 mL, 0.1500 M) was added 11-(2-bromo-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (240.00 mg, 0.6058 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was then cooled to RT and diluted with water (5 mL). The mixture was extracted with ethyl acetate (3×5 mL) and washed with brine, dried over MgSO ₄ and concentrated in vacuo to give 11-(2-azido-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (158.4 mg, 73%, 0.4421 mmol) as a yellow solid. It was used directly without further purification. Rt (Y): 1.40 min

Example 27.3: To a solution of 11-(2-azido-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (200.00 mg, 0.5582 mmol) in THF (5.14 mL, 0.0800 M) was added triphenylphosphine (439.21 mg, 1.6745 mmol). The mixture was stirred at RT for 48 h, then _H2O (1.84 mL, 0.0800 M) was added, and the reaction was heated to 60 °C and allowed to stir for 4 h. The solvent was removed by reduced pressure, and the resulting residue was purified by an ultra-short silica gel column (eluted with 1:10 to 1:5 methanol-DCM) to give 11-(2-amino-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (93.1 mg, 50%, 0.2802 mmol) as a white solid. HPLC/MS m/z 333.1480 [M+H] ⁺ , Rt (R): 0.83 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 7.90 (d, J = 6.0 Hz, 1H), 7.33 (dd, J = 6.0, 0.9 Hz, 1H), 6.99 (d, J = 0.9 Hz, 1H), 5.16 (q, J = 9.1 Hz, 2H), 4.41-4. 37 (m, 2H), 3.87-3.81 (m, 2H).

Example 27.4: DIPEA (0.08 mL, 0.4606 mmol) was added to a mixture of 3-(2-methyl-2H-tetrazol-5-yl)-benzoic acid (31.80 mg, 0.1557 mmol), HATU (102.98 mg, 0.2708 mmol) and 11-(2-amino-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (45.00 mg, 0.1354 mmol) in DCM (1.35 mL, 0.1000 M). This was stirred for 2 h before saturated _aqueous NaHCO3 was added. This was extracted with DCM, filtered over MgSO ₄ and evaporated. Silica gel chromatography using DCM and MeOH as solvent (100:0 to 96:4) gave a slightly impure product by NMR. The compound was subjected to RP column chromatography (10 to 80% MeOH:water + 0.1% formic acid) and the eluate was run through an SCX-II column, liberated with 2N NH3 in _methanol to give after evaporation 3-(2-methyltetrazol-5-yl)-N-[1,1,2,2-tetradeutero-2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2(7),3,5,8-tetraen-11-yl]ethyl]benzamide as a fine white solid (28.7 mg, 41%, 0.0554 mmol). HPLC/MS m/z 519.1961 [M+H] ⁺ , Rt(Z): 2.50 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.84 (s, 1H), 8.50 (t, J = 1.8 Hz, 1H), 8.18 (dt, J = 7.8, 1.4 Hz, 1H), 7.97-7.92 (m, 1H), 7.89 (d, J = 6.0 Hz, 1H ), 7.65 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 6.0, 0.9 Hz, 1H), 7.00 (d, J = 0.9 Hz, 1H), 5.15 (q, J = 9.1 Hz, 2H), 4.43 (s, 3H), 4.41-4.37 (m, 2H ), 3.92-3.87 (m, 2H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 204.66, 166.30, 164.14, 158.89, 156.12, 141.84, 139.40, 135.94, 130.36, 129.88, 129.55, 129.24, 127 .54, 127.37, 125.54, 123.68, 111.17, 103.37, 102.12, 61.71, 61.49, 61.26, 61.03, 46.51, 41.09, 40.17.

Example 28 : 3-(5 -methyl -1,2,4 - oxadiazol - 3- yl )-N-[1,1,2,2 -tetradeutero -2-[10 -oxo -6-(2,2,2 -trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] trideca -2(7),3,5,8- tetraen -11- yl ] ethyl ] benzamide DIPEA (0.09 mL, 0.5417 mmol) was added to a mixture of 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (31.80 mg, 0.1557 mmol), HATU (102.98 mg, 0.2708 mmol) and 11-(2-amino-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (45.00 mg, 0.1354 mmol) in DCM (1.35 mL, 0.1000 M). This was stirred for 2 hours before saturated aqueous _NaHCO3 was added. This was extracted with DCM, filtered over _MgSO4 and evaporated. Silica gel chromatography using DCM and MeOH as solvents (100:0 to 96:4) gave a slightly impure product by NMR. The compound was subjected to RP column chromatography (10 to 80% MeOH:water + 0.1% formic acid) and the clean fractions were collected and evaporated to give 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-[1,1,2,2-tetradeutero-2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl]ethyl]benzamide (19.5 mg, 28%, 0.0376 mmol) as a fine white solid. HPLC/MS m/z 519.1847 [M+H] ⁺ , Rt (Z): 2.60 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.84 (s, 1H), 8.43 (t, J = 1.7 Hz, 1H), 8.11 (dt, J = 7.7, 1.3 Hz, 1H), 7.99 (ddd, J = 7.8, 1.8, 1.2 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.31 (dd, J = 6.0, 0.9 Hz, 1H), 7.00 (d, J = 0.9 Hz, 1H), 5.15 (q, J = 9.1 Hz, 2H), 4.42-4.37 (m, 2H), 3.91-3.86 (m, 2H), 2.67 (s, 3H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 178.14, 167.72, 166.18, 158.90, 156.13, 141.84, 139.40, 135.92, 130.49, 130.36, 129.86, 126.92, 126 .21, 125.53, 123.68, 121.84, 111.17, 103.37, 102.14, 61.72, 61.49, 61.26, 61.03, 46.49, 41.09, 12.48.

Example 29 : 11-[1,1,2,2- tetradeutero -2-[[7-(5 -methyl -1,2,4- oxadiazol -3- yl )-1- isoquinolinyl ] amino ] ethyl ]-6-(2,2,2 -trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] trideca -2(7),3,5,8- tetraen -10- one Example 29.1: To an anhydrous 250 mL round-bottom flask equipped with a stir bar under _N2 was added p-toluenesulfonyl chloride (188.76 mg, 0.9901 mmol), 4-dimethylaminopyridine (11.00 mg, 0.0900 mmol), triethylamine (0.25 mL, 1.8002 mmol) and DCM (3.00 mL, 0.1500 M). The resulting mixture was cooled to 0 °C, and a solution of 11-(1,1,2,2-tetradeutero-2-hydroxy-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (300.00 mg, 0.9001 mmol) in DCM (3.00 mL, 0.1500 M) was added dropwise. The mixture was warmed to RT and allowed to stir overnight. The solution was then washed with saturated aqueous NaHCO ₃ (120 mL) and H ₂ O (120 mL). The combined aqueous layers were extracted with DCM (120 mL) and the combined organic _layers were dried over _Na2SO4 , decanted, and concentrated in vacuo. The residue was purified by flash column chromatography (0 to 80% EtOAc:cyclohexane) to afford 11-(2-chloro-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (208.2 mg, 66%, 0.5919 mmol) as a white solid. HPLC/MS m/z 352.0974 [M+H, ³⁵ Cl] ⁺ , Rt (R): 1.27 min. ¹ H NMR (600 MHz, chloroform-d ): δ 7.91 (d, J = 6.0 Hz, 1H), 7.41 (d, J = 0.9 Hz, 1H), 6.93 (dd, J = 6.0, 0.9 Hz, 1H), 4.92 (q, J = 8.5 Hz, 2H), 4.34-4.29 (m, 2H), 4.01-3.96 (m, 2H).

Example 29.2: To a stirred solution of sodium azide (39.64 mg, 0.6098 mmol) in DMF (3.70 mL, 0.1500 M) was added 11-(2-chloro-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (195.00 mg, 0.5544 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was then cooled to RT and diluted with water (5 mL). The mixture was extracted with ethyl acetate (3 x 5 mL) and washed with brine, dried over MgSO ₄ and concentrated in vacuo to afford 11-(2-azido-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (153.2 mg, 77%, 0.4276 mmol) as a yellow solid. It was used directly without further purification. HPLC/MS m/z 359.1377 [M+H] ⁺ , Rt (R): 1.25 min.

Example 29.3: To a solution of 11-(2-azido-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (150.00 mg, 0.4186 mmol) in THF (5.14 mL, 0.0600 M) was added _PPh3 (329.41 mg, 1.2559 mmol). The mixture was stirred at RT for 48 h, then _H2O (1.84 mL, 0.0600 M) was added, and the reaction was heated to 60 °C and allowed to stir for 4 h. The solvent was removed by reduced pressure, and the resulting residue was purified by an ultra-short silica gel column (using 1:10 to 1:5 methanol-DCM) to give 11-(2-amino-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (73.9 mg, 53%, 0.2224 mmol) as a white solid. HPLC/MS m/z 333.1467 [M+H] ⁺ , Rt (R): 0.84 min.

Example 29.4: DIPEA (0.14 mL, 0.7899 mmol) was added dropwise to 11-(2-amino-1,1,2,2-tetradeutero-ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (70.00 mg, 0.2106 mmol), 5-methyl-3-(2-oxoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole (57.44 mg, 0.2528 mmol) and PyBrop (117.84 mg, 0.2528 mmol). The tube was sealed and this was heated to 60 °C in a microwave for 1 hour. Water was added and this was extracted with DCM. The organic layer was dried over MgSO ₄ and evaporated in vacuo. NP silica gel column chromatography (0 to 7% MeOH/DCM) gave almost pure product. A second NP column (0 to 4% MeOH/DCM) afforded pure 11-[1,1,2,2-tetradeutero-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]ethyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (63.6 mg, 56%, 0.1174 mmol) as a cream solid. HPLC/MS m/z 542.2065 [M+H] ⁺ , Rt (Z): 2.32 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.89-8.85 (m, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.88 (d, J = 6.0 Hz, 1H) , 7.85 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 6.1, 0.9 Hz, 1H), 7.00 (d, J = 0.9 Hz, 1H), 6.96 (dd, J = 5.9, 0.8 Hz, 1H), 5.15 (q, J = 9.1 Hz, 2H), 4. 37-4.32 (m, 2H), 3.88-3.83 (m, 2H), 2.67 (s, 3H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 177.46, 167.61, 158.33, 155.76, 155.65, 143.50, 141.36, 138.90, 138.42, 130.04, 127.67, 127.33, 126 .91, 125.07, 123.33, 123.22, 122.71, 121.40, 117.56, 110.71, 109.30, 102.89, 101.55, 61.25, 61.02, 60.79, 60.56, 46.51, 40.58, 12.03.

Example 30 : 3-(5 -methyltetrazol - 2- yl )-N-[2-[10 -oxo- 6-(2,2,2 -trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] tridec -2,4,6,8 -tetraen -11 - yl ] ethyl ] benzamide Example 30.1: Ethyl 3-aminobenzoate (0.81 mL, 5 mmol) was dissolved in a mixture of water (1.00 mL) and 50% aqueous hydrofluoroboric acid (1.90 mL, 30.293 mmol). Sodium nitrite (689.90 mg, 10 mmol) was dissolved in water (1.00 mL) and added dropwise. The reaction was stirred at 0 °C for 30 min and the formation of a light pink solid was observed. The reaction was filtered and the solid was washed with _Et2O . The solid was transferred to a flask and dried in vacuo for 30 min to give 3-ethoxycarbonylbenzodiazolium tetrafluoroboron (1.10 g, 83%, 4.167 mmol) as a light pink powder. Rt (T): 1.36 min.

Example 30.2: To a solution of acetamidine hydrochloride (0.39 g, 4.167 mmol) and _K2CO3 (2.88 g, 20.835 mmol) in _DMSO (20.25 mL) was added 3-ethoxycarbonylbenzodiazolium tetrafluoroboron (1.10 g, 4.167 mmol) in portions. After stirring at RT for 1.5 h, KI (1.04 g, 6.2505 mmol) and iodine (1.27 g, 5.0004 mmol) were added and stirred at RT for 1.5 _h . Brine and a solution of _Na2S2O3 were added to the mixture. The product was extracted with EtOAc, the organic layer was dried _{over MgSO4} and concentrated in vacuo. The crude product was purified by NP silica gel column chromatography (solvent: 5-30% EtOAc/cyclohexane) to obtain ethyl 3-(5-methyltetrazol-2-yl)benzoate (582 mg, 60%, 2.506 mmol) as a yellow powder. HPLC/MS m/z 233.0991 [M+H] ⁺ , Rt (T): 1.36 min. ¹ H NMR (500 MHz, DMSO- d ₆ ): δ 8.55-8.52 (m, 1H), 8.36 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 8.14 (dt, J = 7.9, 1.2 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H) , 4.39 (q, J = 7.1 Hz, 2H), 2.61 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).

Example 30.3: Ethyl 3-(5-methyltetrazol-2-yl)benzoate (150.00 mg, 0.6459 mmol) was dissolved in THF (3.23 mL) and _H2O (1.00 mL, 0.1500M). LiOH (77.34 mg, 3.2294 mmol) was added, and the mixture was stirred at 50 °C for 2 h. The mixture was cooled to RT, concentrated, and diluted with 1 mL of water. The pH was adjusted to pH ca. 3 and the product was extracted with EtOAc (60 mL). After phase separation, the organic layer was dried over _MgSO4 , filtered and evaporated to dryness to give 3-(5-methyltetrazol-2-yl)benzoic acid (142 mg, 108%, 0.6954 mmol) as a yellow powder. The product was carried forward to the next step without further purification. HPLC/MS m/z 205.0723 [M+H] ⁺ , Rt (R): 1.09 min.

Example 30.4: DIPEA (0.08 mL, 0.4606 mmol) was added to a mixture of 3-(5-methyltetrazol-2-yl)benzoic acid (27.04 mg, 0.1324 mmol), HATU (87.56 mg, 0.2303 mmol) and 11-(2-aminoethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one hydrochloride (42.00 mg, 0.1151 mmol) in DCM (1.15 mL, 0.1000 M). This was stirred for 2 h before saturated aqueous _NaHCO3 was added. This was extracted with DCM, filtered over MgSO ₄ and evaporated. Silica gel chromatography using DCM and MeOH as solvent (100:0 to 96:4) gave a slightly impure product by NMR. The compound was subjected to RP column chromatography (10 to 80% MeOH:water + 0.1% formic acid) and the eluted fraction was passed through an SCX-II column, released with 2N NH ₃ in methanol to give after evaporation 3-(5-methyltetrazol-2-yl)-N-[2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]ethyl]benzamide as a fine white solid (34.3 mg, 56%, 0.0650 mmol). HPLC/MS m/z 515.1768 [M+H] ⁺ , Rt (S): 2.84 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.94 (t, J = 5.8 Hz, 1H), 8.47 (t, J = 2.0 Hz, 1H), 8.20 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.98 (dt, J = 7.9, 1.3 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.31 (dd, J = 6.0, 0.9 Hz, 1H), 6.99 (d, J = 0.9 Hz, 1H), 5.14 (q, J = 9.1 Hz, 2H), 4.42 -4.37 (m, 2H), 3.92-3.87 (m, 2H), 3.76-3.71 (m, 2H), 3.59 (q, J = 5.9 Hz, 2H), 2.59 (s, 3H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 165.57, 163.69, 158.93, 156.12, 141.85, 139.41, 136.77, 136.62, 130.81, 130.33, 128.85, 127.36, 125 .52, 123.68, 122.52, 118.77, 111.17, 103.37, 102.14, 61.72, 61.49, 61.26, 61.03, 46.54, 46.15, 41.09, 37.95, 10.99.

Example 31 : 11-[2-[[7-(2 - methyltetrazolyl- 5-yl ) -1- isoquinolinyl ] amino ] ethyl ]-6-(2,2,2 -trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] trideca -2,4,6,8- tetraen -10- one Example 31.1: To a stirred solution of 5-bromo-2-methyl-1H-tetrazole (75.00 mg, 0.4602 mmol), isoquinoline-7-boronic acid (103.48 mg, 0.5982 mmol), sodium carbonate (73.16 mg, 0.6903 mmol) in a mixture of DME (1.84 mL, 0.2000 M)/water (0.46 mL, 0.2000 M) 4:1 under an atmosphere of argon was added Pd(PPh ₃ ) ₄ (53.18 mg, 0.0460 mmol). The solution was stirred at 90° C. for 18 h and then treated with water. In a standard work-up, the mixture was extracted with DCM and the organic layer was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude material was purified by NP column chromatography (20 to 100% EtOAc:cyclohexane) to give 7-(2-methyltetrazol-5-yl)isoquinoline (72.74 mg, 75%, 0.3444 mmol) as a light yellow solid. HPLC/MS m/z 212.0929 [M+H] ⁺ , Rt (Y): 0.81 min. ¹ H NMR (600 MHz, chloroform-d): δ 9.37 (t, J = 0.9 Hz, 1H), 8.82-8.78 (m, 1H), 8.60 (d, J = 5.7 Hz, 1H), 8.44 (dd, J = 8.6, 1.6 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 5.7 Hz, 1H), 4.46 (s, 3H).

Example 31.2: 7-(2-Methyltetrazol-5-yl)isoquinoline (70.00 mg, 0.3314 mmol) was dissolved in chloroform (2.53 mL, 0.1300 M) and cooled in an ice bath. 3-Chloroperoxybenzoic acid (98.04 mg, 0.3977 mmol) was added. The reaction was stirred at room temperature overnight. K ₂ CO ₃ (183.22 mg, 1.3256 mmol) was added. This was stirred at RT for 4 h before filtering through a pad of anhydrous MgSO ₄ . The filtrate was concentrated in vacuo to give 7-(2-methyltetrazol-5-yl)-2-oxo-isoquinolin-2-ium (78.5 mg, 104%, 0.3455 mmol) as an off-white powder. Significant triphenylphosphine oxide impurity from the ligand was carried forward to the next reaction. HPLC/MS m/z 228.0809 [M+H] ⁺ , Rt (Y): 0.92 min. ¹ H NMR (600 MHz, chloroform-d): δ 8.88 (t, J = 1.3 Hz, 1H), 8.56-8.53 (m, 1H), 8.34 (dd, J = 8.5, 1.5 Hz, 1H), 8.20 (dd, J = 7.1, 1.8 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 4.46 (s, 3H),

Example 31.3: 7-(2-Methyltetrazol-5-yl)-2-oxo-isoquinolin-2-ium (58.14 mg, 0.2559 mmol), PyBrop (119.28 mg, 0.2559 mmol) and DIPEA (0.14 mL, 0.7996 mmol) in DCM (1.08 mL, 0.1200 M) was stirred in a microwave vial under nitrogen atmosphere at 40 °C for 30 min. Then 11-(2-aminoethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (70.00 mg, 0.2132 mmol) in DCM (0.70 mL, 0.1200 M) was added and the reaction was heated at 60 °C for 1 hour by microwave irradiation. Water was added and this was extracted with DCM. The organic layer was dried over MgSO ₄ and evaporated in vacuo. The product was purified using normal phase chromatography (0 to 5% MeOH/DCM) followed by two additional RP columns (10 to 80% MeOH:water + 0.1% formic acid) and the eluate was passed through an SCX-II column and released with 2N _NH3 in methanol to give 11-[2-[[7-(2-methyltetrazol-5-yl)-1-isoquinolinyl]amino]ethyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (6.5 mg, 5%, 0.0114 mmol) as a white solid. HPLC/MS m/z 538.1939 [M+H] ⁺ , Rt(Z): 2.25 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.95 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.88 (dd, J = 7.2, 3.2 Hz, 2H), 7.2 9 (dd, J = 6.0, 0.9 Hz, 1H), 6.99 (d, J = 13.7 Hz, 2H), 5.15 (q, J = 9.1 Hz, 2H), 4.44 (s, 3H), 4.38-4.29 (m, 2H), 3.89-3.77 (m, 6H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 164.13, 158.35, 155.65, 141.37, 138.91, 137.82, 130.02, 127.76, 125.07, 124.13, 123.23, 121.48, 117 .81, 110.71, 109.40, 102.90, 101.57, 61.26, 61.03, 60.80, 60.57, 46.59, 45.56, 40.60, 40.06, 39.68.

Example 32 : 11-[2-[[7-(5 - methyltetrazolyl- 2-yl ) -1- isoquinolinyl ] amino ] ethyl ]-6-(2,2,2 -trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] trideca -2,4,6,8- tetraen -10- one Example 32.1: 7-Aminoisoquinoline (1000.00 mg, 6.9363 mmol) was dissolved in a mixture of 50% aqueous hydrofluoroboric acid (3.47 mL, 27.647 mmol) and EtOH (2.08 mL, 3.33 M). The reaction mixture was cooled to 0 °C and tert-butyl nitrite (1.65 mL, 13.873 mmol) was added dropwise. After stirring at RT for 1 hour, ether (10 mL) was added to precipitate the oxadiazolium compound, which was filtered off and washed with ether (3 x 5 mL). The desired compound tetrafluoroboranoisoquinoline-7-oxadiazolium (1.41 g, 84%, 5.7982 mmol) was dried in vacuo to give a dark red powder. Rt (Y): 0.15 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 9.78-9.73 (m, 2H), 8.97 (d, J = 5.7 Hz, 1H), 8.64 (dd, J = 9.1, 2.1 Hz, 1H), 8.50 (d, J = 9.0 Hz, 1H), 8.19 (d, J = 5 .8 Hz, 1H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 154.52, 149.72, 139.29, 138.64, 130.36, 127.53, 125.83, 121.10, 114.12.

Example 32.2: To a solution of acetamidine hydrochloride (544.74 mg, 5.762 mmol) and potassium carbonate (3.98 g, 28.81 mmol) in DMSO (28.00 mL, 0.2100 M) was added tetrafluoroboranoisoquinolin-7-oxadiazolium (1.40 g, 5.762 mmol) in portions. After stirring at RT for 1.5 h, LC/MS showed complete addition of the acetamidine moiety, KI (1434.75 mg, 8.643 mmol) and _iodine (1754.95 mg, _{6.9144 mmol) were added and stirred at RT for 1.5 h. A solution of brine and Na2S2O3 was} added to the mixture. The product was extracted with EtOAc (7 x 100 mL), the organic layer was dried over MgSO ₄ and concentrated in vacuo. The crude was purified by NP column chromatography (solvent: 0 to 70% EtOAc/cyclohexane) to give 7-(5-methyltetrazol-2-yl)isoquinoline (169.1 mg, 14%, 0.8006 mmol) as an orange powder. Rt (Y): 1.02 min. ¹ H NMR (600 MHz, chloroform-d ): δ 9.40 (d, J = 1.0 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.64 (d, J = 5.7 Hz, 1H), 8.49 (dd, J = 8.9, 2.2 Hz, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.74 (dt, J = 5.7, 1.0 Hz, 1H), 2.69 (s, 3H). ¹³ C NMR (151 MHz, CHLOROFORM-d): δ 163.81, 153.19, 144.54, 135.75, 135.22, 128.91, 128.47, 122.36, 120.47, 117.71, 11.19.

Example 32.3: 7-(5-Methyltetrazol-2-yl)isoquinoline (155.00 mg, 0.7338 mmol) was dissolved in CHCl ₃ (2.45 mL, 0.3000 M) and cooled in an ice bath. 3-Chloroperoxybenzoic acid (0.22 g, 0.8806 mmol) was added. The reaction was stirred at RT for 2 h. K ₂ CO ₃ (0.41 g, 2.9353 mmol) was added and stirred for 0.5 h before filtering. The filtrate was concentrated in vacuo to give a yellow/orange powder. The powder was redissolved in CHCl ₃ , washed with a saturated solution of NaHCO ₃ , dried over MgSO ₄ and concentrated in vacuo to give 7-(5-methyltetrazol-2-yl)-2-oxo-isoquinolin-2-ium (163.6 mg, 98%, 0.7200 mmol) as a yellow powder. Rt (Y): 0.97 min. ¹ H NMR (600 MHz, chloroform-d ): δ 8.86 (dd, J = 1.6, 0.8 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.37 (dd, J = 8.8, 2.1 Hz, 1H), 8.20 (dd, J = 7.1, 1.7 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 7.1 Hz, 1H), 2.68 (s, 3H). ¹³ C NMR (151 MHz, CHLOROFORM-d): δ 164.03, 138.30, 137.07, 136.50, 130.06, 129.02, 128.41, 124.35, 120.63, 114.63, 11.16.

Example 32.4: 7-(5-Methyltetrazol-2-yl)-2-oxo-isoquinolin-2-ium (83.06 mg, 0.3655 mmol), PyBrop (170.40 mg, 0.3655 mmol) and DIPEA (0.20 mL, 1.1423 mmol) in DCM (1.54 mL, 0.1200 M) was stirred in a microwave vial under nitrogen atmosphere at 40 °C for 30 min. Then 11-(2-aminoethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (100.00 mg, 0.3046 mmol) in DCM (1.00 mL, 0.1200 M) was added and the reaction was heated at 60 °C for 1 hour by microwave irradiation. The reaction was evaporated in vacuo and subjected to RP column chromatography (10 to 80% MeOH:water + 0.1% formic acid). The pure fraction was run through an SCX-II column, liberated with 2N _NH3 in methanol and evaporated to give 11-[2-[[7-(5-methyltetrazol-2-yl)-1-isoquinolinyl]amino]ethyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (40 mg, 24%, 0.0744 mmol) as a white powder. HPLC/MS m/z 538.1883 [M+H] ⁺ , Rt (Z): 2.37 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.94 (d, J = 2.1 Hz, 1H), 8.28 (dd, J = 8.8, 2.1 Hz, 1H), 8.08 (t, J = 5.4 Hz, 1H), 8.01-7.95 (m, 2H), 7.88 (d, J = 6 .0 Hz, 1H), 7.28 (dd, J = 6.0, 0.9 Hz, 1H), 7.04-6.98 (m, 2H), 5.15 (q, J = 9.1 Hz, 2H), 4.37-4.32 (m, 2H), 3.89-3.77 (m, 6H), 2.60 (s, 3H ). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 163.13, 158.35, 155.68, 155.65, 143.19, 141.36, 138.92, 137.17, 133.35, 130.00, 128.91, 125.07, 123 .22, 121.49, 117.50, 114.12, 110.71, 109.17, 102.89, 101.58, 61.26, 61.03, 60.79, 60.57, 46.59, 45.57, 40.59, 39.14, 10.58.

Example 33 : 11-[2-[[6-(5 -methyl -1,2,4- oxadiazol-3 - yl ) quinazolin- 4- yl ] amino ] ethyl ]-6-(2,2,2- trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] trideca -2,4,6,8- tetraen - 10- one Example 33.1: 4-Hydroxyquinazoline-6-carbonitrile (500 mg, 2.92 mmol) and triethylamine (0.41 mL, 2.92 mmol) in [bmim]OAc (2.9 mL) were heated at 80 °C. Hydroxylamine hydrochloride (406 mg, 5.84 mmol) was added, after which some foaming was observed. The reaction mixture was stirred at 80 °C for another 30 min. The reaction mixture was cooled to room temperature and water (50 mL) was added. The precipitate was filtered off, washed with water (50 mL) and dried under reduced pressure to give 536 mg (90%) of N ,4-dihydroxyquinazoline-6-carboximidamide. HPLC/MS m/z: 205.1 [M+H] ⁺ , Rt (U): 0.46 min.

Example 33.2: A suspension of N ,4-dihydroxyquinazoline-6-carboximidamide (480 mg, 2.35 mmol) and acetic anhydride (0.27 mL, 2.82 mmol) in anhydrous ACN (4.70 mL) was heated at 180 °C for 10 min under microwave irradiation under argon atmosphere. The reaction mixture was cooled to room temperature and cold water (50 mL) was added. The precipitate was filtered off, washed with water (50 mL) and diethyl ether (10 mL), and dried under reduced pressure to give 293 mg (55%) of 6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-ol. HPLC/MS m/z: 229.0727 [M+H] ⁺ , Rt (U): 1.93 min.

Example 33.3: 6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-ol (60.00 mg, 0.2629 mmol), 11-(2-aminoethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (94.94 mg, 0.2892 mmol) and DIPEA (0.14 mL, 0.7887 mmol) were dissolved in DMF (2.63 mL, 0.1000 M) at RT under argon. PyBOP (191.55 mg, 0.3681 mmol) was added and the reaction was stirred for 3 h. The reaction mixture was mixed with water (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with saturated NaCl (3 x 10 mL), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude material was first purified by NP flash chromatography (0 to 5% MeOH/DCM) to give a semi-pure product. The fractions were combined, evaporated and subjected to RP column chromatography (0 to 80% MeOH: water with 0.1% formic acid) to give 11-[2-[[6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl]amino]ethyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (57 mg, 40%, 0.1041 mmol) as an off-white solid. HPLC/MS m/z 539.1768 [M+H] ⁺ , Rt (Z): 2.26 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.94-8.89 (m, 2H), 8.53 (s, 1H), 8.29 (dd, J = 8.7, 1.8 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H) , 7.30 (dd, J = 6.0, 0.9 Hz, 1H), 6.98 (d, J = 0.9 Hz, 1H), 5.15 (q, J = 9.1 Hz, 2H), 4.38-4.33 (m, 2H), 3.90-3.86 (m, 2H), 3.86 (s, 4H), 2. 67 (s, 3H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 177.67, 167.22, 159.77, 158.40, 156.39, 155.65, 150.87, 141.37, 138.94, 130.27, 129.90, 128.70, 123 .39, 122.44, 115.10, 110.70, 102.91, 101.64, 61.24, 61.02, 60.77, 60.56, 46.46, 45.29, 40.60, 38.75, 12.03.

Example 34 : 3- Fluoro -5-(2 -methyltetrazol - 5- yl )-N-[2-[10 -oxo -6-(2,2,2 -trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] tridec -2,4,6,8 -tetraen -11- yl ] ethyl ] benzamide Example 34.1: To a stirred solution of 5-bromo-2-methyl-1H-tetrazole (70.00 mg, 0.4295 mmol), _Na2CO3 (68.28 mg, 0.6443 mmol), Pd( _PPh3 ) ₄ (49.63 mg, 0.0430 mmol) in a DME/water mixture ( ₄ :1, 0.2000 M) at 60 °C under an argon atmosphere was added (3-fluoro-5-methoxycarbonyl-phenyl)boronic acid (110.53 mg, 0.5584 mmol) in DME (0.36 mL, 0.2000 M) and the reaction was heated to 90 °C for 18 h and then treated with water. In a standard work-up, the mixture was extracted with DCM and the organic layer was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 to 80% EtOAc:cyclohexane) to give methyl 3-fluoro-5-(2-methyltetrazol-5-yl)benzoate (43.6 mg, 43%, 0.1846 mmol) as a light yellow solid. HPLC/MS m/z 237.0783 [M+H] ⁺ , Rt (Y): 1.41 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.44 (t, J = 1.5 Hz, 1H), 8.10 (ddd, J = 9.0, 2.6, 1.5 Hz, 1H), 7.87 (ddd, J = 9.0, 2.6, 1.5 Hz, 1H), 4.47 (s, 3H), 3.93 (s, 3H).

Example 34.2: Methyl 3-fluoro-5-(2-methyltetrazol-5-yl)benzoate (40.00 mg, 0.1693 mmol), THF (0.68 mL, 0.1000 M), MeOH (0.34 mL, 0.1000 M), and H ₂ O (0.68 mL, 0.1000 M) were mixed at ambient temperature. Lithium hydroxide monohydrate (35.53 mg, 0.8467 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction was quenched with 2N HCl and DCM was added. The aqueous layer was extracted with DCM (3 x 20 mL), dried over MgSO ₄ and evaporated under reduced pressure to give 3-fluoro-5-(2-methyltetrazol-5-yl)benzoic acid (34 mg, 90%, 0.1530 mmol) as an off-white crystalline solid. It was used in the next step without further purification. HPLC/MS m/z 223.0627 [M+H] ⁺ , Rt (Y): 1.25 min.

Example 34.3: DIPEA (0.10 mL, 0.5483 mmol) was added to a mixture of 3-fluoro-5-(2-methyltetrazol-5-yl)benzoic acid (33.50 mg, 0.1508 mmol), HATU (104.24 mg, 0.2741 mmol) and 11-(2-aminoethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (45.00 mg, 0.1371 mmol) in DCM (1.22 mL, 0.1100 M) and stirred at RT overnight before addition of saturated aqueous _NaHCO3 . This was extracted with DCM, filtered over MgSO ₄ and evaporated. The compound was subjected to RP column chromatography (10 to 80% MeOH: water) to give 3-fluoro-5-(2-methyltetrazol-5-yl)-N-[2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]ethyl]benzamide (35.4 mg, 49%, 0.0665 mmol) as a white solid. HPLC/MS m/z 533.1660 [M+H] ⁺ , Rt (Z): 2.64 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.95 (t, J = 5.9 Hz, 1H), 8.35 (t, J = 1.5 Hz, 1H), 7.95 (ddd, J = 9.0, 2.6, 1.4 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7 .76 (ddd, J = 9.4, 2.6, 1.5 Hz, 1H), 7.32 (dd, J = 6.0, 0.9 Hz, 1H), 7.00 (d, J = 0.9 Hz, 1H), 5.15 (q, J = 9.1 Hz, 2H), 4.44 (s, 3H), 4.42-4.3 7 (m, 2H), 3.92-3.87 (m, 2H), 3.76-3.71 (m, 2H), 3.58 (q, J = 5.9 Hz, 2H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 164.52, 164.51, 163.02, 162.73, 162.71, 161.39, 158.46, 155.65, 141.38, 138.94, 137.99, 137.94, 129 .86, 129.22, 129.17, 125.05, 123.21, 121.24, 121.22, 116.08, 115.93, 115.56, 115.40, 110.70, 102.91, 101.66, 61.24, 61.01, 60.78, 60.55, 46.08, 45.65, 40.62, 37.50.

Example 35 : 12,12,13,13 -Tetradeutero -11-[2-[[7-(5- methyl -1,2,4- oxadiazol- 3- yl )-1- isoquinolinyl ] amino ] ethyl ]-6-(2,2,2 -trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] trideca -2(7),3,5,8- tetraen -10- one Example 35.1: A solution of methyl 4-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (750.00 mg, 2.7352 mmol), 2-bromo-1,1,2,2-tetradeutero-ethanol (0.35 mL, 4.9234 mmol) and _PPh3 (1076.14 mg, 4.1028 mmol) in THF (6.84 mL, 0.4000 M) was cooled to 0°C. Diisopropyl azodicarboxylate (0.86 mL, 4.3764 mmol) was added dropwise over 20 min, and the resulting mixture was warmed to RT and stirred for 18 h. The crude was evaporated and subjected to NP chromatography (0 to 60% EtOAc: cyclohexane) and the fractions containing the product were combined and evaporated under reduced pressure to give methyl 1-(2-bromo-1,1,2,2-tetradeutero-ethyl)-4-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxylate (591 mg, 56%, 1.5344 mmol) as a white solid. HPLC/MS m/z 385.0285 [M+H, ⁷⁹ Br] ⁺ , 387.0261 [M+H, ⁸¹ Br] ⁺ , Rt (Y): 1.66 min. ¹ H NMR (600 MHz, chloroform-d): δ 7.93 (d, J = 6.1 Hz, 1H), 7.49 (t, J = 0.8 Hz, 1H), 7.07 (dt, J = 6.1, 0.8 Hz, 1H), 4.91 (q, J = 8.5 Hz, 2H), 3.93 (s, 3H). ¹³ C NMR (151 MHz, CHLOROFORM-d): δ 161.89, 157.14, 145.18, 140.77, 126.91, 124.78, 122.94, 111.02, 110.27, 102.43, 62.60, 62.36, 62.13, 61.88, 52.19.

Example 35.2: To a stirred solution of sodium azide (107.68 mg, 1.6564 mmol) in DMF (11.58 mL, 0.1300 M) was added 1-(2-bromo-1,1,2,2-tetradeutero-ethyl)-4-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (580.00 mg, 1.5058 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was then cooled to RT and diluted with water (5 mL). The mixture was extracted with ethyl acetate (3 x 5 mL) and washed with brine, dried over MgSO ₄ and concentrated in vacuo to afford 1-(2-azido-1,1,2,2-tetradeutero-ethyl)-4-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (506.4 mg, 97%, 1.4581 mmol) as a yellow solid. It was used directly without further purification. HPLC/MS m/z 348.1229 [M+H] ⁺ , Rt (R): 1.44 min.

Example 35.3: To a solution of 1-(2-azido-1,1,2,2-tetradeutero-ethyl)-4-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (480.00 mg, 1.3821 mmol) in THF (17.28 mL, 0.0600 M) was added _PPh3 (1087.56 mg, 4.1464 mmol). The mixture was stirred at RT for 16 h, then water (5.76 mL, 0.0600 M) was added, and the reaction was heated to 40 °C and allowed to stir for 4 h. The solvent was removed by reduced pressure, and the resulting residue was purified by RP column chromatography (0 to 5% methanol/DCM) to give 12,12,13,13-tetradeutero-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (401 mg, 100%, 1.3863 mmol) as a white solid. HPLC/MS m/z 290.0985 [M+H] ⁺ , Rt (Y): 1.26 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.26 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.33 (dd, J = 6.0, 0.9 Hz, 1H), 7.00 (d, J = 0.9 Hz, 1H), 5.16 (q, J = 9.1 Hz, 2H).

Example 35.4: 12,12,13,13-Tetradeutero-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (380.00 mg, 1.3137 mmol) was dissolved in DMF (18.77 mL, 0.0700 M). The resulting solution was cooled down to 0 °C in an ice bath followed by the addition of NaH (115.61 mg, 2.8902 mmol). The reaction mixture was stirred at 0 °C for 30 min. N -Boc-2-chloroethylamine (291.96 mg, 1.5765 mmol) dissolved in DMF (2.5 mL) was added dropwise to the reaction mixture and allowed to warm to RT. The reaction mixture was stirred at RT for 5 days. Water was added and the reaction was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with brine, dried over MgSO ₄ and evaporated under reduced pressure. The crude was subjected to NP chromatography (0 to 100% EtOAc: cyclohexane) to give tert-butyl N-[2-[12,12,13,13-tetradeutero-10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]ethyl]carbamate (247 mg, 26%, 0.3427 mmol). The product had a purity of 60% and was used directly without further purification. HPLC/MS m/z 433.1871 [M+H] ⁺ , Rt (Y): 1.49 min.

Example 35.5: tert-butyl N-[2-[12,12,13,13-tetradeutero-10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-11-yl]ethyl]carbamate (240.00 mg, 0.3330 mmol) was mixed with 4N HCl in 1,4-dioxane (3.33 mL, 13.32 mmol) and 1,4-dioxane (3.33 mL, 0.1000 M) at RT under nitrogen and stirred for 2 h. The volatiles were removed under reduced pressure to give 11-(2-aminoethyl)-12,12,13,13-tetradeutero-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one hydrochloride (93.5 mg, 84%, 0.2814 mmol) as a white solid. The crude product was subjected to RP column chromatography (10 to 80% MeOH: water with 0.1% formic acid). The pure fraction was run through an SCX-II column and released with 2N NH ₃ in methanol to give 11-(2-aminoethyl)-12,12,13,13-tetradeutero-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (93.5 mg, 84%, 0.2814 mmol) as a white solid. HPLC/MS m/z 333.1381 [M+H] ⁺ , Rt (Y): 0.96 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 7.90 (d, J = 6.0 Hz, 1H), 7.33 (dd, J = 6.0, 0.9 Hz, 1H), 6.99 (d, J = 0.9 Hz, 1H), 5.16 (q, J = 9.1 Hz, 2H), 3.49 (t, J = 6.5 Hz, 2H), 2.76 (t, J = 6.5 Hz, 2H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 158.25, 155.63, 141.39, 138.82, 130.06, 125.07, 123.23, 110.72, 102.91, 101.42, 61.22, 60.99, 60.77 , 60.53, 49.25, 39.70.

Example 35.6: DIPEA (0.13 mL, 0.7335 mmol) was added dropwise to 11-(2-aminoethyl)-12,12,13,13-tetradeutero-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (65.00 mg, 0.1956 mmol), 5-methyl-3-(2-oxoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole (53.33 mg, 0.2347 mmol) and PyBrop (109.42 mg, 0.2347 mmol) in DCM (1.63 mL, 0.1200 M). The tube was sealed and this was heated to 60 °C in a microwave for 1 hour. The reaction was evaporated in vacuo and subjected to RP column chromatography (10 to 80% MeOH:water + 0.1% formic acid). The pure fraction was run through an SCX-II column, liberated with 2N _NH3 in methanol and evaporated to give 12,12,13,13-tetradeutero-11-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]ethyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (39 mg, 37%, 0.0720 mmol) as a cream-colored powder. HPLC/MS m/z 542.2072 [M+H] ⁺ , Rt (Z): 2.32 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.89-8.86 (m, 1H), 8.15 (dd, J = 8.4, 1.5 Hz, 1H), 8.07 (t, J = 5.5 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.88 (d, J = 6 .0 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 6.0, 0.9 Hz, 1H), 7.00 (d, J = 0.9 Hz, 1H), 6.96 (dd, J = 5.9, 0.8 Hz, 1H), 5.15 (q, J = 9.1 Hz , 2H), 3.84 (t, J = 5.7 Hz, 2H), 3.81-3.76 (m, 2H), 2.67 (s, 3H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 177.47, 167.60, 158.33, 155.73, 155.65, 143.49, 141.37, 138.89, 138.42, 130.03, 127.68, 127.34, 123 .33, 122.70, 117.56, 110.72, 109.32, 102.90, 101.54, 61.02, 60.79, 45.51, 39.15, 12.03.

Example 36 : 3-(2 -methyltetrazol - 5- yl )-N-[2-[12,12,13,13 -tetradeutero - 10-oxo -6-(2,2,2- trifluoroethoxy )-1,5,11 -triazatricyclo [7.4.0.02,7] trideca -2(7),3,5,8 -tetraen - 11 - yl ] ethyl ] benzamide DIPEA (0.05 mL, 0.2648 mmol) was added to a mixture of 3-(2-methyl-2H-tetrazol-5-yl)-benzoic acid (15.55 mg, 0.0761 mmol), HATU (50.34 mg, 0.1324 mmol) and 11-(2-aminoethyl)-12,12,13,13-tetradeutero-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (22.00 mg, 0.0662 mmol) in DCM (0.66 mL, 0.1000 M). This was stirred for 2 hours before saturated _aqueous NaHCO3 was added. This was extracted with DCM, filtered over _MgSO4 and evaporated. The compound was subjected to RP column chromatography (10 to 80% MeOH:water + 0.1% formic acid). The pure fraction was run through an SCX-II column, released with 2N _NH3 in methanol and evaporated to give 3-(2-methyltetrazol-5-yl)-N-[2-[12,12,13,13-tetradeutero-10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl]ethyl]benzamide (26 mg, 76%, 0.0501 mmol) as a white solid. HPLC/MS m/z 519.2021 [M+H] ⁺ , Rt (Z): 2.52 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.86 (t, J = 5.9 Hz, 1H), 8.50 (t, J = 1.7 Hz, 1H), 8.18 (dt, J = 7.8, 1.4 Hz, 1H), 7.95 (dt, J = 7.9, 1.4 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 6.0, 0.9 Hz, 1H), 7.00 (d, J = 0.9 Hz, 1H), 5.15 (q, J = 9.1 Hz, 2H), 4.43 (s, 3 H), 3.73 (t, J = 6.0 Hz, 2H), 3.58 (q, J = 6.0 Hz, 2H). ¹³ C NMR (151 MHz, DMSO-d ₆ ): δ 165.82, 163.66, 158.42, 155.65, 141.39, 138.92, 135.47, 129.89, 129.41, 129.08, 128.77, 127.07, 125 .07, 110.71, 102.91, 101.64, 61.01, 60.76, 45.67, 40.06, 37.43.

Example 37 : 8-(2-((7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1 - yl ) amino ) ethyl )-1 -propoxy -7,8- dihydropyrido [3′,4′:4,5] pyrrolo [1,2-a] pyrrol - 9(6H) -one Example 37.1: A mixture of methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (553 mg, 2.63 mmol, 1.0 eq.), propan-1-ol (28 µL, 3.68 mmol, 1.4 eq.), Cs ₂ CO ₃ (1.20 g, 3.68 mmol, 1.4 eq.), tBuBrettPhos Pd G3 (90 mg, 0.11 mmol, 4 mol%), tBuBrettPhos (102 mg, 0.21 mmol, 8 mol%) and 4Å molecular sieve (1.0 g) in THF (6.56 mL, 0.4 M) was heated at 80 °C overnight. Silica was added and the solvent evaporated. Normal phase column chromatography (0 to 80% EtOAc/cyclohexane) afforded pure methyl 4-propoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (442 mg, 72% yield) as a slightly yellow powder. HPLC/MS m/z: 235.1 [M+H] ⁺ , Rt (Y): 1.188 min.

Example 37.2: Aqueous NaOH (3N, 11.8 mL) was added to a solution of methyl 4-propoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (554.00 mg, 2.37 mmol, 1.0 eq.) in EtOH (11.8 mL) and this was heated to 45 °C for 45 min, after which the solvent was evaporated and the crude solid was triturated with Et ₂ O. The solid was filtered, washed with further Et ₂ O and dried under vacuum to give a mixture of NaOH and sodium 4-propoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylate as a yellow solid, which was carried on to the next step without further purification (crude mass 950 mg). HPLC/MS m/z: 221.1 [M+H] ⁺ , Rt (Y): 0.815 min.

Example 37.3: A mixture of sodium 4-propoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (22 mg, 89 µmol, 1.0 eq) and HATU (41 mg, 107 µmol, 1.2 eq.) in DCM/DMF (2:1, 300 µL) was stirred for 15 min before a solution of tert-butyl N-{2-[(2-hydroxyethyl)amino]ethyl}carbamate (19 mg, 90 µmol, 1.05 eq.) in DCM (200 µL) was added. After 5 min, the reaction was quenched with saturated aqueous NaHCO ₃ solution and extracted with DCM, dried over MgSO ₄ and then evaporated under vacuum. The crude was precipitated with water and the aqueous phase discarded. The product was used in the next step without purification (26.3 mg, 73% crude yield). Rf (EtOAc:DCM, 9:1) = 0.34; HPLC/MS m/z: 407.2 [M+H] ⁺ , Rt (Y): 1.154 min.

Example 37.4: A solution of tert-butyl N-[2-[2-hydroxyethyl-(4-propoxy-1H-pyrrolo[3,2-c]pyridine-2-carbonyl)amino]ethyl]carbamate (221.30 mg, 0.5444 mmol) and triphenylphosphine (428.39 mg, 1.6333 mmol) in THF (5.44 mL, 0.1000 M) was cooled to 0 °C. DIAD (321.58 µL, 1.6333 mmol) was added dropwise over 30 min and the resulting mixture was warmed to RT and stirred for 2 h. After removing the solvent under reduced pressure, the residue was diluted with EtOAc and extracted with saturated HCl (1 M) (x 4). The combined aqueous extracts were basified to pH 8-9 with 10% _{aqueous Na2CO3} , and the resulting mixture was extracted with EtOAc and then filtered sequentially on _MgSO4 and silica pads to give tert-butyl (2-(9-oxo-1-propoxy-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrrol-8(9H)-yl)ethyl)carbamate as a clear oil. HPLC/MS m/z: 398.2 [M+H] ⁺ , Rt(Y): 1.319 min.

Example 37.5: Aqueous HCl (1 M) (1.63 mL, 1.63 mmol, 3.0 eq.) was added to the crude solid and this was stirred for 10 min until everything dissolved, then evaporated to dryness. The solid was triturated with DCM and the solvent was filtered off, washing with additional DCM to give pure 2-(10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl)ethylammonium chloride (90.4 mg, 51% yield over 2 steps) as a white solid. HPLC/MS m/z: 289.2 [M+H] ⁺ , Rt (Y): 0.547 min.

Example 37.6: DIPEA (67.03 µL, 0.3848 mmol) was added to a mixture of 5-methyl-3-(2-oxoisoquinolin-2-yl)-1,2,4-oxadiazole (27.98 mg, 0.1231 mmol), 2-(10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl)ethylammonium chloride (25.00 mg, 0.0770 mmol) and PyBroP (43.06 mg, 0.0924 mmol) in DCM (0.51 mL, 0.1500 M) and this was heated by microwave irradiation (60 °C; 1 h). The solvent was evaporated and the residue was subjected to AccQ Prep reverse phase HPLC (20 to 30% MeCN/ _H2O ) followed by normal phase preparative TLC (5% MeOH/DCM) to give 11-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]ethyl]-6-propoxy-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (6.6 mg, 17%, 0.0127 mmol). HPLC/MS m/z: 498.2 [M+H] ⁺ , Rt (Y): 1.221 min; ¹ H NMR (500 MHz, methanol-d ₄ /chloroform-d; 2:1 ) : δ 8.73 (dt, J = 1.5, 0.8 Hz, 1H ) , 8.17 (dd, J = 8.5, 1.5 Hz, 1H ) , 4.3 4 ( t , J = 6.6 Hz, 2H), 4.30-4.24 (m, 2H), 3.99 (dd, J = 6.6, 5.2 Hz, 2H), 3.96-3.91 (m, 2H), 3.88 (dd, J = 6.6, 5.2 Hz, 2H), 2.67 (s, 3H), 1.85 (dt d, J = 14.0, 7.4, 6.5 Hz, 2H), 1.05 (t, J = 7.4 Hz, 3H).

Example 38 : 3-(2 -methyl -2H- tetrazol -5- yl )-N-(2-(9 -oxo - 1-propoxy -6,7- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H) -yl ) ethyl ) benzamide Using the procedure from Example 54.3, 3-(2-methyltetrazol-5-yl)-N-[2-(10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl)ethyl]benzamide (7.1 mg, 0.0149 mmol) was obtained as a white solid from 2-(10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl)ethylammonium chloride [Example 37.5] and 3-(2-methyl-2H-tetrazol-5-yl)-benzoic acid at 60 °C. HPLC/MS m/z: 475.221 [M+H] ⁺ , Rt (Z): 2.18 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.86 (t, J = 5.8 Hz, 1H), 8.50 (t, J = 1.8 Hz, 1H), 8.18 (dt, J = 7.7, 1.4 Hz, 1H), 7.95 (dt, J = 7.9, 1.5 Hz, 1H), 7.84 (d, J = 6.0 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.15 (dd, J = 6.0, 0.9 Hz, 1H), 6.97 (d, J = 0.8 Hz, 1H), 4.43 (s, 3H), 4.38-4.32 (m, 4H), 3.90-3.85 (m, 2H), 3.72 (t, J = 6.0 Hz, 2H), 3.60-3.54 (m, 2H), 1.81-1.72 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

Example 39 : 1-( Dodeca -11- yn -1- yloxy )-8-(2-((7-(5- methyl -1,2,4- oxadiazol - 3- yl ) isoquinolin -1 -yl ) amino ) ethyl )-7,8- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 9(6H) -one Synthesized in a similar manner to Example 37 using dodecan-11-yn-1-ol as the starting alcohol. Preparative TLC (5% MeOH/DCM) (46.8 mg, 31% yield). Light orange powder. HPLC/MS m/z: 620.3 [M+H] ⁺ , Rt (Y): 1.624 min; ¹ H NMR (600 MHz, methanol-d ₄ /chloroform-d, 1:1): δ 8.71 (dt, J = 1.5, 0.8 Hz, 1H), 8.16 (dd, J = 8.5, 1.6 Hz, 1H), 7.90 (d, J = 5.9 Hz, 1H), 7.78 (d, J = 6.1 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 0.9 Hz, 1H), 6.92 (dd, J = 6.0, 0.9 Hz, 1H), 6.90 (dd, J = 6.1, 0.9 Hz, 1H), 4.38 (t, J = 6.6 Hz, 2H), 4.30-4.24 (m, 2H), 4.00 (dd, J = 6.6, 5.3 Hz, 2H), 3.97-3.92 (m, 2H), 3.88 (dd, J = 6.6, 5.3 Hz, 2H), 2. 68 (s, 3H), 2.14 (td, J = 7.1, 2.7 Hz, 2H), 2.03 (t, J = 2.6 Hz, 1H), 1.83 (quint, J = 6.8 Hz, 2H), 1.51-1.45 (m, 2 x 2 H), 1.37 (m, 2 x 2 H), 1.3 3-1.26 (m, 3 x 2 H).

Example 40 : N-(2-(1- chloro -9- oxo -6,7- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H) -yl ) ethyl )-3-(5 -methyl -1,2,4- oxadiazol -3- yl ) benzamide Example 40.1: Aqueous NaOH (3 N, 21 mL) was added to a solution of methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (1.0 g, 4.75 mmol, 1.0 eq.) in EtOH (21 mL) and this was heated to 45 °C for 1 h, after which the solvent was evaporated and the crude solid was triturated with Et ₂ O. The solid was filtered and washed with additional Et ₂ O, then dried in vacuo to give a mixture of NaOH and sodium 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate as a yellow solid, which was carried on to the next step without further purification (crude mass 1.2 g, quant.). HPLC/MS m/z: 197.0 [M+H] ⁺ , Rt (Y): 0.947 min.

Example 40.2: DMF (9.72 mL) was added dropwise to a mixture of sodium 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (1.71 g, 7.8 mmol, 1.0 eq.) and HATU (3.99 g, 10.5 mmol, 1.34 eq.) in DCM (19.6 mL) and this was stirred for 30 min before a solution of tert-butyl N-{2-[(2-hydroxyethyl)amino]ethyl}carbamate (1.95 g, 9.53 mmol, 1.22 eq.) in DCM (19.6 mL) was added. This was stirred for 4 h before water was added and the solvent was evaporated to dryness. Reverse phase chromatography (0 to 100% MeOH/ _H2O ) removed the major impurities to give the crude product (crude mass 2.535 g) which was carried forward to the next step. HPLC/MS m/z: 383.1 [M+H] ⁺ , Rt (R): 1.083 min.

Example 40.3: DIAD (3.91 mL, 19.868 mmol) was added to a solution of tert-butyl N-[2-[(4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carbonyl)-(2-hydroxyethyl)amino]ethyl]carbamate (2.54 g, 6.6226 mmol) and _PPh3 (5.21 g, 19.868 mmol) in THF (65.30 mL, 0.1000 M) at 0°C over 40 min. After 1 h, the resulting mixture was brought back to RT and stirred for a further 3 h. After the solvent was removed under reduced pressure, the residue was diluted with EtOAc and 10% aqueous Na ₂ CO ₃ solution, extracted with EtOAc and filtered over MgSO ₄ to give crude 2-(6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl)ethylammonium chloride (1.2 g, 60%, 3.9682 mmol) as a yellow solid. HPLC/MS m/z: 365.1 [M+H] ⁺ , Rt (Y): 1.307 min.

Example 40.4: The crude was diluted in DCM (30 mL) and TFA (30 mL) was added at 0 °C, when the solution turned red. This was stirred at RT for 30 min before evaporation of the solvent and redissolution in aqueous HCl (3 N). After concentration, the residue was washed several times with DCM and then reverse phase chromatography (5 to 25% MeOH/ _H2O ) gave 2-(6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl)ethylammonium chloride (1.2 g, 60%, 3.9682 mmol). HPLC/MS m/z: non-ionizing, Rt (Y): 0.522 min.

Example 40.5: DIPEA (0.35 mL, 1.9922 mmol) was added to a mixture of 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (116.95 mg, 0.5728 mmol), HATU (378.75 mg, 0.9961 mmol) and 2-(6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl)ethylammonium chloride (150.00 mg, 0.4981 mmol) in DCM (3.32 mL, 0.1500 M). This was stirred for 2 h before saturated _aqueous NaHCO3 was added. This was extracted with DCM, filtered over MgSO ₄ and evaporated. Slow silica gel chromatography using DCM and MeOH as solvent (100:0 to 96:4) gave N-[2-(6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl)ethyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide (119.5 mg, 53%, 0.2650 mmol). HPLC/MS m/z: 473.1 [M+Na] ⁺ , Rt (Y): 1.305 min; ¹ H NMR (600 MHz, methanol-d ₄ ): δ 8.39 (t, J = 1.8 Hz, 1H), 8.11 (dt, J = 7.8, 1.4 Hz, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.90 (dt, J = 7.8, 1.4 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.43 (dd, J = 5.9, 0.9 Hz, 1H), 7.15 (d, J = 0.9 Hz, 1H), 4.41 (dd, J = 6.9, 4. 9 Hz, 2H), 4.03-3.98 (m, 2H), 3.88 (dd, J = 6.7, 5.0 Hz, 2H), 3.75 (dd, J = 6.7, 5.0 Hz, 2H), 2.61 (s, 3H).

Example 41 : N-(2-(1-(3 -fluoropropoxy )-9 -oxo -6,7- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H)-yl ) ethyl ) -3-(5- methyl -1,2,4- oxadiazol -3- yl ) benzamide Obtained from 3-fluoropropan-1-ol and N-[2-(6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-11-yl)ethyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide using the conditions of Example 37.1. Normal phase silica gel chromatography using DCM and MeOH as solvents (slow gradient elution 100:0 to 96:4) gave N-[2-[6-(3-fluoropropoxy)-10-oxo-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]ethyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide (5.42 mg, 12%, 0.0110 mmol) as a white solid. HPLC/MS m/z: 493.2 [M+H] ⁺ , Rt (Y): 1.31 min; ¹ H NMR (600 MHz, methanol-d ₄ ): δ 8.43 (t, J = 1.7 Hz, 1H), 8.14 (dt, J = 7.8, 1.4 Hz, 1H), 7.91 (dt, J = 7.9, 1.5 Hz, 1H), 7.81 (d, J = 6.1 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 0.8 Hz, 1H), 7.04 (dd, J = 6.1, 0.9 Hz, 1H), 4.67 (t, J = 5.9 Hz, 1 H), 4.59 (t, J = 5.9 Hz, 1H), 4.51 (t, J = 6.3 Hz, 2H), 4.38-4.33 (m, 2H), 4.03-3.93 (m, 2H), 3.87 (dd, J = 6.7, 5.0 Hz, 2H), 3.73 (dd, J = 6.6, 5.1 Hz , 2H), 2.63 (s, 3H), 2.22 (quint, J = 6.1 Hz, 1H), 2.18 (quint, J = 6.1 Hz, 1H).

Example 42 : N-(2-(1-(2,2 -difluoroethoxy )-9 -oxo -6,7 -dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H) -yl ) ethyl )-3-(5- methyl -1,2,4- oxadiazol -3- yl ) benzamide Obtained from 2,2-difluoroethanol and N-[2-(6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl)ethyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide using the conditions of Example 37.1. Preparative TLC using DCM and MeOH as solvent (94:6). (11.4 mg, 20% yield). HPLC/MS m/z: 497.2 [M+H] ⁺ , Rt (Z): 2.44 min; ¹ H NMR (600 MHz, methanol-d ₄ /chloroform-d, 1:1): δ 8.43 (t, J = 1.7 Hz, 1H), 8.13 (dt, J = 7.8, 1.4 Hz, 1H), 7.90 (d t, J = 7.9, 1.4 Hz, 1H), 7.83 (d, J = 6.1 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 0.9 Hz, 1H), 7.00 (dd, J = 6.1, 0.9 Hz, 1H), 6.32-6.05 (m, 1H), 4.61 (td, J = 13.6, 4.2 Hz, 2H), 4.35-4.30 (m, 2H), 3.97-3.92 (m, 2H), 3.85 (dd, J = 6.7, 5.4 Hz, 2H), 3.72 (dd, J = 6.7, 5.4 Hz, 2H), 5 (s, 3H).

Example 43 : 3-(5 -methyl -1,2,4- oxadiazol - 3- yl )-N-(2-(9 -oxo- 1-(2,2,2 -trifluoroethoxy )-6,7- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H) -yl ) ethyl ) benzamide Cs ₂ CO ₃ (98.3 mg, 0.3 mmol, 2.7 eq.), N-[2-(6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl)ethyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide (51 mg, 0.11 mmol, 1.0 eq.), BrettPhos (10 mg, 18.6 µmol, 16 mol%), crotyl(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl)trifluoromethanesulfonate (10 A mixture of 1,4-difluoro-2-[4-(2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2- Normal phase silica gel chromatography using DCM and MeOH as solvents (slow gradient elution 100:0 to 98:2) gave 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-[2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]ethyl]benzamide (7.99 mg, 14% yield) as a white solid. HPLC/MS m/z: 515.2 [M+H] ⁺ , Rt (Z): 2.60 min; ¹ H NMR (600 MHz, methanol-d ₄ ): δ 8.45 (t, J = 1.8 Hz, 1H), 8.16 (dt, J = 7.8, 1.4 Hz, 1H), 7.94-7.89 (m, 1H ), 7.87 (d, J = 6.1 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 0.8 Hz, 1H), 7.15 (dd, J = 6.0, 0.9 Hz, 1H), 4.98 (q, J = 8.8 Hz, 2H), 4.40 (t , J = 5.9 Hz, 2H), 4.02-3.95 (m, 2H), 3.89 (dd, J = 6.6, 5.1 Hz, 2H), 3.74 (dd, J = 6.6, 5.1 Hz, 2H), 2.64 (s, 3H).

Example 44 : 1-(3 -fluoropropoxy )-8-(2-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ) amino ) ethyl )-7,8- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 9(6H) -one Obtained from 1-chloro-8-(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)-7,8-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrrolido[9(6H)-one and 3-fluoropropan-1-ol using the conditions of Example 37.1. Preparative TLC (5% MeOH/DCM) (4.6 mg, 9% yield). HPLC/MS m/z: 516.2 [M+H] ⁺ , Rt (Y): 1.18 min; ¹ H NMR (600 MHz, methanol-d ₄ ): δ 8.75-8.67 (m, 1H), 8.11 (dd, J = 8.5, 1.6 Hz, 1H), 7.89 (d, J = 5.8 Hz, 1H) , 7.75 (d, J = 6.1 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 0.9 Hz, 1H), 6.97 (dd, J = 6.2, 0.9 Hz, 1H), 6.91 (dd, J = 6.0, 0.9 Hz, 1H), 4. 67 (t, J = 5.9 Hz, 1H), 4.59 (t, J = 5.8 Hz, 1H), 4.49 (t, J = 6.3 Hz, 2H), 4.29-4.25 (m, 2H), 3.96 (dd, J = 6.6, 4.9 Hz, 2H), 3.95-3.92 (m, 2H), 3.8 9 (dd, J = 6.6, 5.0 Hz, 2H), 2.59 (s, 3H), 2.25-2.15 (m, 2H).

Example 45 : 3-(2 -methyl -2H- tetrazol -5- yl )-N-(2-(9 -oxo- 1-( propoxy- d7)-6,7- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H) -yl ) ethyl ) benzamide Example 45.1: N-(2-(1-Chloro-9-oxo-6,7-dihydropyrido[3′,4′:4,5]pyrrolo[1,2-a]pyrrol-8(9H)-yl)ethyl)-3-(2-methyl-2H-tetrazol-5-yl)benzamide was obtained from 2-(6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-11-yl)ethylammonium chloride and 3-(2-methyl-2H-tetrazol-5-yl)-benzoic acid using the conditions of Example 40.5. Purification by column chromatography (solvent: 0 to 4% MeOH / DCM) gave N-(2-(1-chloro-9-oxo-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrrol-8(9H)-yl)ethyl)-3-(2-methyl-2H-tetrazol-5-yl)benzamide (288.9 mg, 87% yield). HPLC/MS m/z: 451.1 [M+H] ⁺ , Rt (R): 1.097 min.

Example 45.2: Using the conditions of Example 37.1, 1-propanol-1,1,2,2,3,3,3- _d7 and N-[2-(6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-11-yl)ethyl]-3-(2-methyltetrazol-5-yl)benzamide. Purification by preparative TLC (6% MeOH/DCM) gave 3-(2-methyl-2H-tetrazol-5-yl)-N-(2-(9-oxo-1-(propoxy-d7)-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrrol-8(9H)-yl)ethyl)benzamide (5.0 mg, 9% yield) as a white powder. HPLC/MS m/z: 482.3 [M+H] ⁺ , Rt (R): 1.09 min; ¹ H NMR (600 MHz, methanol-d ₄ /chloroform-d, 1:1): δ 8.51 (d, J = 1.8 Hz, 1H), 8.23 (dt, J = 7.8, 1.4 Hz, 1H), 7.89 (dt, J = 7.9, 1.5 Hz, 1H), 7.82 (d, J = 6.1 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.31-7.28 (m, 1H), 6.98-6.93 (m, 1H), 4.43 (s, 3H), 4.34 (dd, J = 6.9, 4.8 Hz, 2H), 4.00-3.95 (m, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.74 (t, J = 6.0 Hz, 2H).

Example 46 : 3-(2 -methyl -2H- tetrazol -5- yl )-N-(2-(9 -oxo -1-(2,2,2 -trifluoroethoxy -1,1-d2)-6,7- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H) -yl ) ethyl ) benzamide Obtained from 2,2,2-trifluoroethanol-1,1-d2 (45.00 µL, 0.6085 mmol) and N-[2-(6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl)ethyl]-3-(2-methyltetrazol-5-yl)benzamide using the conditions of Example 37.1. Silica gel chromatography (0 to 2% MeOH/DCM) (15.99 mg, 31% yield). White powder. HPLC/MS m/z: 517.2 [M+H] ⁺ , Rt (R): 1.270 min; ¹ H NMR (600 MHz, methanol-d ₄ /chloroform-d, 1:1): δ 8.50 (s, 1H), 8.23 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H) , 7.86 (d, J = 6.0 Hz, 1H), 7.57 (d, J = 15.8 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.05 (d, J = 6.0 Hz, 1H), 4.42 (d, J = 2.0 Hz, 3H), 4.36 (t, J = 5 .9 Hz, 2H), 3.98 (t, J = 5.9 Hz, 2H), 3.89 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 6.1 Hz, 2H).

Example 47 : N-(2-(1-( Dodeca -11- yn -1 -yloxy )-9 -oxo -6,7 -dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H)-yl ) ethyl ) -3-(2- methyl -2H- tetrazol -5- yl ) benzamide Obtained from 3-(2-methyl-2H-tetrazol-5-yl)-benzoic acid and 11-(2-aminoethyl)-6-dodec-11-ynyloxy-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one using the conditions of Example 40.5. Silica gel chromatography (0 to 3.25% MeOH/DCM) followed by preparative TLC (10% MeOH/DCM) and trituration with EtOAc. (72.1 mg, 50% yield). White solid. HPLC/MS m/z: 597.3 [M+H] ⁺ , Rt (R): 1.56 min; ¹ H NMR (600 MHz, methanol-d ₄ /chloroform-d, 1:1): δ 8.51 (t, J = 1.7 Hz, 1H), 8.22 (dt, J = 7.8, 1.4 Hz, 1H), 7.89 ( dt, J = 7.9, 1.4 Hz, 1H), 7.81 (d, J = 6.1 Hz, 1H), 7.60-7.54 (m, 1H), 7.28 (d, J = 0.9 Hz, 1H), 6.94 (dd, J = 6.2, 0.9 Hz, 1H), 4.42 (s, 3H), 4.38 (t, J = 6.6 Hz, 2H), 4.35-4.31 (m, 2H), 4.00-3.94 (m, 2H), 3.88 (dd, J = 6.7, 5.4 Hz, 2H), 3.74 (dd, J = 6.7, 5.3 Hz, 2H), 2.14 (td, J = 7.1, 2.7 Hz, 2H), 2.03 (t, J = 2.7 Hz, 1H), 1.82 (quint, J = 6.8 Hz, 2H), 1.52-1.44 (m, 2 x 2 H), 1.40-1.34 (m, 2 x 2 H), 1.33-1.26 (m, J = 5.5, 4.7 Hz, 3 x 2H).

Example 48 : (S)-8-(3- amino -2-((7-(5 -methyl -1,2,4- oxadiazol-3 - yl ) isoquinolin -1 -yl ) amino ) propyl )-1-(2,2,2 -trifluoroethoxy )-7,8- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 9 (6H) -one Example 48.1: DIPEA (1029.54 µL, 5.9109 mmol) was added to a mixture of Boc-N3-Cbz-L-2,3-diaminopropionic acid (1.00 g, 2.9554 mmol) and HATU (1573.24 mg, 4.1376 mmol) in DCM (14.78 mL). This was heated to 70 °C for 15 min or until the mixture became a clear yellow solution. A solution of ethanolamine (231.89 µL, 3.8421 mmol) in DCM (14.78 mL) was added dropwise at RT, whereupon a precipitate formed, and this was stirred at this temperature for 2 h. The mixture was washed with _H2O , aqueous HCl (1 N), extracted with DCM. The solvent was dried over MgSO ₄ and evaporated. Normal phase column chromatography (0 to 5% MeOH / DCM) gave tert-butyl N-[(1S)-1-(benzyloxycarbonylaminomethyl)-2-(2-hydroxyethylamino)-2-oxo-ethyl]carbamate (1.0 g, 89% yield). HPLC/MS m/z: 382.2 [M+H] ⁺ , Rt (R): 1.127 min.

Example 48.2: BF ₃ .OEt ₂ (7.4 µL, 60.3 µmol, 1.0 eq.) was added dropwise to a solution of tert-butyl N-[(1S)-1-(benzyloxycarbonylaminomethyl)-2-(2-hydroxyethylamino)-2-oxoethyl]carbamate (23 mg, 60.3 µmol) in THF (600 µL) at 0° C., followed immediately by the dropwise addition of BH ₃ .THF (1M in THF) (362 µL, 0.36 mmol, 6.0 eq.). The ice bath was removed, and the solution was stirred at RT for 2 h. The solution was quenched by the addition of MeOH and the solvent was evaporated. Normal phase column chromatography (0 to 20% MeOH/DCM) afforded tert-butyl N-[(1R)-1-(benzyloxycarbonylaminomethyl)-2-(2-hydroxyethylamino)ethyl]carbamate (16.7 mg, 75% yield). HPLC/MS m/z: 368.2 [M+H] ⁺ , Rt (R): 0.93 min.

Example 48.3: A yellow solution of sodium 4-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (208.00 mg, 0.7372 mmol) and HATU (392.43 mg, 1.0321 mmol) in DMF (3.69 mL) pre-stirred for 15 min was added dropwise to a solution of tert-butyl N-[(1R)-1-(benzyloxycarbonylaminomethyl)-2-(2-hydroxyethylamino)ethyl]carbamate (325.05 mg, 0.8846 mmol) and DIPEA (256.81 µL, 1.4744 mmol) in DMF (3.69 mL). After 15 min, water was added and the solvent was evaporated. The residue was washed with water and extracted with DCM. The organic phase was dried over MgSO ₄ and evaporated. Normal phase chromatography (20 to 90% EtOAc / DCM) gave tert-butyl N-[(1S)-1-(benzyloxycarbonylaminomethyl)-2-[2-hydroxyethyl-[4-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carbonyl]amino]ethyl]carbamate (334 mg, 74% yield) as a pale oil. HPLC/MS m/z: 610.2 [M+H] ⁺ , Rt (Y): 1.59 min.

Example 48.4: DIAD (298.74 µL, 1.5172 mmol) was added dropwise to a solution of tert-butyl N-[(1S)-1-(benzyloxycarbonylaminomethyl)-2-[2-hydroxyethyl-[4-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carbonyl]amino]ethyl]carbamate (308.30 mg, 0.5057 mmol) and PPh ₃ (397.96 mg, 1.5172 mmol) in THF (5.06 mL, 0.1000 M) at 0° C. After 1 h, the ice bath was removed and stirred overnight. The reaction was quenched with water, the mixture was extracted with DCM and the organic phase was dried over MgSO ₄ and evaporated in vacuo. Normal phase chromatography (0 to 100% EtOAc / DCM) gave a mixture of Ph ₃ P=O and tert-butyl N-[(1S)-1-(benzyloxycarbonylaminomethyl)-2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]ethyl]carbamate. The product was used in the next step without further purification. HPLC/MS m/z: 592.2 [M+H] ⁺ , Rt (Y): 1.608 min.

Example 48.5: tert-Butyl N-[(1S)-1-(Benzyloxycarbonylaminomethyl)-2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-11-yl]ethyl]carbamate (300.00 mg, 0.5071 mmol) was stirred in DCM/TFA (1:1) (20.00 mL) for 30 min and then evaporated. Impurities were removed by elution with MeOH followed by NH ₄ in MeOH (2M) on an SCX-2 column to afford benzyl N-[(2S)-2-amino-3-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]propyl]carbamate (229.1 mg, 92% yield over 2 steps). HPLC/MS m/z: 492.2 [M+H] ⁺ , Rt (Y): 1.253 min.

Example 48.6: DIPEA (304.48 µL, 1.7481 mmol) was added dropwise to a solution of benzyl N-[(2S)-2-amino-3-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]propyl]carbamate (229.10 mg, 0.4662 mmol), 5-methyl-3-(2-oxoisoquinolin-2-yl)-1,2,4-oxadiazole (127.11 mg, 0.5594 mmol) and PyBrop (260.78 mg, 0.5594 mmol). The tube was sealed and this was heated to 60 °C for 1 hour. Water was added and this was extracted with DCM. The organic layer was dried over MgSO ₄ and evaporated in vacuo. Normal phase chromatography (1 to 1.5% MeOH/DCM) (140.2 mg, 43% yield). Orange oil. HPLC/MS m/z: 701.2509 [M+H] ⁺ , Rt (R): 1.32 min.

Example 48.7: To a solution of Pd(OAc) ₂ (5.6 mg, 24.9 mmol, 23 mol%) in DCM (543 μL) were added successively Et ₃ N (13 μL, 95.3 μmol, 0.9 eq.) and Et ₃ SiH (38 μL, 0.24 mmol, 2.2 eq.) at RT. The dark mixture was stirred for 5 min before a solution of benzyl N-[(2S)-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-3-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-11-yl]propyl]carbamate (76 mg, 0.11 mmol, 1.0 eq.) in DCM (543 µL) was added. The vial was sealed and stirred for 18 h. The black precipitate was washed with saturated aqueous _NaHCO3 , extracted with DCM (3 x 2 mL), and passed through an SCX-2 column eluting with MeOH followed by _NH3 (2M in MeOH) to afford the crude amine. Normal phase silica gel chromatography (0 to 20% _NH3 (2M in MeOH)/DCM) afforded 11-[(2S)-3-amino-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (13.84 mg, 22% yield). HPLC/MS m/z: 567.2 [M+H] ⁺ , Rt (R): 1.153 min; ¹ H NMR (600 MHz, methanol-d ₄ /chloroform-d, 1:1): δ 8.87-8.77 (m, 1H), 8.19 (dd, J = 8.5, 1.6 Hz, 1H), 7.89 (d, J = 5.8 Hz, 1H), 7.84 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 0.9 Hz, 1H), 7.02 (dd, J = 6.0, 0.9 Hz, 1H), 6.93 (dd, J = 5.9, 0.9 Hz, 1H), 4.88 (qt, J = 8.8, 4.4 Hz, 2H), 4.72-4.67 (m, 1H), 4.30-4.24 (m, 2H), 3.99 (dq, J = 7.6, 5.0 Hz, 1H+2H), 3.92 (dd, J = 14.0, 6.2 Hz, 1H), 3.04 (dd, J = 13.4, 5.9 Hz, 1H), 2.99 (dd, J = 13.4, 5.1 Hz, 1H), 2.73 (s, 3H).

Example 49 : (S)-N-(1- amino -3-(9 -oxo -1-(2,2,2 -trifluoroethoxy )-6,7- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H)-yl ) propan - 2- yl )-3-(2- methyl -2H- tetrazol -5- yl ) benzamide Example 49.1: DIPEA (142 µL, 0.8 mmol, 4.0 eq.) was added to a mixture of 3-(2-methyl-2H-tetrazol-5-yl)-benzoic acid (48 mg, 0.23 mmol, 1.15 eq.) and HATU (154.7 mg, 0.41 mmol, 2.0 eq.) in DCM (1.0 mL) and stirred at 40 °C for 30 min, followed by addition of 1% paraformaldehyde (20% ethanol, 0.2% ethanol, 1.1% ethanol, 0.2% ethanol, 1.1% ethanol, 0.2% ethanol, 1.1% ethanol, 0.2% ethanol, 1.1% ethanol, 0.2% ethanol, 1.1% ethanol, 0.2% ethanol, 1.1% ethanol, 0.2% ethanol, 1.1% ethanol, 0.2% ethanol, 1.1% ethanol, 0.2% The mixture was stirred for 4 h, then washed with water, extracted with DCM, filtered over MgSO ₄ and evaporated. Silica gel chromatography (70 to 100% EtOAc/cyclohexane) afforded benzyl N-[(2S)-2-[[3-(2-methyltetrazol-5-yl)benzyl]amino]-3-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl]propyl]carbamate (96.9 mg, 70% yield). HPLC/MS m/z: 678.2 [M+H] ⁺ , Rt (Y): 1.57 min.

Example 49.2: _Et3SiH (50 µL, 0.3 mmol, 5.7 eq.) was added to a mixture of benzyl N-[(2S)-2-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]-3-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl]propyl]carbamate (37 mg, 55.2 µmol, 1.0 eq.) and Pd/C (35 mg, 100% wt/wt) in EtOH (552 µL, 0.1 M) at RT. The mixture was passed through an SCX-2 column, eluting sequentially with MeOH and DCM, then 10% NH ₃ (2N in MeOH)/DCM to collect the desired free amine. Further purification was performed by preparative TLC (10% NH ₃ (2M in MeOH)/DCM). HPLC/MS m/z: 544.2 [M+H] ⁺ , Rt (Y): 1.21 min; ¹ H NMR (600 MHz, methanol-d ₄ /chloroform-d, 1:1): δ 8.53 (t, J = 1.8 Hz, 1H), 8.24 (dt, J = 7.8, 1.4 Hz, 1H), 7.92 (dd d, J = 7.8, 1.9, 1.2 Hz, 1H), 7.86 (d, J = 6.1 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 0.9 Hz, 1H), 7.06 (dd, J = 6.1, 0.9 Hz, 1H), 4.93 -4.84 (m, 2H), 4.58-4.53 (m, 1H), 4.44 (s, 3H), 4.39-4.32 (m, 2H), 4.06-3.99 (m, 1H+1H), 3.96 (ddd, J = 12.9, 6.7, 4.7 Hz, 1H), 3.71 (dd, J = 14. 1, 5.5 Hz, 1H), 3.04 (d, J = 1.5 Hz, 1H), 3.03 (d, J = 3.3 Hz, 1H).

Example 50 : (S)-3-(2 -methyl -2H- tetrazol -5 - yl )-N-(6-( methylamino )-1-(9 -oxo- 1-(2,2,2 -trifluoroethoxy )-6,7- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H)-yl ) hexan - 2- yl ) benzamide Example 50.1: DIPEA (721.88 μL, 4.1445 mmol) was added to a mixture of Fmoc-Lys(Me,Boc)-OH (1.00 g, 2.0722 mmol) and HATU (1.03 g, 2.7037 mmol) in DCM (10.36 mL, 0.1000M). This was heated to 50 °C for 15 min until the mixture became a clear yellow solution. A solution of ethanolamine (162.64 μL, 2.6939 mmol) in DCM (10.36 mL) was added dropwise at RT, whereupon a precipitate formed, and this was stirred at this temperature for 2 h. The mixture was washed with aqueous HCl (1 M) and the solvent was evaporated. Normal phase chromatography (0 to 7% MeOH/DCM) afforded N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-(2-hydroxyethylamino)-6-oxo-hexyl]-N-methyl-carbamic acid tert-butyl ester (5.45 g, quant.) as a white solid. HPLC/MS m/z: 526.3 [M+H] ⁺ , Rt (R): 1.477 min.

Example 50.2: To a solution of tert-butyl N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-(2-hydroxyethylamino)-6-oxo-hexyl] _-N -methyl-carbamate ( _5.45 g, 10.361 mmol) in THF (103.61 mL) was added BF3.OEt2 (1.28 mL, 10.361 mmol) dropwise at 0°C, followed immediately by the dropwise addition of _BH3.THF (1 M in THF) (62.16 mL, 62.164 mmol). The ice bath was removed, and the solution was stirred at RT overnight. The solution was quenched with the addition of MeOH at 0°C, and the solvent was evaporated. Normal phase chromatography (0 to 20% MeOH/DCM) afforded N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-(2-hydroxyethylamino)hexyl]-N-methyl-carbamic acid tert-butyl ester (3.43 g, 65% yield). HPLC/MS m/z: 512.3 [M+H] ⁺ , Rt (Y): 1.401 min.

Example 50.3: A yellow solution of sodium 4-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (1.00 g, 3.5442 mmol) and HATU (4.04 g, 10.633 mmol) in DMF (17.72 mL) pre-stirred for 15 min was added dropwise to a solution of tert-butyl N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-(2-hydroxyethylamino)hexyl]-N-methyl-carbamate (1.81 g, 3.5442 mmol) and DIPEA (1.85 mL, 10.633 mmol) in DMF (17.72 mL). After 1 min, water was added and the solvent was evaporated. The residue was washed with water and extracted with DCM. The organic phase was dried over MgSO ₄ and evaporated. Normal phase chromatography (0 to 5% MeOH / DCM) followed by reverse phase chromatography (20 to 100% MeOH / H ₂ O) gave N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-[2-hydroxyethyl-[4-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carbonyl]amino]hexyl]-N-methyl-carbamic acid tert-butyl ester (1.37 g, 51% yield). _{R f} (DCM:EtOAc, 1:1) = 0.13; HPLC/MS m/z: 754.3 [M+H] ⁺ , Rt (R): 1.59 min.

Example 50.4: A solution of _PPh3 (1.56 g, 6.0 mmol, 3.0 eq.) in THF (9.9 mL) was added to a solution of tert-butyl N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-[2-hydroxyethyl-[4-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carbonyl]amino]hexyl]-N-methyl-carbamate (1.50 g, 2.0 mmol, 1.0 eq.) in THF (9.9 mL) at -40°C to prevent Fmoc removal. DIAD (1.2 mL, 6.0 mmol, 3.0 eq.) was immediately added dropwise, allowing the yellow color to fade between additions. After stirring vigorously at -40 °C for 30 seconds, the reaction was quenched with water. The mixture was extracted with DCM and the organic phase was dried over MgSO ₄ and evaporated in vacuo. Normal phase chromatography (0 to 70% EtOAc/DCM) gave a mixture of triphenylphosphine oxide and N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]hexyl]-N-methyl-carbamic acid tert-butyl ester, which was carried to the next step without further purification. HPLC/MS m/z: 736.3 [M+H] ⁺ , Rt (Y): 1.862 min.

Example 50.5: Piperidine (392 µL, 3.97 mmol, 2.0 eq.) was added to a solution of tert-butyl N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]hexyl]-N-methyl-carbamate (1.46 g, 2.0 mmol, 1.0 eq.) in DMF (19.9 mL, 0.1 M). After 30 minutes, water was added and the solvent was evaporated. Normal phase chromatography (0 to 15% MeOH/DCM) afforded N-[(5S)-5-amino-6-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]hexyl]-N-methyl-carbamic acid tert-butyl ester (824 mg, 81% yield over 2 steps). HPLC/MS m/z: 514.3 [M+H] ⁺ , Rt (R): 1.17.

Example 50.6: DIPEA (60.64 μL, 0.3482 mmol) was added to a mixture of 3-(2-methyl-2H-tetrazol-5-yl)-benzoic acid (20.44 mg, 0.1001 mmol), HATU (66.19 mg, 0.1741 mmol) and N-[(5S)-5-amino-6-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl]hexyl]-N-methyl-carbamic acid tert-butyl ester (44.70 mg, 0.0870 mmol) in DCM (870.41 μL, 0.1000 M). This was stirred for 2 hours after which the solution was washed once with water, then extracted with DCM, filtered over MgSO ₄ and evaporated. Silica gel chromatography (70 to 100% EtOAc/cyclohexane) (51.4 mg, 84%, 0.0735 mmol). The product was carried forward to the next step without further purification. HPLC/MS m/z: 700.3 [M+H] ⁺ , Rt (R): 1.47 min.

Example 50.7: tert-butyl N-methyl-N-[(5S)-5-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]-6-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl]hexyl]carbamate (46.50 mg, 0.0665 mmol) was stirred in DCM/TFA (1:1) (664.55 µL) for 30 min. The solvent was evaporated, redissolved in aqueous HCl (3 N) and evaporated (x2). The solid was washed with DCM, redissolved in MeOH and filtered through an SCX-2 column, eluting with MeOH. The free amine was recovered by washing the column with NH ₃ in MeOH (2M). N-[(1S)-5-(methylamino)-1-[[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl]methyl]pentyl]-3-(2-methyltetrazol-5-yl)benzamide (40 mg, quant. over 2 steps). HPLC/MS m/z: 600.3 [M+H] ⁺ , Rt (Y): 1.248 min; ¹ H NMR (600 MHz, methanol- _{d 4} ): δ 8.46 (dt, J = 1.8, 1.0 Hz, 1H), 8.20 (dt, J = 7.8, 1.5 Hz, 1H), 7.87 (ddd, J = 7.8, 1.9, 1.2 Hz, 1H), 7.84 (d, J = 6.1 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 0.9 Hz, 1H), 7.11 (dd, J = 6.1, 0.9 Hz, 1H), 5.03-4 .89 (m, 2H), 4.58 (dtd, J = 11.1, 7.1, 4.2 Hz, 1H ) , 4.41 (s, 3H), 4.41-4.29 ( m , 2H), 4.10-4.01 (m, 1H+1H), 3.94 (ddd, J = 12.9, 6.9, 4.5 Hz, 1 1.75- 1.67 (m, 1H), 1.67-1.49 (m, 2H).

Example 51 : (S)-N-(6-( methyl ( prop -2- yn -1- yl ) amino )-1-(9 -oxo -1-(2,2,2 -trifluoroethoxy )-6,7- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H)-yl ) hex - 2- yl )-3-(2 -methyl -2H- tetrazol -5- yl ) benzamide A solution of propargyl bromide (80% in toluene) (26 µL, 0.27 mmol, 1.05 eq.) was added to a mixture of N-[(1S)-5-(methylamino)-1-[[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]methyl]pentyl]-3-(2-methyltetrazol-5-yl)benzamide (154 mg, 0.26 mmol, 1.0 eq.) and Cs ₂ CO ₃ (336.8 mg, 1.03 mmol, 4.0 eq.) in DMF (1.3 mL, 0.2M) at 0°C and this was stirred at RT for 18 h. Water was added and the solvent was evaporated. Silica gel chromatography (0 to 6% MeOH/DCM) gave N-[(1S)-5-[methyl(prop-2-ynyl)amino]-1-[[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl]methyl]pentyl]-3-(2-methyltetrazol-5-yl)benzamide (100.4 mg, 61% yield) as a white powder. HPLC/MS m/z: 638.3 [M+H] ⁺ , Rt (Y): 1.10 min; ¹ H NMR (600 MHz, methanol-d ₄ ): δ 8.44 (t, J = 1.8 Hz, 1H), 8.20 (dq, J = 7.9, 1.5 Hz, 1H), 7.85 (m, 1H + 1H) , 7.57 (td, J = 7.8, 1.3 Hz, 1H), 7.18 (t, J = 1.1 Hz, 1H), 7.12 (d, J = 6.1 Hz, 1H), 5.06-4.89 (m, 2H), 4.61-4.52 (m, 1H), 4.42 (d, J = 1.1 Hz, 3H), 4.40-4.31 (m, 2H), 4.12 (dd, J = 13.8, 10.1 Hz, 1H), 4.07 (ddd, J = 12.4, 7.4, 4.6 Hz, 1H), 3.93 (ddd, J = 13.0, 6.9, 4.5 Hz, 1H), 3.50 (dd, J = 13.9, 4.2 Hz, 1H), 3.35 (d, J = 2.5 Hz, 2H), 2.64 (t, J = 2.4 Hz, 1H), 2.50 (td, J = 6.4, 3.5 Hz, 2H), 2.32 (s, 3H), 1.75 (q, J = 7.4 Hz, 2 H), 1.63 (tdd, J = 11.8, 6.5, 3.8 Hz, 1H), 1.59-1.45 (m, 2H + 1H).

Example 52 : (S)-8-(6-( methyl ( prop -2- yn -1- yl ) amino )-2-((7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1 -yl ) amino ) hexyl )-1-(2,2,2 -trifluoroethoxy )-7,8- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 9(6H) -one Example 52.1: DIPEA (0.13 mL, 0.7302 mmol) was added dropwise to a solution of tert-butyl N-[(5S)-5-amino-6-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl]hexyl]-N-methyl-carbamate (100.00 mg, 0.1947 mmol), 5-methyl-3-(2-oxoisoquinolin-2-yl)-1,2,4-oxadiazole (53.09 mg, 0.2337 mmol) and PyBrop (108.93 The product was purified by HPLC-MS/MS: m/z: 723.3 [M+H] ⁺ , Rt (R): 1.36 _min .

Example 52.2: tert-butyl N-methyl-N-[(5S)-5-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-6-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl]hexyl]carbamate (112.00 mg, 0.1550 mmol) was stirred in DCM/TFA (1:1) (1.55 mL) for 30 min. The solvent was evaporated, dissolved back in MeOH and filtered through an SCX-2 column, washing with MeOH. The free amine was recovered by washing the column with NH ₃ in MeOH (2M). (76.9 mg, 80% yield). HPLC/MS m/z: 300.6 [M+2H] ⁺ , Rt (Y): 1.248 min.

Example 52.3: Propargyl bromide solution (80% in toluene) (12 µL, 0.13 mmol, 1.05 eq.) was added to 11-[(2S)-6-(methylamino)-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]hexyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (76.9 mg, 0.12 mmol, 1.0 eq.) and Cs ₂ CO ₃ (162 mg, 0.49 mmol, 4.0 eq.) and this was stirred at RT for 18 h. Water was added and the solvent was evaporated. Preparative TLC (5% MeOH/DCM) gave 11-[(2S)-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-6-[methyl(prop-2-ynyl)amino]hexyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (38.8 mg, 48% yield) as a white powder. Rf (DCM:MeOH, 95:5) = 0.46; HPLC/MS m/z: 661.3 [M+H] ⁺ , Rt (Z): 2.21 min (broad); ¹ H NMR (500 MHz, methanol-d ₄ ): δ 8.83 (quint, J = 0.8 Hz, 1H), 8.10 (dd, J = 8.4, 1. 6 Hz, 1H), 7.81 (d, J = 5.9 Hz, 1H), 7.79 (d, J = 6.0 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 0.9 Hz, 1H), 7.01 (dd, J = 6.0, 0.9 Hz, 1H), 6.81 (dd, J = 5.9, 0.9 Hz, 1H), 5.00-4.86 (m, 2H+1H), 4.19 (ddd, J = 11.7, 6.9, 4.6 Hz, 1H), 4.13 (ddd, J = 12.3, 7.4, 4.5 Hz, 1H), 4.04-3.86 (m , 2H + 1H), 3.79 (dd, J = 13.8, 4.9 Hz, 1H), 3.28 (d, J = 2.5 Hz, 2H), 2.66 (s, 3H), 2.57 (t, J = 2.4 Hz, 1H), 2.46-2.41 (m, 2H), 2.25 (s, 3H ), 1.91-1.76 (m, 2H), 1.64-1.47 (m, 2H + 2H).

Example 53 : N-[(1S)-4-( methylamino )-1-[2 -oxo -2-[(7 -propoxy -1,3- benzothiazol -2- yl ) amino ] ethyl ] butyl ]-3-(5- methyl -1,2,4- oxadiazol -3- yl ) benzamide Example 53.1: To a solution of tert-butyl (3S)-3-amino-6-[tert-butoxycarbonyl(methyl)amino]hexanoate (500.00 mg, 1.5801 mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (354.88 mg, 1.7381 mmol) in anhydrous DMF (7.70 mL) was added T3P in DMF (3.72 mL, 3.1602 mmol) and triethylamine (0.67 mL, 4.7402 mmol). The reaction mixture was stirred at room temperature for 2 h 15 min. The mixture was diluted with EtOAc (50 mL) and washed with water (75 mL). After phase separation, the organic layer was washed with saturated aqueous NaHCO ₃ solution (50 mL) and saturated aqueous NH ₄ Cl solution (75 mL), then dried over Na ₂ SO ₄ and concentrated in vacuo to give tert-butyl (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]hexanoate (710 mg, 89%) as a light yellow oil. HPLC/MS m/z: 503.3 [M+H] ⁺ , Rt (R): 1.47 min.

Example 53.2: To a solution of tert-butyl (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]hexanoate (710.00 mg, 1.4127 mmol) in THF (14.13 mL) was added potassium hydroxide (792.64 mg, 14.127 mmol) and water (0.5 mL, enough to dissolve the KOH) and 8 drops of MeOH. The mixture was stirred at 50 °C for 2 h. The mixture was allowed to cool and the volatiles were removed under reduced pressure. Water (20 mL) was added and this was acidified to pH 3 with 2M aqueous HCl. This was extracted with EtOAc x 2 and _the combined organics were dried over _Na2SO4 and then concentrated under reduced pressure to give a light yellow foam/solid, 381 mg. Purification by reverse phase flash chromatography (solvent: 0 to 80% MeOH/ _H2O + 0.1% formic acid) gave rac-(3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]hexanoic acid as a clear oil, 196 mg (31%). HPLC/MS m/z: 347.1 [M-BOC+H] ⁺ , Rt (R): 1.29 min.

Example 53.3: To a mixture of rac-(3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]hexanoic acid ( _20.00 mg, 0.0448 mmol), 7-propoxy-1,3-benzothiazol-2-amine [Example 75.3] (12.13 mg, 0.0582 mmol), 1-hydroxybenzotriazole (12.10 mg, 0.0896 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.17 mg, 0.0896 mmol) was added anhydrous DMF (0.22 mL) under N2. The mixture was stirred at 60 °C for 23 h. The mixture was concentrated under reduced pressure. Purification by reverse phase flash chromatography (solvent: 10 to 80% MeOH/H ₂ O + 0.1% formic acid) gave tert-butyl N-methyl-N-[(4S)-4-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]-6-oxo-6-[(7-propoxy-1,3-benzothiazol-2-yl)amino]hexyl]carbamate as an off-white solid, 9 mg (32%). HPLC/MS m/z: 537.2 [M-BOC+H] ⁺ , Rt (S): 2.54 min.

Example 53.4: To a flask charged with tert-butyl N-methyl-N-[(4S)-4-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]-6-oxo-6-[(7-propoxy-1,3-benzothiazol-2-yl)amino]hexyl]carbamate (9.00 mg, 0.0141 mmol) was added 4M HCl in dioxane (1.00 mL, 4 mmol). The solution was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to give a light yellow solid. The crude was dissolved in MeOH and purified using a 1 g SCX-2 column, first rinsing through MeOH and then eluting with 2N _NH3 in MeOH. The alkaline fraction was concentrated under reduced pressure to give 5.4 mg (69%) of N-[(1S)-4-(methylamino)-1-[2-oxo-2-[(7-propoxy-1,3-benzothiazol-2-yl)amino]ethyl]butyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide as a light orange solid. HPLC/MS m/z: 537.3 [M+H] ⁺ , Rt (Z): 2.45 min. ¹ H NMR (600 MHz, chloroform- d): δ 8.49 (t, J = 1.8 Hz, 1H), 8.16 (dt, J = 7.8, 1.4 Hz, 1H), 8.02 (dt, J = 7.9, 1.4 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7. 38 (dd, J = 8.1, 0.8 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 6.72 (dd, J = 8.0, 0.8 Hz, 1H), 4.43 (s, 1H), 4.08 (t, J = 6.4 Hz, 2H), 2.99 (dd, J = 14.7, 4.7 Hz, 1H), 2.80 (dd, J = 14.7, 6.2 Hz, 3H), 2.72-2.67 (m, 3H), 2.65 (s, 3H), 2.40 (s, 3H), 1.98-1.80 (m, 4H), 1.72 (qquint, J = 13.6, 6.5 Hz, 2H ), 1.07 (t, J = 7.4 Hz, 3H).

Example 54 : (3S)-6-( Methylamino )-3-[[7-(5 -methyl -1,2,4- oxadiazol-3 - yl )-1- isoquinolinyl ] amino ]-N-(7 -propoxy -1,3- benzothiazol -2- yl ) hexanamide Example 54.1: To a solution of tert-butyl 3-amino-6-[tert-butoxycarbonyl(methyl)amino]hexanoate (522.25 mg, 1.6504 mmol) in anhydrous DCM (8.63 mL) was added 5-methyl-3-(2-oxoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole (300 mg, 1.32 mmol), PyBroP (0.75 g, 1.6108 mmol) and DIPEA (0.86 mL, 4.9511 mmol). This mixture was stirred at room temperature under _N2 for 16 h. Additional PyBroP (300 mg, 0.644 mmol) was added and this was stirred for another 18 h under _N2 . The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (solvent: 20 to 50% EtOAc/cyclohexane) to give tert-butyl (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]hexanoate as a green gum, 522 mg (75%). HPLC m/z: 526.3 [M+H] ⁺ , Rt (R): 1.24 min.

Example 54.2: To a solution of tert-butyl (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]hexanoate (522.00 mg, 0.9931 mmol) in THF (9.93 mL) was added potassium hydroxide (557.21 mg, 9.9308 mmol) and water (0.5 mL was enough to dissolve the KOH) followed by 8 drops of MeOH. The mixture was allowed to stir at 50 °C for 18 h. Additional potassium hydroxide (557.21 mg, 9.9308 mmol) was added and stirring was continued at 50 °C for 13 days. Additional MeOH (1 mL) and water (1 mL) were required for complete conversion. The mixture was allowed to cool and the volatiles were removed under reduced pressure. Water (20 mL) was added and this was acidified to pH 3 with 2M aqueous HCl. Extraction with EtOAc (3x) was performed and the combined organics _were dried over _Na2SO4 . These were then concentrated under reduced pressure to give a light yellow solid. Purification by reverse phase flash chromatography (solvent: 10 to 100% MeOH/ _H2O + 0.1% formic acid) gave (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]hexanoic acid as a light yellow glassy solid, 177 mg (38%). HPLC m/z: 470.2 [M+H] ⁺ , Rt (R): 1.12 min.

Example 54.3: To a mixture of (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino] _hexanoic acid (30.00 mg, 0.0639 mmol) and 7-propoxy-1,3-benzothiazol-2-amine [Example 75.3] (13.31 mg, 0.0639 mmol) in DMF (0.32 mL) under N2 was added triethylamine (0.03 mL, 0.1917 mmol) and then 1-propanephosphonic anhydride (50% in DMF) (0.08 mL, 0.1278 mmol). This mixture was stirred at 70 °C under _N2 for 5 days and then at 60 °C for another 3 days. Purification by reverse phase flash chromatography (solvent: 20 to 80% MeOH/H ₂ O + 0.1% formic acid) gave tert-butyl N-methyl-N-[(4S)-4-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-6-oxo-6-[(7-propoxy-1,3-benzothiazol-2-yl)amino]hexyl]carbamate as a light yellow solid, 31 mg (73%). HPLC/MS m/z: 452.2 [M+H] ⁺ , Rt (R): 1.40 min.

Example 54.4: To a flask charged with tert-butyl N-methyl-N-[(4S)-4-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-6-oxo-6-[(7-propoxy-1,3-benzothiazol-2-yl)amino]hexyl]carbamate (34.00 mg, 0.0515 mmol) was added 4M HCl in dioxane (1.03 mL, 4.1225 mmol). The solution was stirred at RT for 20 min. The mixture was concentrated under reduced pressure and then purified using preparative HPLC to give (3S)-6-(methylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-N-(7-propoxy-1,3-benzothiazol-2-yl)hexanamide as an off-white amorphous solid, 10.5 mg (36%). HPLC/MS m/z: 560.2 [M+H] ⁺ , Rt (S): 2.28 min. ¹ H NMR (600 MHz, methanol- _{d 4} ): δ 8.90 (s, 1H), 8.19 (dd, J = 8.4, 1.6 Hz, 1H), 7.96 (d, J = 5.9 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.37-7.30 (m, 2H) , 6.97 (d, J = 5.9 Hz, 1H), 6.83 (dd, J = 7.4, 1.3 Hz, 1H), 4.82 (d, J = 8.7 Hz, 1H), 4.12 (t, J = 6.4 Hz, 2H), 3.03 (dd, J = 14.7, 5.9 Hz, 1H), 2 .85 (dd, J = 14.7, 6.8 Hz, 1H), 2.81-2.65 (m, 5H), 2.44 (s, 3H), 2.01-1.69 (m, 6H), 1.09 (t, J = 7.4 Hz, 3H).

The following examples were synthesized by a similar procedure.

Example 55 : (S)-N-(4 -fluoro - 7-propoxybenzo [d] thiazol -2 -yl )-3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1 -yl ) amino )-6-( methylamino ) hexanamide (S)-N-(4-fluoro-7-propoxybenzo[d]thiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-6-(methylamino)hexanamide dichloride (430 mg, 95%, 0.6603 mmol) was obtained from 4-fluoro-7-propoxy-1,3-benzothiazol-2-amine [Example 77.2] and (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]hexanoic acid [Example 54.2] as a white solid. HPLC/MS m/z: 578.234 [M+H] ⁺ , Rt (AE): 2.33 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 13.52 (br s, 1H), 12.88 (s, 1H), 9.57 (br s, 1H), 9.31 (s, 1H), 8.78-8.63 (m, 2H), 8.46 (d, J = 8.5 Hz, 1H), 8. 13 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 6.7 Hz, 1H), 7.22-7.17 (m, 1H), 6.85-6.82 (m, 1H), 4.89-4.84 (m, 1H), 4.06 (t d, J = 6.4, 1.1 Hz, 2H), 3.18 (dd, J = 16.8, 7.8 Hz, 1H), 3.11 (dd, J = 16.8, 4.6 Hz, 1H), 2.99-2.87 (m, 2H), 2.71 (s, 3H), 2.51 (d, J = 5.4 Hz, 3H), 1 .93-1.83 (m, 2H), 1.79-1.69 (m, 4H), 0.97 (t, J = 7.4 Hz, 3H).

Example 56 : N-[4- fluoro -7-(3 -fluoropropoxy )-1,3- benzothiazol -2 - yl ]-3-[[7-(5 -methyl -1,2,4- oxadiazol -3- yl )-1- isoquinolinyl ] amino ] propionamide Example 56.1: To a solution of 2-amino-4-fluoro-1,3-benzothiazol-7-ol (80.00 mg, 0.4343 mmol) in DMF (4.01 mL, 0.1100 M) stirred at RT under _N2 was added potassium carbonate (120.06 mg, 0.8687 mmol). This was stirred for 30 min before 1-iodo-3-fluoropropane (0.04 mL, 0.4343 mmol) was added. This was then stirred under _N2 for 7 h. The mixture was diluted with water (2 mL), acidified to pH 6 with 2N HCl solution and then MeOH (20 mL) was added. This was loaded onto a 5 g SCX-2 column, washed with MeOH and then dissolved with 2N _NH3 in MeOH. The alkaline washings were concentrated under reduced pressure to give 4-fluoro-7-(3-fluoropropoxy)-1,3-benzothiazol-2-amine as a dark grey solid, 70 mg (66%). HPLC/MS m/z: 245.1 [M+H] ⁺ , Rt (R): 1.11 min.

Example 56.2: To a mixture of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoic acid B2 (25.00 mg, 0.0838 mmol) and 4-fluoro-7-(3-fluoropropoxy)-1,3-benzothiazol-2-amine (20.47 mg, 0.0838 mmol) in DMF (0.84 mL) was added triethylamine (0.04 mL, 0.2514 mmol) and then 1-propanephosphonic anhydride (50% in DMF) (0.10 mL, 0.1676 mmol). This mixture was stirred at 70 °C under _N2 for 3 days. Another 2 eq. 1-propanephosphonic anhydride (50% in DMF) (0.10 mL, 0.1676 mmol) was added and this was stirred at 70 °C under _N2 for 18 h. Another 2 eq. 1-propanephosphonic anhydride (50% in DMF) (0.10 mL, 0.1676 mmol) was added and the mixture was stirred at 70 °C under _N2 for 4 h. The crude was purified by preparative HPLC to give N-[4-fluoro-7-(3-fluoropropoxy)-1,3-benzothiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide as a white solid, 8.5 mg (19%). HPLC/MS m/z: 525.2 [M+H] ⁺ , Rt (Z): 2.41 min. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 12.74 (s, 1H), 8.91-8.87 (m, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.04 (t, J = 5.5 Hz, 1H), 7.97 (d, J = 5.8 Hz, 1H ), 7.85 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 10.5, 8.8 Hz, 1H), 7.00-6.95 (m, 1H), 6.89 (dd, J = 8.8, 3.1 Hz, 1H), 4.68 (t, J = 5.9 Hz, 1H), 4.59 (t, J = 5.8 Hz, 1H), 4.24 (t, J = 6.2 Hz, 2H), 3.84 (q, J = 6.5 Hz, 2H), 2.94 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.16 (dquint, J = 25.9, 6.0 Hz, 2H).

Example 57 : N-[4- fluoro -7-(3 -fluoroethoxy )-1,3- benzothiazol -2 - yl ]-3-[[7-(5 -methyl -1,2,4- oxadiazol -3- yl )-1- isoquinolinyl ] amino ] propionamide Example 57.1: To a solution of 2-amino-4-fluoro-1,3-benzothiazol-7-ol (80.00 mg, 0.4343 mmol) in DMF (4.01 mL, 0.1100 M) stirred at RT under _N2 was added potassium carbonate (120.06 mg, 0.8687 mmol). This was stirred for 30 min before 1-iodo-3-fluoroethane (0.05 mL, 0.4343 mmol) was added. This was then stirred under _N2 for 25 h. The mixture was diluted with water (2 mL), acidified to pH 6 with 2N aqueous HCl and then MeOH (20 mL) was added. This was loaded onto a 5 g SCX-2 column, washed with MeOH and then dissolved with 2N _NH3 in MeOH. The alkaline washings were concentrated under reduced pressure to give 4-fluoro-7-(2-fluoroethoxy)-1,3-benzothiazol-2-amine as a dark grey solid, 93 mg (93%). HPLC/MS m/z: 231.0 [M+H] ⁺ , Rt (R): 0.96 min.

Example 57.2: To a mixture of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoic acid B2 (35.00 mg, 0.1173 mmol) and 4-fluoro-7-(2-fluoroethoxy)-1,3-benzothiazol-2-amine (32.42 mg, 0.1408 mmol) in DMF (0.50 mL) was added 1-propanephosphonic anhydride (0.06 mL, 0.2347 mmol). This mixture was stirred at 70 °C under _N2 for 3 days. Additional 1-propanephosphonic anhydride (50% in DMF) (0.06 mL, 0.2347 mmol) was added and this was stirred at 70 °C under _N2 for 3 days. Purification by NP silica gel column chromatography (solvent: 0-10% MeOH/DCM) followed by reverse phase flash chromatography (solvent: 20-100% MeOH/H ₂ O) gave N-[4-fluoro-7-(3-fluoroethoxy)-1,3-benzothiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide as a white solid, 22 mg (36%). HPLC/MS m/z: 511.2 [M+H] ⁺ , Rt (Z): 2.25 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 12.74 (s, 1H), 8.89 (d, J = 1.6 Hz, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.05 (t, J = 5.4 Hz, 1H), 7.97 (d, J = 5.7 Hz , 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.23 (dd, J = 10.5, 8.8 Hz, 1H), 6.97 (d, J = 5.7 Hz, 1H), 6.90 (dd, J = 8.8, 3.0 Hz, 1H), 4.86-4.81 (m, 1H), 4.78-4.73 (m, 1H), 4.46-4.42 (m, 1H), 4.41-4.37 (m, 1H), 3.84 (q, J = 6.6 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H).

The following examples were followed by similar procedures: Example 58 : 3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1- yl ) amino )-N-(7 -propoxybenzo [d] thiazol -2 -yl ) propionamide The product B2 was obtained using 7-propoxy-1,3-benzothiazol-2-amine [Example 73.1] and 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionic acid. White powder (37 mg, 0.0757 mmol). HPLC/MS m/z: 489.158 [M+H] ⁺ , Rt (Z): 2.50 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 12.42 (s, 1H), 8.91-8.87 (m, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.04 (t, J = 5.4 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H ), 7.85 (d, J = 8.5 Hz, 1H), 7.39-7.30 (m, 2H), 6.97 (dd, J = 5.9, 0.8 Hz, 1H), 6.89 (dd, J = 7.7, 1.2 Hz, 1H), 4.12 (t, J = 6.4 Hz, 2H), 3.84 ( q, J = 6.6 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 1.86-1.75 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

Example 59 : (1s,3s)-3-((7-(5 -methyl -1,2,4- oxadiazol-3 - yl ) isoquinolin- 1 - yl ) amino )-N-(7 -propoxybenzo [d] thiazol -2- yl ) cyclobutane -1- carboxamide 3-[[7-(5-Methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarboxylic acid B3 (46.72 mg, 0.1440 mmol) and BTFFH (91.09 mg, 0.2881 mmol) were mixed in DCM (0.53 mL, 0.1800M) at RT under argon. DIPEA (0.11 mL, 0.6242 mmol) was added, and the reaction mixture was stirred for 30 min. 7-Propoxy-1,3-benzothiazol-2-amine [Example 73.1] (0.07 mL, 0.0960 mmol) was added, followed by DMF (0.010 mL). The vial was capped and the reaction was heated to 80 °C in a microwave for 1 h. Purification by reverse phase flash chromatography (solvent: 20 to 70% MeOH/ _H2O + 0.1% formic acid) followed by ion exchange SCX-2 chromatography eluting with 2M NH3 _in MeOH afforded 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-N-(7-propoxy-1,3-benzothiazol-2-yl)cyclobutanecarboxamide (15 mg, 29%, 0.0277 mmol) as a colorless oil. HPLC/MS m/z: 515.185 [M+H] ⁺ , Rt (S): 2.74 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 12.36 (s, 1H), 9.02 (s, 1H), 8.15 (dd, J = 8.5, 1.4 Hz, 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7. 84 (d, J = 8.5 Hz, 1H), 7.42-7.32 (m, 2H), 6.97 (d, J = 5.7 Hz, 1H), 6.90 (dd, J = 7.5, 1.1 Hz, 1H), 4.76-4.66 (m, 1H), 4.13 (t, J = 6.4 Hz, 2H ), 3.19-3.07 (m, 1H), 2.71 (s, 3H), 2.63 (qd, J = 7.9, 2.5 Hz, 2H), 2.49-2.41 (m, 2H), 1.80 (sext, J = 7.2 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H).

The following examples were followed by similar procedures: Example 60 : (1s,3s)-N-(7 -methoxy -4- methylbenzo [d] thiazol -2- yl )-3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ) amino ) cyclobutane -1- carboxamide White powder, 10 mg, 0.0190 mmol. HPLC/MS m/z: 501.168 [M+H] ⁺ , Rt (S): 2.34 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 12.46 (s, 1H), 9.04-9.02 (m, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H ), 7.85 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 8.0, 1.1 Hz, 1H), 6.98 (dd, J = 5.9, 0.8 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 4.73 (ddt, J = 16.7, 9.3, 7 .3 Hz, 1H), 3.92 (s, 3H), 3.23-3.08 (m, 1H), 2.72 (s, 3H), 2.66-2.59 (m, 2H), 2.50 (d, J = 1.7 Hz, 3H), 2.47 (dt, J = 11.6, 9.5 Hz, 2H).

Example 61 : (1s,3s)-N-(7- methoxybenzo [d] thiazol -2- yl )-3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ) amino ) cyclobutane -1- carboxamide Off-white solid, 32 mg, 0.0645 mmol. HPLC/MS m/z: 487.154 [M+H] ⁺ , Rt (X): 2.68 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 2.47 (td, J = 2.5, 9.5 Hz, 2H), 2.63 (qd, J = 2.6, 7.8 Hz, 2H), 2.72 (s, 3H), 3.16 (tt, J = 7.8, 9.7 Hz, 1H), 3.9 5 (s, 3H), 4.74 (ddt, J = 7.4, 9.1, 16.7 Hz, 1H), 6.92 (dd, J = 1.1, 7.8 Hz, 1H), 6.98 (d, J = 5.7 Hz, 1H), 7.35-7.43 (m, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 8.14-8.17 (m, 1H), 9.03 (d, J = 1.6 Hz, 1H), 12.38 (s, 1H).

Example 62 : N-(4- fluoro - 7-propoxybenzo [d] thiazol -2 - yl )-3-((7-(5- methyl -1,2,4- oxadiazol-3 - yl ) isoquinolin -1- yl ) amino ) propionamide Example 62.1: A mixture of 2-amino-4-fluorobenzo[ d ]thiazol-7-ol (200 mg, 1.09 mmol, 1.00 eq ), potassium carbonate (599 mg, 4.33 mmol, 3.99 eq ) and 1-iodopropane (222 mg, 1.30 mmol, 1.20 eq ) in acetonitrile (2.00 mL) was stirred at 50 °C for 12 hours. After the reaction was completed, the mixture was filtered. The filtrate was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 2/1) to give 4-fluoro-7-propoxybenzo[ d ]thiazol-2-amine (160 mg, 707 μmol, 65% yield) as a white solid. ¹ H NMR (400 MHz, chloroform-d): δ = 6.96 (dd, J = 8.8, 10.4 Hz, 1H), 6.51 (dd, J = 3.2, 8.8 Hz, 1H), 5.86 (br s, 2H), 4.03 (t, J = 6.4 Hz, 2H), 1.84 (sext, J = 7.0 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H).

Example 62.2: A mixture of 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanoic acid (60.0 mg, 201 μmol, 1.00 eq), 4-fluoro-7-propoxybenzo[d]thiazol-2-amine (50.0 mg, 221 μmol, 1.10 eq), propylphosphonic anhydride (256 mg, 402 μmol, 239 μL, 50% purity in dimethylformamide, 2.00 eq) in dimethylformamide (0.500 mL) was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was poured into saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20% to 50%, 10 min) and lyophilized to give N-(4-fluoro-7-propoxybenzo[d]thiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide (25.37 mg, 45.4 μmol, 22% yield, 99% purity) as a white solid. HPLC/MS m/z: 507.1 [M+H] ⁺ , Rt (E): 0.87 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.72 (br s, 1H), 8.89 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.14 (s, 1H), 8.07-8.01 (m, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.8, 10.8 Hz, 1H), 6.97 (d, J = 5.6 Hz, 1H), 6.85 (dd, J = 3.2, 8.8 Hz, 1H), 4.10 (t, J = 6.4 Hz, 2H), 3.87-3.80 (m, 2H), 2.94 (br t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 1.83-1.72 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H).

Example 63 : N-(4- chloro - 7-propoxybenzo [d] thiazol -2 - yl )-3-((7-(5- methyl -1,2,4- oxadiazol-3 - yl ) isoquinolin -1- yl ) amino ) propionamide Example 63.1: To a solution of potassium thiocyanate (1.36 g, 14.0 mmol, 1.10 eq ) in acetone (20 mL) at 20 °C was added a solution of acetyl chloride (1.10 g, 14.0 mmol, 0.996 mL, 1.10 eq ) in acetone (10 mL). The mixture was stirred at 50 °C for 0.2 h. To the mixture was then added a solution of 2-chloro-5-methoxyaniline (2.00 g, 12.7 mmol, 1.00 eq ) in acetone (20 mL). The resulting mixture was stirred at 50 °C for 0.5 h. The mixture was then poured into water (200 mL) and filtered. The filter cake was dried under reduced pressure to give a residue. The residue was diluted with methanol (10 mL) and potassium carbonate (3.51 g, 25.4 mmol, 2.00 eq ) was added to the mixture. The mixture was stirred at 25 °C for 12 hours. The mixture was poured into water (200 mL) and filtered. The filter cake was dried under reduced pressure to give 1-(2-chloro-5-methoxyphenyl)thiourea (2.00 g, 9.23 mmol, 72% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.27 (s, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.35 (d, J = 3.0 Hz, 1H), 6.82 (dd, J = 3.0, 9.0 Hz, 1H), 3.74 (s, 3H).

Example 63.2: To a solution of 1-(2-chloro-5-methoxyphenyl)thiourea (1.50 g, 6.92 mmol, 1.00 eq ) in acetic acid (15 mL) at 0°C was added bromine (608 mg, 3.81 mmol, 196 μL, 0.55 eq ). The mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filter cake was dried under reduced pressure to give 4-chloro-7-methoxybenzo[ d ]thiazol-2-amine (1.50 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.86 (br s, 2H), 7.25 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H).

Example 63.3: To a solution of 4-chloro-7-methoxybenzo[ d ]thiazol-2-amine (1.70 g, 7.92 mmol, 1.00 eq ) in dichloromethane (10 mL) at 0 °C was added boron tribromide (9.92 g, 39.6 mmol, 3.82 mL, 5.00 eq ). The mixture was stirred at 30 °C for 12 h. The mixture was then carefully poured into methanol (50 mL) at 0 °C. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column chromatography (C18, 40 g; conditions: water/acetonitrile = 1/0 to 0/1, 0.1% formic acid) to give 2-amino-4-chlorobenzo[ d ]thiazol-7-ol (1.10 g, 5.48 mmol, 69% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.30 (br s, 1H), 7.94 (br s, 2H), 7.11 (d, J = 8.5 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H).

Example 63.4: To a solution of 2-amino-4-chlorobenzo[ d ]thiazol-7-ol (0.400 g, 1.99 mmol, 1.00 eq ) in dimethylformamide (5 mL) was added potassium carbonate (551 mg, 3.99 mmol, 2.00 eq ) and 1-iodopropane (407 mg, 2.39 mmol, 234 μL, 1.20 eq ). The mixture was stirred at 30 °C for 12 h. The mixture was then filtered. The filtrate was purified by reverse phase column chromatography (C18, 120 g; conditions: water/acetonitrile = 1/0 to 0/1, 0.1% formic acid) to give 4-chloro-7-propoxybenzo[ d ]thiazol-2-amine (0.24 g, 989 μmol, 49% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.82 (s, 2H), 7.21 (d, J = 8.6 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 4.04 (t, J = 6.5 Hz, 2H), 1.80-1.65 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

Example 63.5: To a solution of 4-chloro-7-propoxybenzo[d]thiazol-2-amine (100 mg, 412 μmol, 1.00 eq ) and 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanoic acid B2 (123 mg, 0.412 mmol, 1.00 eq ) in dimethylformamide (3 mL) were added 1-methylimidazole (67.7 mg, 0.824 mmol, 65.7 μL, 2.00 eq ) and N,N,N,N-tetramethylammonium chloroformyl hexafluorophosphate (347 mg, 1.24 mmol, 3.00 eq ). The mixture was stirred at 30 °C for 4 h. The mixture was then filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge 150*25 mm* 5 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 58% to 88%, 9 min) and lyophilized to give N- (4-chloro-7-propoxybenzo[ d ]thiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide (24 mg, 45.43 μmol, 11% yield, 99% purity) as a white solid. HPLC/MS m/z: 523.1 [M+H] ⁺ , Rt (E): 0.87 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.84 (br s, 1H), 8.89 (s, 1H), 8.15 (br d, J = 8.5 Hz, 1H), 8.03 (br t, J = 5.0 Hz, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7 .85 (d, J = 8.4 Hz, 1H), 7.43 (br d, J = 8.5 Hz, 1H), 6.97 (br d, J = 5.6 Hz, 1H), 6.90 (br d, J = 8.5 Hz, 1H), 4.12 (br t, J = 6.2 Hz, 2H), 3.90-3. 76 (m, 2H), 2.93 (br t, J = 6.5 Hz, 2H), 2.72-2.65 (m, 3H), 1.79 (qd, J = 6.8, 13.8 Hz, 2H), 1.01 (t, J = 7.3 Hz, 3H).

Example 64 : 3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1 -yl ) amino )-N-(4 -propoxypyrazolo [1,5-a] pyridin -2- yl ) propionamide Example 64.1: To a solution of 2-bromopyridin-3-ol (12.0 g, 69.0 mmol, 1.00 eq ) in DMF (90 mL) was added potassium carbonate (11.4 g, 82.8 mmol, 1.20 eq ). The mixture was stirred at 90 °C for 1 h. 1-Iodopropane (21.1 g, 124 mmol, 1.80 eq ) was added to the mixture. The mixture was stirred at 90 °C for 3 h. The mixture was diluted with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-bromo-3-propoxypyridine (14.0 g, 64.8 mmol, 93% yield) as a brown oil. ¹ H NMR (400 MHz, chloroform-d): δ 7.95 (dd, J = 1.5, 4.6 Hz, 1H), 7.50 (dd, J = 1.4, 8.2 Hz, 1H), 7.39 (dd, J = 4.6, 8.2 Hz, 1H), 4.06 (t, J = 6.4 Hz, 2H), 1.86-1.64 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

Example 64.2: To a solution of acetonitrile (3.06 g, 74.5 mmol, 2.80 eq ) in tetrahydrofuran (100 mL) at -78 °C was added n-butyl lithium (2.5 M in hexanes, 74.5 mmol, 29.8 mL, 2.80 eq ) dropwise. The mixture was stirred at -78 °C for 0.2 h. To the mixture was added a solution of 2-bromo-3-propoxy-pyridine (5.75 g, 26.6 mmol, 1.00 eq ) in tetrahydrofuran (10 mL). The mixture was stirred at -78 °C for 1 h, warmed to 0 °C and stirred at 0 °C for 3 h. The mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1) to give 2-(3-propoxypyridin-2-yl)acetonitrile (5.00 g, crude) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.10 (dd, J = 1.3, 4.6 Hz, 1H), 7.47 (dd, J = 1.3, 8.4 Hz, 1H), 7.36 (dd, J = 4.7, 8.3 Hz, 1H), 4.06 (s, 2H), 4.03-4 .01 (m, 2H), 1.77 (s, 2H), 1.17 (t, J = 7.1 Hz, 3H).

Example 64.3: To a solution of ethyl (1 E ) -N -(2,4,6-trimethylphenyl)sulfonyloxyacetimidate (10.0 g, 35.0 mmol, 1.00 eq ) in dioxane (20 mL) at 0°C was added perchloric acid (9.32 g, 64.9 mmol, 5.61 mL, 70% purity, 1.85 eq ). The mixture was then stirred at 0°C for 0.5 h. The solution was diluted with ice water (30 mL) and filtered. The filter cake was extracted with dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered to give a solution of O- (mesitylsulfonyl)hydroxylamine (6.50 g) in dichloromethane (0.6 M, 50 mL) as a colorless solution which was used directly in the next step.

Example 64.4: To a solution of amino 2,4,6-trimethylbenzenesulfonate (0.600 M, 15.3 mmol, 25.5 mL, 1.35 eq ) in dichloromethane (15 mL) was added 2-(3-propoxypyridin-2-yl)acetonitrile (2.00 g, 11.4 mmol, 1.00 eq ). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give 1-amino-2-(cyanomethyl)-3-propoxypyridin-1-ium 2,4,6-trimethylbenzenesulfonate (5.00 g, crude) as a brown oil. It was used directly in the next step.

Example 64.5: To a solution of 1-amino-2-(cyanomethyl)-3-propoxypyridin-1-ium 2,4,6-trifluorobenzenesulfonate in methanol (60 mL) was added potassium carbonate (2.82 g, 20.4 mmol, 2.00 eq ). The mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 1/1), reverse phase column chromatography (C18, 40 g; conditions: water/acetonitrile = 1/0 to 0/1, 0.1% formic acid) and concentrated under reduced pressure to give 4-propoxypyrazolo[1,5- a ]pyridin-2-amine (0.130 g, crude) as a yellow oil. ¹ H NMR (400 MHz, chloroform-d): δ 7.81 (d, J = 6.8 Hz, 1H), 6.45-6.39 (m, 1H), 6.29 (d, J = 7.5 Hz, 1H), 5.86 (s, 1H), 4.01-3.98 (m, 2H), 1.88-1.84 (m, 2H), 1.07-1.04 (m, 3H).

Example 64.6: To a solution of 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanoic acid B2 (46.8 mg, 0.157 mmol, 1.00 eq ), 4-propoxypyrazolo[1,5- a ]pyridin-2-amine (30.0 mg, 0.157 mmol, 1.00 eq ) and 1-methylimidazole (51.5 mg, 0.628 mmol, 50.0 μL, 4.00 eq ) in DMF (1 mL) was added N , N , N , N -tetramethylammonium chloroformyl hexafluorophosphate (132 mg, 0.471 mmol, 3.00 eq ). The mixture was stirred at 20 °C for 12 h. The three batches of the reaction mixture were combined and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (ethyl acetate/methanol = 20/1), preparative HPLC (column: Shim-pack C18 150*25*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 21% to 51%, 10 min) and lyophilized to give 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino) -N- (4-propoxypyrazolo[1,5- a ]pyridin-2-yl)propanamide (9.78 mg, 18.52 μmol, 3.93% yield, 98% purity, formate) as a white solid. HPLC/MS m/z: 472.2 [M+H] ⁺ , Rt (E): 0.83 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.91 (br s, 1H), 9.11 (br s, 1H), 8.35 (br s, 1H), 8.13 (s, 1H), 8.10 (d, J = 6.9 Hz, 1H), 8.03 (br s, 1H), 7.86 (br s, 1H), 7.20 (br s, 1H), 6.85 (s, 1H), 6.74-6.67 (m, 1H), 6.61 (d, J = 7.6 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.85 (br d, J = 5.6 Hz, 2H), 2.89 (br s, 2H), 2.70 (s, 3H), 1.84-1.76 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

Example 65 : 3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1 -yl ) amino )-N-(4 -propoxypyrazolo [1,5-a] pyrrolidone - 2- yl ) propionamide To a solution of 3-nitro- 1H -pyrazole-5-carboxylic acid (6.00 g, 38.2 mmol, 1.00 eq ) in acetonitrile (60 mL) was added 1,1 carbon diimidazole (7.43 g, 45.8 mmol, 1.20 eq ). The mixture was stirred at 60 °C for 3 hours. To the mixture was added 2,2-dimethoxyethylamine (4.02 g, 38.2 mmol, 1.00 eq ) and the mixture was stirred at 60 °C for 12 hours. The mixture was concentrated to give a residue. The residue was dissolved in ethyl acetate (60 mL) and washed with aqueous hydrochloric acid (1 M, 3 x 20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N- (2,2-dimethoxyethyl)-3-nitro- 1H -pyrazole-5-carboxamide (6.00 g, 24.6 mmol, 64% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 14.82 (br s, 1H), 8.90 (br t, J = 5.6 Hz, 1H), 7.67 (s, 1H), 4.49 (t, J = 5.4 Hz, 1H), 3.42-3.38 (m, 2H), 3.31 (s, 6H).

Example 65.2: A solution of N- (2,2-dimethoxyethyl)-3-nitro- 1H -pyrazole-5-carboxamide (6.00 g, 24.57 mmol, 1.00 eq ) in hydrochloric acid (5.00 M, 20 mL) was stirred at 20 °C for 12 h. The mixture was filtered. The filter cake was concentrated under reduced pressure to give 7-hydroxy-2-nitro-6,7-dihydroxypyrazolo[1,5- a ]pyrrolidone-4( 5H )-one (5.00 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.57 (br d, J = 3.6 Hz, 1H), 7.85 (br d, J = 5.9 Hz, 1H), 7.43 (s, 1H), 5.89 (br s, 1H), 3.87 (dd, J = 2.9, 13.9 Hz, 1 H), 3.67-3.42 (m, 1H).

Example 65.3: To a solution of 7-hydroxy-2-nitro-6,7-dihydropyrazolo[1,5- a ]pyrrolidone-4( 5H )-one (2.00 g, 10.1 mmol, 1.00 eq ) in toluene (50 mL) was added sulfinyl chloride (2.40 g, 20.2 mmol, 2.00 eq ) and dimethylformamide (73.8 mg, 1.01 mmol, 0.10 eq ). The mixture was stirred at 125 °C for 12 h. After cooling to room temperature, the mixture was filtered. The filter cake was triturated with acetonitrile (5 mL) and dimethylformamide (1.5 mL) to give 2-nitropyrazolo[1,5- a ]pyrrolidone-4-ol (1.60 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.75 (br d, J = 1.2 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 0.7 Hz, 1H), 7.22 (t, J = 5.9 Hz, 1H).

Example 65.4: To a solution of 2-nitropyrazolo[1,5- a ]pyrrolidone-4-ol (0.800 g, 4.44 mmol, 1.00 eq ) in phosphorus trichloride (6 mL) was added dimethylformamide (16.2 mg, 0.05 eq ). The mixture was stirred at 100 °C for 12 h. The mixture was poured into water (20 mL) and the pH was adjusted to pH 8 with sodium carbonate. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2-nitropyrazolo[1,5- a ]pyridine (0.600 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.03 (dd, J = 0.9, 4.8 Hz, 1H), 8.10 (d, J = 4.9 Hz, 1H), 7.92 (d, J = 0.9 Hz, 1H).

Example 65.5: To a solution of propan-1-ol (363 mg, 6.04 mmol, 2.00 eq ) in tetrahydrofuran (20 mL) at 0 °C was added sodium hydride (266 mg, 6.65 mmol, 60% purity, 2.20 eq ). The mixture was stirred at 20 °C for 0.5 h. To the mixture was added 4-chloro-2-nitropyrazolo[1,5- a ]pyrrolidone (0.600 g, 3.02 mmol, 1.00 eq ). The mixture was stirred at 20 °C for 2 h. The mixture was diluted with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-nitro-4-propoxypyrazolo[1,5- a ]pyridine (0.6 g, 2.70 mmol, 89% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.54 (dd, J = 0.8, 4.8 Hz, 1H), 7.75 (d, J = 4.9 Hz, 1H), 7.68 (d, J = 0.7 Hz, 1H), 4.46 (t, J = 6.6 Hz, 2H), 1.86-1. 79 (m, 2H), 1.03-0.98 (m, 3H).

Example 65.6: To a solution of 2-nitro-4-propoxypyrazolo[1,5- a ]pyrrolidone (300 mg, 1.35 mmol, 1.00 eq ) in methanol (8 mL) and water (8 mL) were added iron powder (377 mg, 6.75 mmol, 5.00 eq ) and ammonium chloride (361 mg, 6.75 mmol, 5.00 eq ). The mixture was stirred at 80 °C for 3 h. The mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column chromatography (C18, 40 g; conditions: water/acetonitrile = 1/0 to 0/1, 0.1% hydrochloric acid) and concentrated under reduced pressure to give 4-propoxypyrazolo[1,5- a ]pyrrolidone-2-amine (200 mg, 1.04 mmol, 77% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.01 (d, J = 4.6 Hz, 1H), 7.15 (d, J = 4.6 Hz, 1H), 5.89 (s, 1H), 4.33 (t, J = 6.7 Hz, 2H), 1.84-1.68 (m, 2H), 0.9 8 (t, J = 7.4 Hz, 3H).

Example 65.7: To a solution of 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanoic acid B2 (15.5 mg, 52.0 μmol, 1.00 eq ), 4-propoxypyrazolo[1,5- a ]pyrrolidone-2-amine (10 mg, 52.02 μmol, 1.00 eq ) and 1-methylimidazole (12.8 mg, 156 μmol, 3.00 eq ) in DMF (1 mL) was added N- (chloro(dimethylamino)methylene)-N-methylammonium(V) hexafluorophosphate (29.2 mg, 104.05 μmol, 2.00 eq ). The mixture was stirred at 20° C. for 12 h. Four batches of the reaction mixture were combined and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (ethyl acetate/methanol = 20/1), preparative HPLC (column: Shim-pack C18 150*25*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 19% to 52%, 11 min) and lyophilized to give 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino) -N- (4-propoxypyrazolo[1,5- a ]pyrrolidone-2-yl)propanamide (9.47 mg, 19.0 μmol, 9% yield, 95% purity) as a white solid. HPLC/MS m/z: 473.1 [M+H] ⁺ , Rt (E): 0.82 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.17 (s, 1H), 9.23 (br s, 1H), 8.55-8.39 (m, 1H), 8.21 (d, J = 4.9 Hz, 1H), 8.13 (br d, J = 8.4 Hz, 1H), 7.80 (br d, J = 7.0 Hz, 1H), 7.37 (d, J = 4.8 Hz, 1H), 7.33 (br d, J = 7.1 Hz, 1H), 7.01 (s, 1H), 4.39 (t, J = 6.6 Hz, 2H), 3.89 (q, J = 6.0 Hz, 2H), 2.96 (br t, J = 6.2 Hz, 2H), 2.71 (s, 3H), 1.84-1.75 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

Example 66 : N-(4- ethoxypyrazolo [1,5-a] pyrrolidone - 2- yl )-3-((7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1- yl ) amino ) propionamide 4-Ethoxypyrazolo[1,5- a ]pyrroline-2-amine (0.16 g, 898 μmol) was prepared by a similar procedure to Example 65 using ethanol. To a solution of 4-ethoxypyrazolo[1,5- a ]pyrroline-2-amine (70.0 mg, 393 μmol, 1.00 eq ) and 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanoic acid (105 mg, 354 μmol, 0.900 eq ) in dimethylformamide (5.00 mL) was added propylphosphonic anhydride (500 mg, 786 μmol, 467 μL, 50% in dimethylformamide, 2.00 eq ). The mixture was stirred at 30 °C for 12 hours. The mixture was diluted with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25 mm* 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 13% to 43%, 10 min) and lyophilized to give N- (4-ethoxypyrazolo[1,5- a ]pyrrolidone-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide (66.32 mg, 143 μmol, 36% yield, 99% purity) as a white solid. HPLC/MS m/z: 459.2 [M+H] ⁺ , Rt (E): 0.77 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.03 (s, 1H), 8.89 (s, 1H), 8.21 (d, J = 4.6 Hz, 1H), 8.17-8.11 (m, 1H), 7.99 (d, J = 5.8 Hz, 2H), 7.85 (d, J = 8 .5 Hz, 1H), 7.36 (d, J = 4.8 Hz, 1H), 7.03 (s, 1H), 6.97 (d, J = 5.8 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.84-3.75 (m, 2H), 2.83 (br t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H).

Example 67 : N-(4-(3 -fluoropropoxy ) pyrazolo [1,5-a] pyrrolidone - 2- yl )-3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ) amino ) propionamide Example 67.1: A mixture of 4-chloro-2-nitro-pyrazolo[1,5- a ]pyrrolidone [Example 65] (300 mg, 1.51 mmol, 1.00 eq ), cesium carbonate (985 mg, 3.02 mmol, 2.00 eq ) and 3-fluoropropan-1-ol (142 mg, 1.81 mmol, 1.20 eq ) in acetonitrile (6.00 mL) was stirred at 50 °C for 2 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 6/1 to 2/1) to give 4-(3-fluoropropoxy)-2-nitropyrazolo[1,5- a ]pyrrolidone (180 mg, 749 μmol, 49% yield) as a yellow solid. ¹ H NMR (400 MHz, chloroform-d): δ 8.06 (dd, J = 0.8, 4.8 Hz, 1H), 7.63 (d, J = 5.2 Hz, 1H), 7.41 (d, J = 0.8 Hz, 1H), 4.74 (t, J = 5.6 Hz, 1H), 4.70 (t, J = 6.4 Hz, 2H), 4.62 (t, J = 5.6 Hz, 1H), 2.36-2.21 (m, 2H).

Example 67.2: A mixture of 4-(3-fluoropropoxy)-2-nitro-pyrazolo[1,5- a ]pyrrolidone (170 mg, 708 μmol, 1.00 eq) and palladium on activated carbon (17.0 mg, 10% purity, wet) in ethyl acetate (10.0 mL) was stirred at 25 °C under a hydrogen atmosphere (15 Psi) for 2 h. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to give 4-(3-fluoropropoxy)pyrazolo[1,5- a ]pyrrolidone-2-amine (140 mg, 666 μmol, 94% yield) as a yellow oil. ¹ H NMR (400 MHz, chloroform-d): δ 7.76 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.4 Hz, 1H), 5.98 (s, 1H), 4.71 (t, J = 5.6 Hz, 1H), 4.62-4.57 (m, 3H), 2.31- 2.17 (m, 2H).

Example 67.3: A mixture of 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanoic acid B2 (50.0 mg, 167 μmol, 1.00 eq), propylphosphonic anhydride (213 mg, 335 μmol, 50% in DMF, 2.00 eq) and 4-(3-fluoropropoxy)pyrazolo[1,5- a ]pyrrolidone-2-amine (38.8 mg, 184 μmol, 1.10 eq) in DMF (0.500 mL) was stirred at 40 °C for 2 h. After completion of the reaction, the mixture was poured into saturated aqueous sodium bicarbonate solution (6 mL) and extracted with ethyl acetate (3 x 4 mL). The combined organic layers were concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 42% to 72%, 10 min) and lyophilized to give N- (4-(3-fluoropropoxy)pyrazolo[1,5- a ]pyrrolidone-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide (42.53 mg, 85.8 μmol, 51% yield, 99% purity) as a yellow solid. HPLC/MS m/z: 494.4 [M+H] ⁺ , Rt (G): 0.90 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.04 (s, 1H), 8.89 (s, 1H), 8.23 (dd, J = 0.8, 4.8 Hz, 1H), 8.14 (dd, J = 1.6, 8.4 Hz, 1H), 8.04-7.96 (m, 2H), 7 .85 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 4.8 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J = 5.6 Hz, 1H), 4.69 (t, J = 6.0 Hz, 1H), 4.57 (t, J = 6.0 Hz, 1H), 4. 54 (t, J = 6.0 Hz, 2H), 3.84-3.77 (m, 2H), 2.83 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.22 (quin, J = 6.0 Hz, 1H), 2.16 (quin, J = 6.0 Hz, 1H).

The following examples were prepared by a similar procedure.

Example 68 : N-(4-(2 -fluoroethoxy ) pyrazolo [1,5-a] pyrrolidone - 2- yl )-3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ) amino ) propionamide White solid, 41.12 mg, 77.1 μmol, 98% purity, formate. HPLC/MS m/z: 477.2 [M+H] ⁺ , Rt (E): 0.80 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.06 (s, 1H), 8.89 (s, 1H), 8.26 (d, J = 4.8 Hz, 1H), 8.17 (s, 1H), 8.14 (dd, J = 1.2, 8.4 Hz, 1H), 8.04-7.92 (m , 2H), 7.85 (d, J =8.4 Hz, 1H), 7.38 (d, J =4.8 Hz, 1H), 7.07 (s, 1H), 6.97 (d, J =6.0 Hz, 1H), 4.92-4.85 (m, 1H), 4.81-4.70 (m, 2H), 4. 68-4.63 (m, 1H), 3.84-3.77 (m, 2H), 2.83 (br t, J = 6.8 Hz, 2H), 2.69 (s, 3H).

Example 69 : 3-((7-(5 -methyl -1,2,4- oxadiazol -3 -yl ) isoquinolin- 1 -yl ) amino )-N-(4-( oxacyclobutane -3 -yloxy ) pyrazolo [1,5-a] pyrrolidone - 2- yl ) propanamide White solid, 3.29 mg, 6.70 μmol, 99% purity. HPLC/MS m/z: 487.4 [M+H] ⁺ , Rt (G): 0.86 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.07 (s, 1H), 8.90 (br s, 1H), 8.30-8.24 (m, 1H), 8.19-8.10 (m, 1H), 8.04-7.95 (m, 2H), 7.92-7.81 (m, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.12 (s, 1H), 7.04-6.91 (m, 1H), 5.78-5.68 (m, 1H), 4.97-4.91 (m, 2H), 4.70-4.65 (m, 2H), 3.85-3.79 (m, 2H) , 2.87-2.82 (m, 2H), 2.70 (s, 3H).

Example 70 : N-(4 -cyclopropoxypyrazolo [1,5-a] pyrrolidone - 2- yl )-3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1- yl ) amino ) propionamide 4-(Cyclopropoxy)pyrazolo[1,5-a]pyrrolidone-2-amine (20.00 mg, 0.1052 mmol), 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoic acid B2 (34.50 mg, 0.1157 mmol), EDC (40.32 mg, 0.2103 mmol), HOBt (32.21 mg, 0.2103 mmol) and DIPEA (0.04 mL, 0.2103 mmol) were mixed in anhydrous DMF (0.53 mL, 0.2000 M) under argon at ambient temperature. The reaction mixture was heated to 70 °C for 24 hours. The crude reaction mixture was purified directly by preparative HPLC (AccqPrep, focused gradient, 34 to 44% MeOH/water, pH 3) to afford N-[4-(cyclopropoxy)pyrazolo[1,5-a]pyrrolidone-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide (5.3 mg, 10%, 0.0109 mmol) as an off-white solid. HPLC/MS m/z: 471.189 [M+H] ⁺ , Rt (Z): 2.19 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 11.04 (s, 1H), 8.88 (d, J = 1.6 Hz, 1H), 8.26 (dd, J = 4.7, 1.0 Hz, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 7.96-8.01 ( m, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 4.7 Hz, 1H), 6.98 (s, 1H), 6.96 (d, J = 5.7 Hz, 1H), 4.45 (tt, J = 6.2, 3.3 Hz, 1H), 3.77-3.83 (m, 2H), 2.82 (t, J = 7.0 Hz, 2H), 2.69 (s, 3H), 0.78-0.86 (m, 4H).

Example 71 : 3-((7-(5 -methyl -1,2,4- oxadiazol - 3- yl ) isoquinolin- 1- yl ) amino )-N-(1 -methyl - 4-propoxy -1H- pyrrolo [3,2-c] pyridin -2- yl ) propionamide Example 71.1: To a mixture of methyl 4-chloro- 1H -pyrrolo[3,2- c ]pyridine-2-carboxylate (900 mg, 4.27 mmol, 1.00 eq) and cesium carbonate (2.78 g, 8.55 mmol, 2.00 eq) in N ,N-dimethylacetamide (9.00 mL) was added iodomethane (728 mg, 5.13 mmol, 1.20 eq ). The mixture was stirred at 25 °C for 2 h. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were concentrated to give a residue. The residue was triturated with methyl tert-butyl ether (20 mL) for 10 min. The suspension was filtered and the filter cake was dried to give methyl 4-chloro-1-methyl- 1H -pyrrolo[3,2- c ]pyridine-2-carboxylate (930 mg, 4.14 mmol, 96% yield) as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d): δ 8.18 (d, J = 6.0 Hz, 1H), 7.41 (s, 1H), 7.24 (d, J = 6.0 Hz, 1H), 4.09 (s, 3H), 3.96 (s, 3H).

Example 71.2: To a suspension of methyl 4-chloro-1-methyl- 1H -pyrrolo[3,2- c ]pyridine-2-carboxylate (700 mg, 3.12 mmol, 1.00 eq ) in acetic acid (7.00 mL) was added ammonium acetate (480 mg, 6.23 mmol, 2.00 eq ). The mixture was stirred at 120 °C for 12 h. After completion of the reaction, the mixture was concentrated to give a residue. The residue was triturated with water (5 mL) at 25 °C for 0.5 h. The suspension was filtered and the filter cake was dried to give methyl 4-hydroxy-1-methyl- 1H -pyrrolo[3,2- c ]pyridine-2-carboxylate (600 mg, 2.91 mmol, 93% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.02 (br s, 1H), 7.24 (s, 1H), 7.22-7.17 (m, 1H), 6.58 (d, J = 7.2 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 3H).

Example 71.3: A mixture of methyl 4-hydroxy-1-methyl- 1H -pyrrolo[3,2 -c ]pyridine-2-carboxylate (700 mg, 3.39 mmol, 1.00 eq ), silver carbonate (1.87 g, 6.79 mmol, 2.00 eq ) and 1-iodopropane (866 mg, 5.09 mmol, 1.50 eq ) in chloroform (7.00 mL) was stirred at 65 °C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 15/1 to 4/1) to give methyl 1-methyl-4-propoxy- 1H -pyrrolo[3,2- c ]pyridine-2-carboxylate (500 mg, 2.01 mmol, 59% yield) as a white solid. ¹ H NMR (400 MHz, chloroform-d): δ 7.92 (d, J = 6.4 Hz, 1H), 7.42 (s, 1H), 6.89 (d, J = 6.0 Hz, 1H), 4.42 (t, J = 6.8 Hz, 2H), 4.04 (s, 3H), 3.92 (s, 3H ), 1.88 (sext, J = 7.2 Hz, 2H), 1.08 (t, J = 7.6 Hz, 3H).

Example 71.4: A mixture of methyl 1-methyl-4-propoxy- 1H -pyrrolo[3,2- c ]pyridine-2-carboxylate (480 mg, 1.93 mmol, 1.00 eq ) and lithium hydroxide monohydrate (163 mg, 3.87 mmol, 2.00 eq ) in a mixed solvent of tetrahydrofuran (200 μL) and water (200 μL) was stirred at 30 °C for 12 hours. The mixture was concentrated to remove tetrahydrofuran and diluted with water (10 mL). The pH of the aqueous phase was adjusted to about 4 by adding hydrochloric acid (1 M). A white solid was precipitated and filtered. The filter cake was dried to give 1-methyl-4-propoxy- 1H -pyrrolo[3,2- c ]pyridine-2-carboxylic acid (400 mg, 1.71 mmol, 88% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 13.31 (s, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.29-7.14 (m, 2H), 4.38 (br t, J = 6.8 Hz, 2H), 4.00 (s, 3H), 1.84-1.71 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H).

Example 71.5: A mixture of 1-methyl-4-propoxy- 1H -pyrrolo[3,2- c ]pyridine-2-carboxylic acid (200 mg, 854 μmol, 1.00 eq ), diphenylphosphinoyl azide (352 mg, 1.28 mmol, 1.50 eq ) and triethylamine (259 mg, 2.56 mmol, 3.00 eq ) in tert-butanol (2.00 mL) was stirred at 100 °C for 12 h. The mixture was concentrated to give a residue and purified by flash silica gel chromatography (solvent: 0 to 45% ethyl acetate/petroleum ether, gradient 25 mL/min) to give tert-butyl (1-methyl-4-propoxy- 1H -pyrrolo[3,2- c ]pyridin-2-yl)carbamate (140 mg, 458 μmol, 53% yield) as a colorless oil. ¹ H NMR (400 MHz, chloroform-d): δ 7.83 (d, J = 6.0 Hz, 1H), 6.81 (d, J = 6.0 Hz, 1H), 6.47 (s, 1H), 6.33-6.17 (m, 1H), 4.39 (t, J = 6.8 Hz, 2H), 3.61 ( s, 3H), 1.85 (sext, J = 7.2 Hz, 2H), 1.52 (s, 9H), 1.06 (t, J = 7.2 Hz, 3H).

Example 71.6: A mixture of tert-butyl (1-methyl-4-propoxy- 1H -pyrrolo[3,2- c ]pyridin-2-yl)carbamate (140 mg, 458 μmol, 1.00 eq ) in hydrochloric acid/ethyl acetate (4 M, 500 μL) was stirred at 25 °C for 1 h. The mixture was concentrated to give 1-methyl-4-propoxy-pyrrolo[3,2- c ]pyridin-2-amine (110 mg, crude, hydrochloride) as a white solid. HPLC/MS m/z: 206.2 [M+H] ⁺ , Rt (F): 0.75 min.

Example 71.7: A mixture of 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanoic acid B2 (85.0 mg, 285 μmol, 1.00 eq ), 1-methyl-4-propoxy-pyrrolo[3,2- c ]pyridin-2-amine (58.5 mg, 285 μmol, 1.00 eq ) and propylphosphonic anhydride (181 mg, 285 μmol, 169 μL, 50% in DMF, 1.00 eq ) in DMF (2.00 mL) was stirred at 30 °C for 2 h. After completion of the reaction, the mixture was poured into saturated aqueous sodium bicarbonate solution (7 mL) and extracted with ethyl acetate (3 x 4 mL). The combined organic layers were concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) -ACN]; B%: 32% to 62%, 8 min) and lyophilized to give 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino) -N- (1-methyl-4-propoxy- 1H -pyrrolo[3,2- c ]pyridin-2-yl)propanamide (18.75 mg, 38.2 μmol, 13% yield, 99% purity) as a pink solid. HPLC/MS m/z: 486.2 [M+H] ⁺ , Rt (E): 0.74 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.01 (s, 1H), 8.92 (s, 1H), 8.16 (dd, J = 1.2, 8.4 Hz, 1H), 8.07-7.97 (m, 2H), 7.86 (d, J = 8.4 Hz, 1H), 7.69 (d , J = 6.0 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 6.98 (d, J = 5.6 Hz, 1H), 6.38 (s, 1H), 4.31 (t, J = 6.8 Hz, 2H), 3.87-3.79 (m, 2H), 3.55 (s, 3H) , 2.84 (br t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 1.75 (sext, J = 7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H).

Example 72 : ( cis ) -N- (4- methoxypyrazolo [1,5- a ] pyridin -2- yl )-3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ) amino ) cyclobutanecarboxamide Example 72.1: To a solution of acetonitrile (769 mg, 18.7 mmol, 4.40 eq) in tetrahydrofuran (10 mL) at -78 °C was added n-butyl lithium (2.50 M, 6.81 mL, 17.0 mmol, 4.00 eq) dropwise. The mixture was stirred at -78 °C for 0.2 h. To the mixture was added a solution of 2-bromo-3-methoxy-pyridine (0.800 g, 4.25 mmol, 1.00 eq) in tetrahydrofuran (3 mL). The mixture was stirred at -78 °C for 1 h. The mixture was then warmed to 0 °C and stirred at 0 °C for 3 h. The mixture was diluted with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1) and preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 6% to 36%, 8 min) to obtain 2-(3-methoxypyridin-2-yl)acetonitrile (0.300 g, 2.02 mmol, 47% yield) as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d): δ 8.19 (dd, J = 1.3, 4.7 Hz, 1H), 7.30-7.27 (m, 1H), 7.23-7.18 (m, 1H), 3.92 (s, 2H), 3.91 (s, 3H).

Example 72.2: To a solution of O- (mesitylenesulfonyl)hydroxylamine [Example 64.3] (0.140 M, 14.5 mL, 2.03 mmol, 1.20 eq ) in dichloromethane (15 mL) was added 2-(3-methoxy-2-pyridinyl)acetonitrile (0.250 g, 1.69 mmol, 1.00 eq ). The mixture was stirred at 20 °C for 12 h. The mixture was concentrated to give 1-amino-2-(cyanomethyl)-3-methoxypyridin-1-ium 2,4,6-trimethylbenzenesulfonate (0.600 g, crude) as a brown oil. This was used directly in the next step. HPLC/MS m/z: 164.0 [M+H] ⁺ , Rt (G): 0.67 min.

Example 72.3: To a solution of 1-amino-2-(cyanomethyl)-3-methoxypyridin-1-ium 2,4,6-trimethylbenzenesulfonate (0.600 g, 1.65 mmol, 1.00 eq ) in methanol (10 mL) was added potassium carbonate (570 mg, 4.13 mmol, 2.50 eq ). The mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 1/1) to give 4-methoxypyrazolo[1,5- a ]pyridin-2-amine (75.0 mg, 460 μmol, 28% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.89-7.87 (m, 1H), 6.47-6.42 (m, 2H), 5.62 (d, J = 0.6 Hz, 1H), 5.17 (s, 2H), 3.85 (s, 3H).

Example 72.4: To a solution of ( cis )-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutanecarboxylic acid B3 (139 mg, 429 μmol, 1.00 eq ), O- (7-azabenzotriazol-1-yl) -N , N , N' , N' -tetramethyluronium hexafluorophosphate and diisopropylethylamine (166 mg, 1.29 mmol, 3.00 eq ) in dimethylformamide (2 mL) was added 4-methoxypyrazolo[1,5- a ]pyridin-2-amine (70.0 mg, 429 μmol, 1.00 eq ). The mixture was stirred at 20 °C for 12 h. The mixture was filtered. The filtrate was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water (0.225% formic acid)-ACN]; B%: 25% to 45%, 10 min), preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 30% to 60%, 8 min) and lyophilized to obtain ( cis ) -N- (4-methoxypyrazolo[1,5- a ]pyridin-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutanecarboxamide (29.0 mg, 61.2 μmol, 14% yield, 99% purity). HPLC/MS m/z: 470.3 [M+H] ⁺ , Rt (G): 1.00 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.72 (s, 1H), 9.04 (s, 1H), 8.19-8.06 (m, 3H), 7.96 (d, J = 5.8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 5 .8 Hz, 1H), 6.89 (s, 1H), 6.77-6.70 (m, 1H), 6.62 (d, J = 7.8 Hz, 1H), 4.75-4.58 (m, 1H), 3.92 (s, 3H), 3.12-2.98 (m, 1H), 2.71 (s, 3H) , 2.60-2.53 (m, 2H), 2.48-2.36 (m, 2H).

Example 73 : 3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1 -yl ) amino )-N-(4 -methyl - 7-propoxybenzo [d] thiazol -2 -yl ) propionamide Example 73.1: 2-Amino-4-methyl-1,3-benzothiazol-7-ol (100.00 mg, 0.5548 mmol) and K ₂ CO ₃ (153.36 mg, 1.1097 mmol) were mixed in anhydrous DMF (0.55 mL, 1M ) at RT under argon. 1-Iodopropane (0.05 mL, 0.5548 mmol) was added and the reaction mixture was stirred for 24 h. The reaction mixture was mixed with water (2 mL), acidified to pH 6 with 1M HCl and diluted with MeOH (20 mL), filtered through a 2 g SCX2 column. The product was released with 2M ammonia in MeOH to give 4-methyl-7-propoxy-1,3-benzothiazol-2-amine (110 mg, 89%, 0.4948 mmol) as an off-white solid, which was used in the next step without further purification. HPLC/MS m/z: 223.091 [M+H] ⁺ , Rt (Z): 2.12 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 7.45 (s, 2H), 6.95 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 4.00 (t, J = 6.5 Hz, 2H), 2.33 (s, 3H), 1.68-1.7 6 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

Example 73.2: Under argon, 4-methyl-7-propoxy-1,3-benzothiazol-2-amine (39.13 mg, 0.1760 mmol) and 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoic acid B2 (50.00 mg, 0.1676 mmol) were mixed in anhydrous DMF (0.34 mL, 0.5000 M) at ambient temperature. 1-Propanephosphonic anhydride (50% in DMF) (0.20 mL, 0.3352 mmol) was added, and the reaction mixture was stirred for 18 h. Purification by preparative HPLC gave 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-N-(4-methyl-7-propoxy-1,3-benzothiazol-2-yl)propanamide (45 mg, 53%, 0.0890 mmol) as an off-white solid. HPLC/MS m/z: 503.187 [M+H] ⁺ , Rt (Z): 2.68 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 12.47 (br s, 1H), 8.87-8.91 (m, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.03 (t, J = 5.4 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.16 (dd, J = 8.0, 1.0 Hz, 1H), 6.97 (dd, J = 5.9, 0.8 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 4.08 (t, J = 6.4 Hz, 2H), 3.81-3.87 (m, 2H), 2.92 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.47 (s, 3H), 1.74-1.81 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

Example 74 : 3-(5 -methyl -1,2,4- oxadiazol -3- yl )-N-(3-((4 -methyl - 7-propoxybenzo [d] thiazol -2- yl ) amino )-3 -oxopropyl ) benzamide Prepared by a similar procedure to Example 73 and Example 74 using B1. Off-white solid, 2.2 mg, 0.0045 mmol. HPLC/MS m/z: 480.170 [M+H] ⁺ , Rt (Z): 3.01 min. ¹ H NMR (600 MHz, chloroform-d): δ 9.45 (s, 1H), 8.41-8.44 (m, 1H), 8.15-8.20 (m, 1H), 7.96 (ddd, J = 7.8, 1.8, 1.2 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H) , 7.13 (dd, J = 8.0, 1.0 Hz, 1H), 7.06 (t, J = 6.2 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.90 (q, J = 5.9 Hz, 2H), 2.90 (t, J = 5.7 Hz, 2H), 2.65 (s, 3H), 2.52 (s, 3H), 1.81-1.89 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H).

Example 75 : 3-(2 -methyl -2H- tetrazol -5- yl )-N-(3 -oxo -3-((7 -propoxybenzo [d] thiazol -2- yl ) amino ) propyl ) benzamide Example 75.1: To methyl 3-aminopropanoate hydrochloride (100.00 mg, 0.7164 mmol), 3-(2-methyl-2H-tetrazol-5-yl)-benzoic acid (146.29 mg, 0.7164 mmol) in DMF (4.21 mL) was added DIPEA (0.50 mL, 2.8657 mmol) followed by HATU (252.83 mg, 1.0747 mmol). The resulting yellow solution was stirred for 18 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (120 mL). The water was extracted with fresh EtOAc (100 mL). The organics were combined and washed with saturated aqueous bicarbonate solution (150 mL) and brine (200 mL), then dried over MgSO _4. After filtration and concentration in vacuo, methyl 3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propanoate (170 mg, 82%, 0.5876 mmol) was obtained as a light yellow film and used without further purification. HPLC/MS m/z: 290.13 [M+H] ⁺ , Rt (P): 1.15 min.

Example 75.2: To methyl 3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propanoate (170.00 mg, 0.5876 mmol) in THF (2.90 mL) was added water (2.90 mL) followed by lithium hydroxide monohydrate (98.63 mg, 2.3506 mmol). After stirring for 45 min, water (25 mL) was added and the THF was removed in vacuo. The solution was acidified to pH 3 with 1 M citric acid solution and extracted with EtOAc (2 x 60 mL). The organics were combined, washed with brine (60 mL) and dried over MgSO ₄ to give 3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propionic acid (137 mg, 85%, 0.4977 mmol) as a white solid. HPLC/MS m/z: 276.12 [M+H] ⁺ , Rt (P): 1.03 min.

Example 75.3: 2-Amino-1,3-benzothiazol-7-ol (79.00 mg, 0.4753 mmol) and K ₂ CO ₃ (78.83 mg, 0.5704 mmol) were dissolved in anhydrous DMF (3.17 mL) and the mixture was stirred at RT for 30 min. 1-Iodopropane (0.05 mL, 0.4753 mmol) was then added at 0°C. The mixture was stirred at 0°C for 1 h 30 min. The ice bath was then removed and the reaction mixture was stirred for 2 days. Additional K ₂ CO ₃ (24 mg) was added and stirred for 20 min. 1-Iodopropane (14 mL) was added at 0°C. The mixture was stirred at 0°C for 1 h and then at RT for 30 min. A few drops of water were added to the reaction mixture. Purification by reverse phase flash chromatography (solvent: 10 to 80% MeOH/H ₂ O + 0.1% formic acid) followed by ion exchange SCX-2 chromatography using 2M NH ₃ in MeOH afforded 7-propoxy-1,3-benzothiazol-2-amine (75.9 mg, 77%, 0.3644 mmol) as a white amorphous solid. HPLC/MS m/z: 209.072 [M+H] ⁺ , Rt (R): 1.02 min.

Example 75.4: To a mixture of 7-propoxy-1,3-benzothiazol-2-amine (15.13 mg, 0.0727 mmol), 3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propionic acid (20.00 mg, 0.0727 mmol), HOBt (22.25 mg, 0.1453 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.86 mg, 0.1453 mmol) was added DMF (0.36 mL) under an atmosphere of argon. The resulting solution was stirred at 70 °C overnight. The reaction mixture was cooled to ambient temperature, diluted with DMSO and purified directly by preparative HPLC (AccqPrep, focused gradient, ACN/water, pH 3) to afford 3-(2-methyltetrazol-5-yl)-N-[3-oxo-3-[(7-propoxy-1,3-benzothiazol-2-yl)amino]propyl]benzamide (24 mg, 71%, 0.0512 mmol) as an off-white solid. HPLC/MS m/z: 466.166 [M+H] ⁺ , Rt (Z): 2.81 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 12.41 (s, 1H), 8.88 (t, J = 5.5 Hz, 1H), 8.52-8.56 (m, 1H), 8.16-8.21 (m, 1H), 7.97-8.02 (m, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.32-7.38 (m, 2H), 6.89 (dd, J = 7.6, 1.2 Hz, 1H), 4.44 (s, 3H), 4.12 (t, J = 6.4 Hz, 2H), 3.60-3.66 (m, 2H), 2.83 (t, J = 6.8 Hz, 2H), 1.75-1.83 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

Example 76 : 3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1 -yl ) amino )-N-(7 -propoxy- 4-( trifluoromethyl ) benzo [d] thiazol -2 -yl ) propionamide Example 76.1: 3-Nitro-4-(trifluoromethyl)phenol (410.00 mg, 1.9796 mmol), cesium carbonate (300.96 mg, 2.1776 mmol) and 1-iodopropane (0.21 mL, 2.1776 mmol) were mixed in anhydrous acetone (3.96 mL, 0.5000 M) in a microwave vial under argon. The reaction mixture was heated at 100 °C for 2 h under microwave irradiation. Purification by NP flash chromatography (solvent: 0 to 10% EtOAc/cyclohexane) gave 2-nitro-4-propoxy-1-(trifluoromethyl)benzene (463 mg, 94%, 1.858 mmol) as an off-white crystalline solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.92 (d, J = 8.9 Hz, 1H), 7.71 (d, J = 2.6 Hz, 1H), 7.41 (ddd, J = 8.9, 2.6, 0.9 Hz, 1H), 4.11 (t, J = 6.5 Hz, 2H), 1 .71-1.81 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

Example 76.2: 2-Nitro-4-propoxy-1-(trifluoromethyl)benzene (455.00 mg, 1.8259 mmol) and zinc (596.89 mg, 9.1296 mmol) were mixed under argon at 0 °C. Acetic acid (5.00 mL, 0.3700 M) was added and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with EtOAc (10 mL) and loaded directly onto silica gel. The crude was directly purified by NP chromatography (0 to 20% EtOAc/cyclohexane) to give 5-propoxy-2-(trifluoromethyl)aniline (272 mg, 68%, 1.2409 mmol) as a clear oil. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.20 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 6.19 (dd, J = 8.6, 2.4 Hz, 1H), 5.48 (s, 2H), 3.87 (t, J = 6.6 Hz, 2H), 1.66-1.75 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).

Example 76.3: To a suspension of potassium thiocyanate (129.23 mg, 1.3298 mmol) in acetone (2.00 mL) was added dropwise a solution of acetyl chloride (0.09 mL, 1.3298 mmol) in acetone (2.00 mL) at ambient temperature. The mixture was stirred at 50 °C for 15 min. Then, a solution of 5-propoxy-2-(trifluoromethyl)aniline (265.00 mg, 1.2089 mmol) in acetone (2.00 mL) was added and the reaction mixture was stirred at 50 °C for a further 15 min. The reaction mixture was stirred for a further 15 min before being removed from the heat. Water (50 mL) was added, and the precipitated intermediate was filtered off, washed with water and dried under reduced pressure. The solid was dissolved in MeOH (4.00 mL) at ambient temperature. Potassium carbonate (339.04 mg, 2.4179 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 hour. Water (50 mL) was added. The precipitated product was filtered off, washed with water and dried under reduced pressure to give [5-propoxy-2-(trifluoromethyl)phenyl]thiourea (228 mg, 68%, 0.8193 mmol) as an off-white solid, which was used in the next reaction without further purification. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 9.18 (s, 1H), 7.86 (br s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.28 (br s, 1H), 7.07 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 8.6 , 2.6 Hz, 1H), 3.99 (t, J = 6.5 Hz, 2H), 1.69-1.80 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

Example 76.4: To a solution of [5-propoxy-2-(trifluoromethyl)phenyl]thiourea (220.00 mg, 0.7905 mmol) in AcOH (3.95 mL) maintained at ambient temperature under argon was added a solution of bromine (0.04 mL, 0.7905 mmol) in AcOH (3.95 mL) over 15 min. The reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The crude was dissolved in MeOH and filtered through an SCX2 ion exchange column. The product was released with 2M ammonia in MeOH to give 7-propoxy-4-(trifluoromethyl)-1,3-benzothiazol-2-amine (185 mg, 85%, 0.6696 mmol) as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.98 (s, 2H), 7.48 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 4.13 (t, J = 6.5 Hz, 2H), 1.71-1.81 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

Example 76.5: Under argon, 7-propoxy-4-(trifluoromethyl)-1,3-benzothiazol-2-amine B2 (27.79 mg, 0.1006 mmol) and 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionic acid (30.00 mg, 0.1006 mmol) were mixed in anhydrous DMF (0.20 mL, 0.5000 M) at ambient temperature. 1-Propanephosphonic anhydride (50% in DMF) (0.12 mL, 0.2011 mmol) and TEA (0.04 mL, 0.3017 mmol) were added successively, and the reaction mixture was stirred for 30 min. The reaction mixture was heated to 60 °C for 1 hour and then at 80 °C for 1 hour. 2 x 1-propanephosphonic anhydride (50% in DMF) (0.12 mL, 0.2011 mmol) was added and the reaction was continued to stir at 80 °C for 1 hour. The reaction mixture was cooled to ambient temperature, quenched with a few drops of water, diluted with DMSO and purified directly by preparative HPLC (AccqPrep, focused gradient, 35.2 to 45.2% ACN/water, pH 3). The fractions containing the product were filtered through a 2 g SCX2 ion exchange column. The product was released with 2M ammonia in MeOH to give 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(7-propoxy-4-(trifluoromethyl)benzo[d]thiazol-2-yl)propanamide (6.8 mg, 12%, 0.0121 mmol) as an off-white solid. HPLC/MS m/z: 557.158 [M+H] ⁺ , Rt (Z): 2.76 min. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 12.90 (s, 1H), 8.89 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.04 (br s, 1H), 7.97 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 5.8 Hz, 1H), 4.22 (t, J = 6.5 Hz, 2H), 3.81-3.89 (m, 2H), 2.96 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 1.78-1.86 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

Example 77 : (R)-2- amino -N-(4 -fluoro - 7-propoxybenzo [d] thiazol -2 -yl )-3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ) amino ) propionamide Example 77.1: To a solution of 4-fluoro-7-methoxy-1,3-benzothiazol-2-amine (1.00 g, 5.0449 mmol) in DCM (9.01 mL) at 0 °C was added dropwise a solution of BBr ₃ (1 M) in DCM (9.23 mL, 9.2322 mmol) and the mixture was allowed to reach RT and stirred overnight. MeOH was then added at 0 °C and this was stirred for a further 10 min before the solvent was evaporated in vacuo. The cyclic dissolution/evaporation with MeOH was repeated two more times to give 2-amino-4-fluoro-1,3-benzothiazol-7-ol (929 mg, 100%, 5.0437 mmol) as a dark powder. The product was carried forward to the next step without further purification. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.00 (dd, J = 10.7, 8.8 Hz, 1H), 6.53 (dd, J = 8.8, 3.3 Hz, 1H).

Example 77.2: To a mixture of 2-amino-4-fluoro-1,3-benzothiazol-7-ol (838.00 mg, 4.5496 mmol) and cesium carbonate (2.98 g, 9.0993 mmol) in MeCN (11.00 mL, 0.3800 M) were added DMF (1.00 mL) and 1-bromopropane (454.59 μL, 5.0046 mmol) successively. This was stirred at 65 °C for 2 h. The solvent was evaporated and the residue was taken back into EtOAc and water, extracted with EtOAc, dried over MgSO ₄ and evaporated. Purification by NP silica gel column chromatography (0 to 40% EtOAc/cyclohexane) gave pure 4-fluoro-7-propoxy-1,3-benzothiazol-2-amine (503.8 mg, 49%, 2.2265 mmol). HPLC/MS m/z: 227.065 [M+H] ⁺ , Rt (R): 1.25 min,

Example 77.3: Ethyl (2R)-3-amino-2-(benzyloxycarbonylamino)propanoate (367 mg, 1.38 mmol), 5-methyl-3-(2-oxoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole (345 mg, 1.52 mmol), PyBroP (707 mg, 1.52 mmol), DIPEA (0.90 ml) and anhydrous DCM (2.8 mL, 0.50 M) were mixed in a microwave vial at RT under argon. The reaction mixture was heated at 60 °C for 1 hour by microwave irradiation. The volatiles were removed and the crude was purified by RP flash chromatography (30 to 60% MeOH/water). The fraction containing the product was filtered through 1 g of SCX-2 ion exchange resin. The product was released by MeOH containing 2M ammonia to give ethyl (2R)-2-(benzyloxycarbonylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoate (409 mg, 62%, 0.8601 mmol) as an off-white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.84 (d, J = 1.7 Hz, 1H), 8.17 (dd, J = 8.5, 1.6 Hz, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7.92-7.83 (m, 3H), 7.35-7.24 (m , 5H), 7.01 (d, J = 5.7 Hz, 1H), 5.02 (s, 2H), 4.48 (q, J = 6.7 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.88 (t, J = 6.1 Hz, 2H), 2.70 (s, 3H), 1.0 4 (t, J = 7.1 Hz, 3H).

Example 77.4: Ethyl (2R)-2-(benzyloxycarbonylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoate (200.00 mg, 0.4206 mmol) was dissolved in THF (2.10 mL) at ambient temperature. EtOH (0.42 mL) and 2M aqueous NaOH (0.42 mL, 0.8412 mmol) were added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was neutralized with aq. 2M HCl and concentrated under reduced pressure. The crude material was directly purified by RP flash column chromatography (20 to 80% MeOH/water) to give (2R)-2-(benzyloxycarbonylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoic acid (94 mg, 50%, 0.2101 mmol) as an off-white powder. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 12.71 (s, 1H), 8.85 (d, J = 1.6 Hz, 1H), 8.17 (dd, J = 8.5, 1.6 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.91 (t, J = 5.9 Hz , 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.40-7.17 (m, 5H), 7.01 (d, J = 5.7 Hz, 1H), 5.01 (s, 2H), 4.45 (td, J = 7.7, 5.1 Hz, 1H), 3.92 (dt, J = 13.5, 5.2 Hz, 1H), 3.79 (ddd, J = 13.6, 7.9, 5.9 Hz, 1H), 2.70 (s, 3H).

Example 77.5: (2R)-2-(Benzyloxycarbonylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoic acid (50.00 mg, 0.1117 mmol), 4-fluoro-7-propoxy-1,3-benzothiazol-2-amine (25.28 mg, 0.1117 mmol) and TEA (0.05 mL, 0.3352 mmol) were mixed in anhydrous DMF (0.22 mL, 0.5000 M) under argon at ambient temperature. 50% T3P in DMF (0.13 mL, 0.2235 mmol) was added and the reaction mixture was heated at 70 °C (on a preheated heating block) for 2.5 h. The reaction mixture was cooled to room temperature and quenched with water. Purification by NP column chromatography (solvent: 0 to 100% EtOAc/cyclohexane) gave benzyl N-[(1R)-2-[(4-fluoro-7-propoxy-1,3-benzothiazol-2-yl)amino]-1-[[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]methyl]-2-oxo-ethyl]carbamate (55 mg, 75%, 0.0839 mmol) as an off-white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 12.95 (s, 1H), 8.83 (s, 1H), 8.19-8.14 (m, 1H), 7.98 (d, J = 6.7 Hz, 2H), 7.85 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 5 .7 Hz, 1H), 7.42-7.25 (m, 5H), 7.21 (dd, J = 10.5, 8.7 Hz, 1H), 6.94 (d, J = 5.9 Hz, 1H), 6.85 (dd, J = 8.9, 3.1 Hz, 1H), 5.07 (d, J = 12.5 Hz, 1H), 5.02 (d, J = 12.6 Hz, 1H), 4.65-4.58 (m, 1H), 4.19-4.11 (m, 1H), 4.09 (t, J = 6.4 Hz, 2H), 3.91-3.83 (m, 1H), 2.67 (s, 3H), 1.80-1.71 (m, 2H ), 0.99 (t, J = 7.4 Hz, 3H).

Example 77.6: Benzyl N-[(1R)-2-[(4-fluoro-7-propoxy-1,3-benzothiazol-2-yl)amino]-1-[[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]methyl]-2-oxo-ethyl]carbamate (50.00 mg, 0.0763 mmol) was suspended in acetic acid (1.80 mL, 0.0400 M) at room temperature under an atmosphere of argon. HBr in AcOH (33% w/w, 0.93 mL, 5.3378 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was cooled in an ice bath and neutralized with 3 M NaOH. The precipitate was filtered off, washed with water, dissolved in DMSO/MeOH and purified by preparative HPLC (AccqPrep, focused gradient, 72.3 to 82.3% MeOH/water [+ 0.1% NH ₃ ]) to give (2R)-2-amino-N-(4-fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide (7.6 mg, 18%, 0.0138 mmol) as a white solid. HPLC/MS m/z: 522.172 [M+H] ⁺ , Rt (Z): 2.57 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.89 (d, J = 1.6 Hz, 1H), 8.15 (dd, J = 8.4, 1.5 Hz, 1H), 7.98 (br s, 1H), 7.91 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.12 (dd, J = 10.5, 8.7 Hz, 1H), 6.97 (d, J = 5.8 Hz, 1H), 6.77 (dd, J = 8.8, 3.0 Hz, 1H), 6.27 (br s, 3H), 4.08 (t, J = 6.4 Hz, 2H), 3. 98 (t, J = 6.3 Hz, 1H), 3.96-3.90 (m, 1H), 3.78-3.72 (m, 1H), 2.68 (s, 3H), 1.81-1.72 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).

Example 78 : (S)-2- Hydroxy -3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1 - yl ) amino )-N-(7 -propoxybenzo [d] thiazol -2 -yl ) propionamide To a mixture of (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionic acid B4 (15.0 mg, 0.048 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18.3 mg, 0.096 mmol), 7-propoxy-1,3-benzothiazol-2-amine (Example 75.3) (11.9 mg, 0.057 mmol) in anhydrous DMF (0.3 mL) was added 1-hydroxybenzotriazole (12.9 mg, 0.096 mmol) under nitrogen atmosphere. The resulting solution was stirred at 45 °C overnight. Reverse phase flash chromatography (solvent: 20 to 80% MeOH/H ₂ O + 0.1% formic acid) followed by ion exchange SCX-2 chromatography using 2M NH ₃ in MeOH gave (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-N-(7-propoxy-1,3-benzothiazol-2-yl)propanamide (10 mg, 42%, 0.02 mmol) as a beige amorphous powder. HPLC/MS m/z: 505.2 [M+H] ⁺ , Rt (U): 2.65 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.97-8.86 (m, 1H), 8.17 (dd, J = 8.5, 1.5 Hz, 1H), 8.10 (t, J = 5.6 Hz, 1H), 7.93 (d, J = 5.8 Hz, 1H), 7.87 (d, J = 8 .5 Hz, 1H), 7.42-7.27 (m, 2H), 7.00 (dd, J = 5.9, 0.8 Hz, 1H), 6.91 (dd, J = 7.8, 1.1 Hz, 1H), 6.48 (s, 1H), 4.63 (t, J = 5.6 Hz, 1H), 4.13 (t , J = 6.4 Hz, 2H), 3.99-3.69 (m, 2H), 2.69 (s, 3H), 1.80 (dt, J = 7.4, 6.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H).

Example 79 : N-(7- ethoxybenzo [d] thiazol -2- yl )-3-((7-(5 -methyl -1,2,4- oxadiazol- 3- yl ) isoquinolin- 1- yl ) amino ) propionamide Example 79.1: 2-Amino-1,3-benzothiazol-7-ol (94.0 mg, 0.56 mmol) and K ₂ CO ₃ (93.8 mg, 0.68 mmol) were dissolved in anhydrous DMF (3.8 mL) and the resulting mixture was stirred at room temperature for 40 minutes. Then iodoethane (51 μL, 0.56 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 hour. The ice bath was then removed, and the reaction mixture was stirred at room temperature for 3 days. Then water (about 1 mL) was added to the reaction mixture. The crude solution was purified by reverse phase column chromatography using 10 to 80% MeOH/water (both + 0.1% formic acid). The pure fractions were combined and concentrated, then purified using an SCX-II ion exchange cartridge (2 g, 15 mL) and eluted with MeOH and 2M NH ₃ in MeOH. The basic fractions were combined and concentrated in vacuo to give 7-ethoxy-1,3-benzothiazol-2-amine (74.3 mg, 68%, 0.38 mmol) as a white amorphous solid. HPLC/MS m/z: 195.1 [M+H] ⁺ , Rt (T): 0.86 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 7.42 (s, 2H), 7.14 (t, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.0, 0.8 Hz, 1H), 6.65 (dd, J = 8.2, 0.8 Hz, 1H), 4.14 (q, J = 7 .0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H).

Example _79.2 : To a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [B2] (32.1 mg, 0.17 mmol), 7-ethoxy-1,3-benzothiazol-2-amine (19.5 mg, 0.10 mmol) in DMF (0.52 mL) under N2 was added 1-hydroxybenzotriazole (22.6 mg, 0.17 mmol). The resulting solution was stirred at 60 °C overnight. The reaction crude was purified by reverse phase column chromatography using 20 to 100% MeOH/water (both + 0.1% formic acid). The fractions with the pure compound were combined and evaporated to dryness and further purified by SCX-II ion exchange cartridge (2 g, 15 mL) using MeOH and 2M _NH3 in MeOH as solvents. The basic fractions were combined and evaporated to dryness to give N-(7-ethoxy-1,3-benzothiazol-2-yl)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide (22.1 mg, 56%, 0.05 mmol) as a beige amorphous powder. HPLC/MS m/z: 475.2 [M+H] ⁺ , Rt (U): 2.54 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 12.05 (s, 1H), 8.90 (d, J = 1.6 Hz, 1H), 8.16 (dd, J = 8.4, 1.5 Hz, 1H), 8.05 (t, J = 5.4 Hz, 1H), 7.99 (d, J = 5.7 Hz , 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.49-7.24 (m, 2H), 6.98 (d, J = 5.7 Hz, 1H), 6.89 (dd, J = 7.7, 1.1 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H), q 3.85 , J = 6.6 Hz, 2H), 2.94 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H).

Example 80 : (S)-N-(7- ethoxybenzo [d] thiazol -2- yl )-2- hydroxy -3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ) amino ) propionamide To a mixture of (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionic acid [B4] (25.0 mg, 0.08 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg, 0.16 mmol), 7-ethoxy-1,3-benzothiazol-2-amine [Example 79.1] (18.5 mg, 0.096 mmol) in anhydrous DMF (0.50 mL) was added 1-hydroxybenzotriazole (21.5 mg, 0.16 mmol) under nitrogen atmosphere. The resulting solution was stirred at 60° C. overnight. The crude was purified by reverse phase column chromatography (eluent: 20 to 100% MeOH/water (both + 0.1% formic acid)). The fractions of the pure product were combined and evaporated to dryness and further purified by SCX-II ion exchange cartridge (2 g, 15 mL) using MeOH and 2M NH3 in _MeOH as eluents. The basic fractions were combined and evaporated to dryness to give the desired product, but this was not pure (8.5 mg, 88%). The impure product was further purified by preparative TLC (500 microns) using 5% MeOH/DCM as solvent to give (2S)-N-(7-ethoxy-1,3-benzothiazol-2-yl)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide (4 mg, 10%, 0.0082 mmol) as a white amorphous powder. HPLC/MS m/z: 491.1 [M+H] ⁺ , Rt (U): 1.18 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 12.11 (s, 1H), 8.91 (d, J = 1.7 Hz, 1H), 8.16 (dd, J = 8.5, 1.5 Hz, 1H), 8.09 (t, J = 5.6 Hz, 1H), 7.93 (d, J = 5.7 Hz , 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.44-7.29 (m, 2H), 7.04-6.96 (m, 1H), 6.89 (dd, J = 7.8, 1.0 Hz, 1H), 6.46 (s, 1H), 4.61 (t, J = 5.6 Hz, 1H ), 4.21 (q, J = 6.9 Hz, 2H), 3.86 (ddt, J = 49.6, 13.5, 5.6 Hz, 2H), 2.68 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H).

Example 81 : 3-(5 -methyl -1,2,4- oxadiazol -3- yl )-N-[3 -oxo -3-[(7 -propoxy -1,3- benzothiazol -2- yl ) amino ] propyl ] benzamide To a mixture of 2-amino-1,3-benzothiazol-7-ol (9.8 mg, 0.047 mmol), B1 (10.0 mg, 0.036 mmol), HOBt (9.8 mg, 0.073 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.9 mg, 0.073 mmol) was added DMF (0.18 mL) under nitrogen atmosphere. The resulting solution was stirred at 60 °C for 19 hours. The crude was purified by reverse phase column chromatography using 20 to 100% MeOH/water (both + 0.1% formic acid) to give the desired compound (11 mg, 65%, 0.024 mmol) as a white amorphous solid. HPLC/MS m/z: 466.2 [M+H] ⁺ , Rt (T): 1.46 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 12.41 (s, 1H), 8.88 (t, J = 5.5 Hz, 1H), 8.47 (t, J = 1.8 Hz, 1H), 8.13 (dt, J = 7.7, 1.4 Hz, 1H), 8.04 (dt, J = 7.8 , 1.5 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.45-7.22 (m, 2H), 6.89 (dd, J = 7.7, 1.2 Hz, 1H), 4.12 (t, J = 6.4 Hz, 2H), 3.63 (q, J = 6.7 Hz, 2H), 2.83 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 1.79 (sext, J = 7.0 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H).

Example 82 : (R)-N-(7- ethoxybenzo [d] thiazol -2- yl )-2- hydroxy -3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin -1- yl ) amino ) propionamide Example 82.1: A1 (200.0 mg, 0.88 mmol) and (2R)-3-amino-2-hydroxy-propionic acid methyl ester hydrochloride (150.6 mg, 0.99 mmol) were dissolved/suspended in anhydrous DCM (2.93 mL) in a microwave vial. DIPEA (0.77 mL, 4.40 mmol) was added followed by PyBroP (533.4 mg, 1.14 mmol) and the mixture was stirred at room temperature for 4 days. The volatiles were evaporated and the crude was purified by RP column chromatography (solvent: 0 to 70% MeOH/water (both + 0.1% formic acid modifier)) to give the desired product (2R)-methyl 2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoate (107.5 mg, 37%, 0.33 mmol) as a clear oil. HPLC/MS m/z: 329.1 [M+H] ⁺ , Rt (Y): 0.87 min. ¹ H NMR (500 MHz, methanol- _{d 4} ): δ 8.98 (dd, J = 1.6, 0.8 Hz, 1H), 8.38 (dd, J = 8.5, 1.5 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 6.4 Hz, 1H), 7. 16 (dd, J = 6.4, 0.9 Hz, 1H), 4.61 (dd, J = 6.3, 3.9 Hz, 1H), 4.11-3.89 (m, 2H), 3.80 (s, 3H), 2.72 (s, 3H).

Example 82.2: Methyl (2R)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoate (107.5 mg, 0.33 mmol) was dissolved in anhydrous THF (0.82 mL) and water (0.82 mL). To this was added lithium hydroxide monohydrate (30.2 mg, 0.72 mmol) and the resulting mixture was stirred at RT for 21 h. Volatiles were removed in vacuo and the crude was dissolved in DMSO (2 mL) and purified by reverse phase column chromatography (solvent: 5 to 80% MeOH/water (both + 0.1% formic acid modifier)) to give (2R)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoic acid (68.8 mg, 67%, 0.22 mmol) as the formate salt as a white solid. HPLC/MS m/z: 315.1 [M+H] ⁺ , Rt (Y): 0.88 min. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.94-8.89 (m, 1H), 8.16 (dd, J = 8.5, 1.5 Hz, 1H), 8.14 (s, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 5.8 Hz, 1H) , 7.87 (d, J = 8.6 Hz, 1H), 6.99 (dd, J = 5.9, 0.8 Hz, 1H), 4.38 (dd, J = 7.1, 4.6 Hz, 1H), 3.81 (dt, J = 13.6, 4.4 Hz, 1H), 3.71-3.60 (m, 1H), 2.71 (s, 3H).

Example 82.3: To a mixture of (2R)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionic acid (30.0 mg, 0.096 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg, 0.16 mmol), 7-ethoxy-1,3-benzothiazol-2-amine [Example 79.1] (22.2 mg, 0.11 mmol) in anhydrous DMF (0.60 mL) under nitrogen atmosphere was added 1-hydroxybenzotriazole (25.8 mg, 0.19 mmol). The resulting solution was stirred at 60 °C overnight. The crude material was purified by reverse phase column chromatography (eluent: 20 to 100% MeOH/water (both + 0.1% formic acid modifier)). The fractions of the pure product were combined and evaporated to dryness (23.3 mg) and further purified by SCX-II ion exchange cartridge (2 g, 15 mL) using MeOH and 2M _NH3 in MeOH as eluent. Further purification by preparative TLC (500 μm) using 5% MeOH/DCM as solvent gave (2R)-N-(7-ethoxy-1,3-benzothiazol-2-yl)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide (5 mg, 11%, 0.0102 mmol) as a white amorphous powder. HPLC/MS m/z: 491.1 [M+H] ⁺ , Rt (Y): 1.32 min. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 12.13 (s, 1H), 8.92 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 12.7 Hz, 1H), 7.92 (d, J = 5.8 Hz, 1H), 7.87 (d , J = 8.5 Hz, 1H), 7.43-7.27 (m, 2H), 7.00 (d, J = 5.8 Hz, 1H), 6.90 (dd, J = 7.8, 1.2 Hz, 1H), 6.50 (d, J = 16.2 Hz, 1H), 4.62 (t, J = 5.6 Hz, 1 H), 4.22 (q, J = 7.0 Hz, 2H), 3.95-3.80 (m, 2H), 2.68 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H).

Example 83 : 3-(5 -methyl -1,2,4- oxadiazol -3- yl )-N-(2-(9 -oxo - 1-propoxy -6,7- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8(9H) -yl ) ethyl ) benzamide 3-(5-Methyl-1,2,4-oxadiazol-3-yl)benzoic acid (20.7 mg, 0.10 mmol) and 2-(10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-11-yl)ethylammonium chloride [Example 37.5] (30.00 mg, 0.0924 mmol) were dissolved in anhydrous DMF (0.46 mL). Triethylamine (40 μL, 0.28 mmol) and T3P (0.11 mL, 0.18 mmol) were then added. After 4 hours, more T3P (109 μL) and TEA (39 μL) were added to the reaction mixture. This was stirred at RT for 2 days. The crude material was purified by reverse phase column chromatography (eluent: 20 to 90% MeOH/water (both + 0.1% formic acid)). Fractions with the pure product were combined and concentrated, then purified by SCX-II ion exchange cartridge (2 g, 15 mL). The basic fractions were combined and evaporated to dryness to give 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-[2-(10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02,7]tridec-2,4,6,8-tetraen-11-yl)ethyl]benzamide (10 mg, 23%, 0.02 mmol) as a clear film. HPLC/MS m/z: 475.2 [M+H] ⁺ , Rt (Y): 1.33 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.86 (t, J = 5.9 Hz, 1H), 8.43 (t, J = 1.8 Hz, 1H), 8.11 (dt, J = 7.7, 1.4 Hz, 1H ), 7.99 (dt, J = 7.8 , 1.5 Hz, 1H ) , 3.9 4-3.79 (m, 2H), 3.72 (t, J = 6.0 Hz, 2H), 3.56 (q, J = 5.9 Hz, 2H), 2.67 (s, 3H), 1.77 (sext, J = 7.2 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H).

Example 84 : N-(2,2 -difluoro -3-((4 -fluoro - 7-propoxybenzo [d] thiazol -2- yl ) amino )-3 -oxopropyl )-3-(5- methyl -1,2,4- oxadiazol - 3- yl ) benzamide Example 84.1: DIPEA (0.70 mL, 4.00 mmol) was added to a solution of ethyl 2,2-difluoro-3-aminopropanoate hydrochloride (200.0 mg, 1.00 mmol), 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (204.6 mg, 1.00 mmol) and HATU (571.7 mg, 1.50 mmol) in DMF (6.68 mL). The yellow reaction mixture was stirred at room temperature for 2 days. The reaction mixture was then diluted with EtOAc (50 mL) and washed with water (100 mL). The organic layer was washed with saturated aqueous bicarbonate solution (70 mL) and brine (70 mL) and then dried over magnesium sulfate. The organic layer was then filtered and evaporated to dryness. The crude product obtained was purified by NP flash silica gel column chromatography using a gradient of 0 to 10% MeOH/DCM as the eluent to afford ethyl 2,2-difluoro-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoate (305 mg, 79%, 0.79 mmol) as a pink oil. HPLC/MS m/z: 362.1 [M+Na] ⁺ , Rt (Y): 1.30 min. ¹ H NMR (600 MHz, chloroform-d): δ 8.43 (t, J = 1.8 Hz, 1H), 8.26 (dt, J = 7.8, 1.4 Hz, 1H), 8.00 (ddd, J = 7.8, 1.9, 1.2 Hz, 1H), 7.66-7.57 (m, 1H), 6 .53 (d, J = 6.6 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 4.17 (td, J = 13.6, 6.3 Hz, 2H), 2.70 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).

Example 84.2: Lithium hydroxide (47.4 mg, 1.98 mmol) was added to a solution of ethyl 2,2-difluoro-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoate (305.0 mg, 0.90 mmol) in THF (2.25 mL) and water (2.25 mL). The reaction mixture was stirred at room temperature for 2 h 20 min. The reaction mixture was concentrated and the aqueous solution was acidified to pH 3 with 1 M aqueous citric acid solution and extracted with EtOAc (60 mL). After phase separation, the organic layer was washed with brine (30 mL), dried over magnesium sulfate, filtered and evaporated to dryness to give 2,2-difluoro-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid (183 mg, 65%, 0.59 mmol) as an off-white solid which was used in the next step without further purification. HPLC/MS m/z: 312.1 [M+H] ⁺ , Rt (T): 0.87 min. ¹ H NMR (600 MHz, methanol- _{d 4} ): δ 8.53 (t, J = 1.6 Hz, 1H), 8.24 (dt, J = 7.8, 1.4 Hz, 1H), 8.00 (ddd, J = 7.8, 1.9, 1.2 Hz, 1H), 7.65 (td, J = 7.8, 0 .6 Hz, 1H), 4.26-3.83 (m, 2H), 2.69 (s, 3H).

Example 84.3: 2,2-Difluoro-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid (34.3 mg, 0.11 mmol), 4-fluoro-7-propoxy-1,3-benzothiazol-2-amine [Example 77.2] (24.9 mg, 0.11 mmol) and TEA (50 uL, 0.33 mmol) were mixed in anhydrous DMF (0.22 mL) at room temperature. 50% T3P in DMF (0.17 mL, 0.29 mmol) was added and the reaction mixture was heated at 70 °C for 3 h, the reaction was cooled down to room temperature, quenched with water (0.2 mL), diluted with DMSO (0.5 mL) and loaded directly onto a Biotage C18 SNAP Ultra column and purified by reverse phase. Fractions with pure compound were combined and further purified by SCX-II column (2 g, 15 mL) using MeOH and 2M ammonia solution in MeOH as eluents to give the desired product (14.7 mg, 26%, 0.028 mmol) as an off-white solid. HPLC/MS m/z: 520.1 [M+H] ⁺ , Rt (T): 1.47 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 13.75 (s, 1H), 9.22 (t, J = 6.2 Hz, 1H), 8.43 (t, J = 1.8 Hz, 1H), 8.20-8.09 (m, 1H), 8.01 (dt, J = 7.8, 1.5 Hz, 1 H), 7.66 (t, J = 7.8 Hz, 1H), 7.27 (dd, J = 10.4, 8.7 Hz, 1H), 6.93 (dd, J = 8.8, 3.0 Hz, 1H), 4.23-4.06 (m, 4H), 2.67 (s, 3H), 1.78 (sext, J = 7 .0 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H).

Example 85 : 3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1 -yl ) amino )-N-(1 -methyl -7 -propoxy- 1H- benzo [d] imidazol -2 -yl ) propionamide Example 85.1: 7-Propoxy-1H-benzimidazol-2-amine [Example 86] (83.0 mg, 0.43 mmol), potassium hydroxide (43.8 mg, 0.78 mmol) and iodomethane (28 μL, 0.45 mmol) were stirred in ethanol (5.4 mL) at RT for 2 days. Potassium hydroxide (61 mg) and iodomethane (20 μL) were added to the reaction mixture and this was stirred overnight. The volatiles were evaporated and the crude was dissolved in ethyl acetate (30 mL) and this was washed with saturated aqueous sodium bicarbonate solution (30 mL), water (30 mL) and brine (30 mL). The organic layer was then dried over MgSO ₄ , filtered and evaporated to dryness. The obtained crude product (58 mg) was purified by normal phase silica gel column chromatography (eluent: 0 to 20% MeOH/DCM gradient) to give the desired positional isomer 1-methyl-7-propoxy-1H-benzo[d]imidazol-2-amine (9.2 mg). The fractions with the mixture of positional isomers were combined and further purified by preparative TLC (500 microns) using 10% MeOH/DCM as eluent to give an additional 4.6 mg of pure desired product. The pure products obtained from column chromatography and preparative TLC were combined to give 1-methyl-7-propoxy-benzimidazol-2-amine (13.8 mg, 15.5%, 0.067 mmol). HPLC/MS m/z: 206.1 [M+H] ⁺ , Rt (Y): 1.01 min. ¹ H NMR (600 MHz, methanol-d ₄ ): δ 6.94 (t, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.0, 0.9 Hz, 1H), 6.59 (dd, J = 8.1, 0.9 Hz, 1H), 4.05 (t, J = 6.3 Hz, 2H), 3. 81 (s, 3H), 1.88 (dtd, J = 13.9, 7.5, 6.4 Hz, 2H), 1.11 (t, J = 7.5 Hz, 3H).

Example 85.2: To a 5 mL microwave vial was added B2 (10.00 mg, 0.033 mmol), 1-methyl-7-propoxy-benzimidazol-2-amine (13.8 mg, 0.067 mmol), PyBrop (37.5 mg, 0.080 mmol), followed by anhydrous DMF (0.2 mL) and DIPEA (21 μL, 0.12 mmol). The resulting solution was stirred at RT for 2 days. The reaction was diluted with DMSO (0.3 mL) and purified by reverse phase column chromatography (solvent: 20 to 100% MeOH/water (both + 0.1% formic acid modifier)). The pure fractions were combined and evaporated to dryness and further purified by SCX-II ion exchange column (2 g, 15 mL) using MeOH and 2M NH ₃ solution in MeOH as solvents. The basic fractions were combined and concentrated under reduced pressure to give 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(1-methyl-7-propoxy-1H-benzo[d]imidazol-2-yl)propanamide (5 mg, 31%, 0.01 mmol) as a light pink solid. HPLC/MS m/z: 486.2 [M+H] ⁺ , Rt (T): 1.11 min. ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 10.54 (s, 1H), 8.96-8.83 (m, 1H), 8.21-8.12 (m, 1H), 8.09-7.94 (m, 2H), 7.85 (d, J = 8.4 Hz, 1H), 7.16-6.98 ( m, 2H), 6.96 (t, J = 5.7 Hz, 1H), 6.75 (dd, J = 11.6, 7.7 Hz, 1H), 4.05 (t, J = 6.1 Hz, 2H), 3.87-3.79 (m, 2H), 3.74 (brs, 3H), 2.89-2.84 (m, 2H), 2.69 (t, J = 5.8 Hz, 3H), 1.79 (q, J = 6.9 Hz, 2H), 1.02 (q, J = 7.6 Hz, 3H) [Note: tautomeric forms exist].

Example 86 : 3-((7-(5 -methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1 -yl ) amino )-N-(7 -propoxy- 1H- benzo [d] imidazol -2 -yl ) propionamide Example 86.1: 1-Iodopropane (0.35 mL, 3.57 mmol) was added to _a mixture of 2-amino-3-nitrophenol (500.0 mg, 3.24 mmol) and _K2CO3 (672.6 mg, 4.87 mmol) in anhydrous DMF (32.4 mL). The reaction was stirred at RT for 22 h 30 min. The crude was partitioned between EtOAc (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). After phase separation, the aqueous layer was further extracted with EtOAc (50 mL). The combined organic layers were washed with water (80 mL), saturated aqueous sodium bicarbonate solution (80 mL), brine (50 mL), dried over MgSO ₄ , filtered and evaporated to dryness. The crude was purified by SCX-II ion exchange column using MeOH and 2M NH ₃ solution in MeOH as eluents. After evaporation of the solvent, the obtained crude (0.99 g) was purified by NP silica gel column chromatography (eluent: 0 to 10% EtOAc/cyclohexane) to give 2-nitro-6-propoxy-phenylamine (576 mg, 90%, 2.94 mmol) as a bright orange solid. HPLC/MS m/z: 197.1 [M+H] ⁺ , Rt (Y): 1.44 min. ¹ H NMR (500 MHz, chloroform-d): 6.74 (dd, J = 8.8, 1.3 Hz, 1H), 6.89 (dd, J = 7.7, 1.2 Hz, 1H), 6.61 (dd, J = 8.9, 7.7 Hz, 1H), 6.45 (s, 2H), 4.02 (t, J = 6.5 Hz, 2H), 1.90 (dtd, J = 13.8, 7.4, 6.5 Hz, 2H), 1.09 (t, J = 7.4 Hz, 3H).

Example 86.2: 2-Nitro-6-propoxy-aniline (280.0 mg, 1.43 mmol) and tin(II) chloride (1367.4 mg, 7.14 mmol) were dissolved in EtOH (14.0 mL) in a 20 mL microwave vial. The reaction mixture was heated in a microwave at 140 °C for 10 min. Additional tin(II) chloride (317 mg) was added and after the microwave vial was resealed, the reaction mixture was further heated at 135 °C for 5 min. After cooling, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (75 mL). The bicarbonate phase was extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (75 mL), water (10 mL) and brine (50 mL). The organic layer was then dried, filtered, and evaporated to dryness to give 3-propoxybenzene-1,2-diamine (209.5 mg, 88%, 1.26 mmol) as a yellow solid. HPLC/MS m/z: 167.1 [M+H] ⁺ , Rt (Y): 0.76 min. ¹ H NMR (500 MHz, chloroform-d): δ 6.66 (t, J = 8.0 Hz, 1H), 6.41 (td, J = 8.2, 1.2 Hz, 2H), 3.97 (t, J = 6.5 Hz, 2H), 3.40 (brs, 4H), 1.85 (dtd, J = 13.9 , 7.4, 6.5 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H).

Example 86.3: Bromine cyanide 5M in MeCN (0.19 mL, 0.97 mmol) was added to a mixture of 3-propoxybenzene-1,2-diamine (135.0 mg, 0.81 mmol) in MeCN (3.9 mL) and water (0.99 mL). The reaction mixture was stirred at RT overnight. The volatiles were evaporated to dryness and the obtained crude was purified by normal phase silica gel column chromatography (solvent: 2 to 15% MeOH / DCM gradient) to give 7-propoxy-1H-benzimidazol-2-amine (65 mg, 42%, 0.34 mmol). HPLC / MS m / z: 192.1 [M + H] ⁺ , Rt (Y): 0.99 min. ¹ H NMR (500 MHz, CHLOROFORM-d): δ 7.10-6.80 (m, 2H), 6.63 (dd, J = 7.6, 1.3 Hz, 1H), 4.61 (brs, 6H), 4.09 (t, J = 6.7 Hz, 2H), 1.83 (sext, J = 7.2 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H) [Note: tautomers exist].

Example 86.4: B2 (31.2 mg, 0.1 mmol) and 7-propoxy-1H-benzimidazol-2-amine (20 mg, 0.1 mmol) were dissolved in anhydrous DMF (0.52 mL), followed by the addition of triethylamine (59 μL, 0.42 mmol). The reaction mixture was placed in a preheated heating block at 70 °C, and 50% T3P in DMF (0.18 mL, 0.31 mmol) was added dropwise over 5 min. The reaction mixture was stirred at 70 °C for 18 h. More T3P (92 μL) and TEA (28 μL) were added to the reaction mixture, and this was further stirred at 70 °C for 18 h. The reaction was quenched with water (0.3 mL) and stirred for 5 minutes, then diluted with DMSO (0.4 mL) and purified by reverse phase column chromatography (solvent: 20 to 100% MeOH/water (both + 0.1% formic acid)). The pure compound fractions were combined and concentrated, then purified by SCX-II ion exchange cartridge (2 g, 15 mL). The basic fractions were evaporated to dryness to give the desired product as a light yellow amorphous solid. [96% pure by LC-MS]. The compound crystallized in deuterated MeOH solution over 2 days, so the mother liquor was pipetted off and the crystals were washed with MeOH to give pure 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-N-(7-propoxy-1H-benzimidazol-2-yl)propanamide (4 mg, 8%, 0.0085 mmol) as a light yellow solid. HPLC/MS m/z: 472.2 [M+H] ⁺ , Rt (Y): 1.29 min. ¹ H NMR (500 MHz, methanol- _{d 4} ): 8.82 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 5.9 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), 6.99 (d, J = 5.9 Hz, 1H), 6.72 (dd, J = 6.1, 2.7 Hz, 1H), 4.11 (t, J = 6.6 Hz, 2H), 3.98 (t, J = 6.6 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H), 2.66 (s, 3H), q 1.88 , J = 7.2 Hz, 2H), 1.15-1.04 (m, 3H) [Note: 1 aromatic proton was not observed].

Example 87 : 8-(2-((7-(5- methyl -1,2,4- oxadiazol -3- yl ) isoquinolin- 1 - yl ) amino ) ethyl -1,1,2,2-d4)-1-(2,2,2 -trifluoroethoxy -1,1-d2)-7,8- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 9(6H) -one - 6,6,7,7-d4 Example 87.1: A solution of NaOH (1.04 g, 26.0 mmol, 1.0 eq.) in _H2O (21.1 mL) was added to a solution of glycine-2,2-d2 (2.0 g, 26.0 mmol, 1.0 eq.) in water (21.1 mL). Then, a solution of _Boc2O (7.04 g, 31.3 mmol, 1.2 eq.) in dioxane (44.3 mL) was added dropwise and the resulting reaction mixture was stirred at room temperature overnight. After evaporation, the residue was redissolved in water and extracted with ether. The ethereal fractions were washed with water and the aqueous fractions were combined, acidified with 1 M HCl and extracted with EtOAc. The combined EtOAc fractions were dried over anhydrous MgSO ₄ and then concentrated under reduced pressure. Crude 2-(tert-butoxycarbonylamino)-2,2-dideutero-acetic acid (4.43 g, crude yield 96%) was separated as a colorless oil. Rf (iPrOH: AcOH: H ₂ O = 3:1:1) = 0.86; ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.03 (s, 1H), 1.47 (s, 9H).

Example 87.2: 1,1'-Carbonyldiimidazole (5.37 g, 33.1 mmol, 1.3 eq.) was added to a solution of 2-(tert-butoxycarbonylamino)-2,2-dideutero-acetic acid (4.42 g, 24.9 mmol, 1 eq.) in THF (83.1 mL, 0.2 M) at RT. After 15 min, the solution was cooled to 0 °C and a solution of NaBD ₄ (1.06 g, 25.4 mmol) in H ₂ O (41.6 mL, 0.2 M) was added. After 1 h, HCl (1 M) was added and the mixture was extracted with EtOAc. The combined organics were dried over MgSO ₄ and concentrated under vacuum. Purification by NP column chromatography (0% to 20% to 50% EtOAc/cHex) gave tert-butyl N-(1,1,2,2-tetradeutero-2-hydroxy-ethyl)carbamate (3.19 g, 77%) as a colorless oil. Rf (CHCl ₃ :MeOH = 9:1) = 0.54. ¹ H NMR (500 MHz, CDCl 3 ) δ 4.92 (s, 1H), 1.46 (s, 9H).

Example 87.3: Methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (1.21 g, 5.73 mmol, 1 eq.), 2,2,2-trifluoroethanol-1,1-d2 (683 μL, 9.18 mmol, 1.6 eq.), 4Å molecular sieve (3.49 g), tBuBrettPhos Pd G3 (215 mg, 0.252 mmol, 4 mol%), tBuBrettPhos (125 mg, 0.250 mmol, 4 mol%) and Cs ₂ CO ₃ (3.49 g, 10.7 mmol, 1.9 eq.) was heated at 80 °C in a sealed vial under an argon atmosphere for 24 h. The mixture was filtered on a silica gel pad, eluted with MeOH and the solvent was evaporated. The residue was purified using NP column chromatography (solvent: 0% to 42% EtOAc/cHex) and concentrated under vacuum. Purified 4-(1,1-dideutero-2,2,2-trifluoro-ethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (1.18 g, 75%) was isolated as a white crystalline solid. Rf (cHex:EtOAc = 7:3) = 0.50. HPLC/MS m/z: 277.1 [M+H] ⁺ , Rt (Y): 1.43 min. ¹ H NMR (600 MHz, DMSO) δ 12.55 (s, 1H), 7.87 (d, J = 5.9 Hz, 1H), 7.17 – 7.13 (m, 2H), 3.89 (s, 3H).

Example 87.4: DIAD (2.3 mL, 11.6 mmol, 3.2 eq.) was added to a solution of tert-butyl N-(1,1,2,2-tetradeutero-2-hydroxy-ethyl)carbamate (2.16 g, 13.1 mmol, 3.6 eq.), _PPh3 (2.86 g, 10.9 mmol, 3.0 eq.) and methyl 4-(1,1-dideutero-2,2,2-trifluoro-ethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (1.0 g, 3.63 mmol, 1.0 eq.) in THF (9.1 mL, 0.4 M) at 0° C. over 50 min. After 1 h, the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction was then quenched with water, extracted with DCM and the organic phase was dried over MgSO ₄ and evaporated in vacuo. The crude mixture was dissolved in DCM/TFA (1:1) (40 mL, 0.09 M) and stirred at RT for 30 min. The solvent was evaporated and the crude mixture was passed through an SCX-2 column eluting with DCM then MeOH and then NH ₃ (2 M in MeOH) to recover 12,12,13,13-tetradeutero-6-(1,1-dideutero-2,2,2-trifluoro-ethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (1.19 g, 112%) as a white powder. Rf (EtOAc) = 0.57; HPLC/MS m/z: 292.1 [M+H] ⁺ , Rt (T): 1.10 min. ¹ H NMR (500 MHz, DMSO) δ 8.25 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.33 (d, J = 6.0 Hz, 1H), 7.00 (d, J = 0.9 Hz, 1H).

Example 87.5: A solution of TsCl (2.08 g, 10.9 mmol, 2 eq.) in DCM (18.2 mL) was slowly added to a solution of tert-butyl N-(1,1,2,2-tetradeutero-2-hydroxy-ethyl)carbamate (0.90 g, 5.45 mmol, 1 eq.), DMAP (50.6 mg, 0.414 mmol, 8 mol%) and _Et3N (2.3 mL, 16.3 mmol, 3 eq.) in DCM (36.3 mL, 0.1 M) at 0° C. The resulting solution was stirred at 0° C. for 30 min and then at RT for 3 h. After concentration in vacuo, the product was purified by normal phase flash chromatography (solvent: 10% to 40% EtOAc/cHex) to give 4-methylbenzenesulfonic acid [2-(tert-butoxycarbonylamino)-1,1,2,2-tetradeutero-ethyl] ester (1.56 g, 90%) as a white solid. Rf (cHex:EtOAc = 7:3) = 0.44. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.80 (d, 2H), 7.36 (d, 2H), 4.83 (s, 1H), 2.46 (s, 3H), 1.42 (s, 9H).

Example 87.6: A solution of 4-methylbenzenesulfonic acid [2-(tert-butoxycarbonylamino)-1,1,2,2-tetradeutero-ethyl] ester (1.35 g, 4.22 mmol, 1.2 eq.) in DMSO (8.7 mL) was added to a solution containing 12,12,13,13-tetradeutero-6-(1,1-dideutero-2,2,2-trifluoro-ethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (0.99 g, 3.39 mmol, 1 _eq .), KOH (0.40 g, 7.11 mmol, 2.1 eq.), _K2CO3 (1.40 g, 10.2 mmol, 3 eq.) and TBAB. (0.44 g, 1.35 mmol, 0.4 eq.) in DMSO (17.37 mL, 0.13 M). The mixture was stirred at RT for 10 min, at 40 °C for 4 h and then at 55 °C overnight. The reaction was quenched with HCl (3 M). The solvent was evaporated and the crude was dissolved in TFA / DCM (1:1, 20 mL) with stirring for 30 min. After evaporation, the crude was applied to an SCX-2 column and eluted sequentially with DCM, MeOH and then _NH3 (2N in MeOH) to afford 11-(2-amino-1,1,2,2-tetradeutero-ethyl)-12,12,13,13-tetradeutero-6-(1,1-dideutero-2,2,2-trifluoro-ethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one. HPLC/MS m/z: 339.2 [M+H] ⁺ , Rt (U): 0.85 min.

Example 87.7: DIPEA (96.52 μL, 0.5542 mmol) was added dropwise to a suspension of 11-(2-amino-1,1,2,2-tetradeutero-ethyl)-12,12,13,13-tetradeutero-6-(1,1-dideutero-2,2,2-trifluoro-ethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (50.00 mg, 0.1478 mmol), A1 (40.29 mg, 0.1773 mmol) and PyBroP (82.67 mg, 0.1773 mmol) in DCM (1.48 mL, 0.1 M). The tube was sealed and this was heated to 60 °C for 1 hour. Water was added and this was extracted with DCM. The organic layer was dried over MgSO ₄ and evaporated in vacuo. Purification by semipreparative HPLC (solvent: 55 to 65% MeCN / pH 10 0.1% [NH ₃ in H ₂ O]) gave 12,12,13,13-tetradeutero-6-(1,1-dideutero-2,2,2-trifluoro-ethoxy)-11-[1,1,2,2-tetradeutero-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]ethyl]-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one (20.16 mg, 25%, 0.0368 mmol) as a yellow oil. ¹ H NMR (600 MHz, DMSO) δ 8.88 (dd, J = 1.8, 0.9 Hz, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H) , 8.06 (s, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.89 (d, J = 6.0 Hz, HPLC/MS m/z: 548. 2 [ M +H ] +, Rt (U): 2.45 min

Example 88 : 3-(2 -methyl -2H- tetrazol -5- yl )-N-(2-(9 -oxo -1-(2,2,2 -trifluoroethoxy -1,1-d2)-6,7- dihydropyrido [3',4':4,5] pyrrolo [1,2-a] pyrrol - 8 (9H) -yl -6,6,7,7-d4) ethyl -1,1,2,2-d4) benzamide DIPEA (164.73 μL, 0.9458 mmol) was added to 11-(2-amino-1,1,2,2-tetradeutero-ethyl)-12,12,13,13-tetradeutero-6-(1,1-dideutero-2,2,2-trifluoro-ethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraen-10-one [see Example 87.6] (80.00 mg, 0.2364 mmol), 3-(2-methyl-2H-tetrazol-5-yl)-benzoic acid (55.52 mg, 0.2719 mmol) and HATU (179.80 mg, 0.4729 This was stirred at 50° C. for 1 hour, after which the mixture was washed once with water, then extracted with DCM, dried over MgSO ₄ and evaporated. Purification by flash column chromatography (solvent: 0 to 3.25% MeOH/DCM) followed by preparative TLC (10% MeOH/DCM) and trituration with EtOAc gave 3-(2-methyl-2H-tetrazol-5-yl)-N-(2-(9-oxo-1-(2,2,2-trifluoroethoxy-1,1-d2)-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrrol-8(9H)-yl-6,6,7,7-d4)ethyl-1,1,2,2-d4)benzamide (27.4 mg, 22%, 0.0522 mmol) as a white solid. HPLC/MS m/z: 525.2 [M+H]+, Rt (U): 2.65 min.

Examples 89 ：Compound structure and IUPAC Name No. Structure IUPAC Name 1 N-{4-ethoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 2 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-[4-(propan-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propanamide 3 N-{4-cyclobutoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 4 N-[4-(Butyl-2-oxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 5 N-[4-(2,2-difluoroethoxy)-[1,3]thiazo[5,4-c]pyridin-2-yl]-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 6 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-[4-(2,2,2-trifluoroethoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propanamide 7 N-[4-(3,3-difluorocyclobutoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 8 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-{4-[(1,1,1-trifluoropropan-2-yl)oxy]-[1,3]thiazo[5,4-c]pyridin-2-yl}propanamide 9 N-{4-ethoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 10 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-propoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}propionamide 11 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[4-(propan-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propionamide 12 N-[4-(Butyl-2-oxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 13 N-{4-cyclobutoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 14 N-[4-(3,3-difluorocyclobutoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 15 N-[4-(3-fluoropropoxy)-[1,3]thiazo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 16 N-[4-(2,2-difluoropropoxy)-[1,3]thiazo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 17 N-[4-(2,2-difluoroethoxy)-[1,3]thiazo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 18 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[4-(2,2,2-trifluoroethoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propionamide 19 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-[(1,1,1-trifluoropropan-2-yl)oxy]-[1,3]thiazo[5,4-c]pyridin-2-yl}propionamide 20 (1s,3s)-N-{4-methoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}cyclobutane-1-carboxamide twenty one (1s,3s)-N-{4-ethoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}cyclobutane-1-carboxamide twenty two (1s,3s)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-propoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}cyclobutane-1-carboxamide twenty three N-{1-ethoxypyrrolo[1,2-a]pyrroline-7-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide twenty four 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{1-propoxypyrrolo[1,2-a]pyrroline-7-yl}propionamide 25 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 26 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 27 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2(7),3,5,8-tetraen-11-yl](1,1,2,2-2H4)ethyl}benzamide 28 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2(7),3,5,8-tetraen-11-yl](1,1,2,2-2H4)ethyl}benzamide 29 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}(1,1,2,2-2H4)ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 30 3-(5-methyl-2H-1,2,3,4-tetrazolyl-2-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 31 11-(2-{[7-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 32 11-(2-{[7-(5-methyl-2H-1,2,3,4-tetrazolyl-2-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 33 11-(2-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 34 3-Fluoro-5-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 35 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)(12,12,13,13-2H4)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2(7),3,5,8-tetraen-11-yl]ethyl}benzamide 36 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)(12,12,13,13-2H4)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 37 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-6-propoxy-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 38 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-(2-{10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl}ethyl)benzamide 39 1-(Dodeca-11-yn-1-yloxy)-8-(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)-7,8-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrro[9(6H)-one 40 N-(2-{6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl}ethyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide 41 N-{2-[6-(3-fluoropropoxy)-10-oxo-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide 42 N-{2-[6-(2,2-difluoroethoxy)-10-oxo-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide 43 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 44 6-(3-fluoropropoxy)-11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 45 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-(2-{10-oxo-6-[(1,1,2,2,3,3,3-2H7)propoxy]-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl}ethyl)benzamide 46 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-(2-{10-oxo-6-[2,2,2-trifluoro(1,1-2H2)ethoxy]-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl}ethyl)benzamide 47 N-(2-(1-(Dodeca-11-yn-1-yloxy)-9-oxo-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrro-8(9H)-yl)ethyl)-3-(2-methyl-2H-tetrazolyl-5-yl)benzamide 48 11-(3-amino-2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclic[[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 49 (S)-3-(2-methyl-2H-tetrazolyl-5-yl)-N-(6-(methylamino)-1-(9-oxo-1-(2,2,2-trifluoroethoxy)-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrroline-8(9H)-yl)hexan-2-yl)benzamide 50 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-[6-(methylamino)-1-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2(7),3,5,8-tetraen-11-yl]hexan-2-yl]benzamide 51 N-{6-[methyl(prop-2-yn-1-yl)amino]-1-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]hex-2-yl}-3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)benzamide 52 11-[(2S)-6-[methyl(prop-2-yn-1-yl)amino]-2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}hexyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 53 N-{(S)-4-methylamino-1-[(7-propoxy-benzothiazol-2-ylaminomethyl)-methyl]-butyl}-3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzamide 54 (3S)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-6-(methylamino)-N-(7-propoxy-1,3-benzothiazol-2-yl)hexanamide 55 (3S)-N-(4-fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-6-(methylamino)hexanamide 56 N-[4-fluoro-7-(3-fluoropropoxy)-1,3-benzothiazol-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 57 N-[4-fluoro-7-(2-fluoroethoxy)-1,3-benzothiazol-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 58 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(7-propoxy-benzothiazol-2-yl)-propionamide 59 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (7-propoxy-benzothiazol-2-yl)-amide 60 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (7-methoxy-4-methyl-benzothiazol-2-yl)-amide 61 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (7-methoxy-benzothiazol-2-yl)-amide 62 N-(4-fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 63 N-(4-chloro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 64 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-propoxypyrazolo[1,5-a]pyridin-2-yl}propionamide 65 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(4-propoxypyrazolo[1,5-a]pyridine-2-yl)-propionamide 66 N-{4-ethoxypyrazolo[1,5-a]pyrroline-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 67 N-[4-(3-fluoropropoxy)pyrazolo[1,5-a]pyrroline-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 68 N-[4-(2-fluoroethoxy)pyrazolo[1,5-a]pyrroline-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 69 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[4-(oxacyclobutane-3-yloxy)pyrazolo[1,5-a]pyridine-2-yl]propionamide 70 N-{4-cyclopropoxypyrazolo[1,5-a]pyrroline-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 71 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{1-methyl-4-propoxy-1H-pyrrolo[3,2-c]pyridin-2-yl}propionamide 72 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (4-methoxy-pyrazolo[1,5-a]pyridin-2-yl)-amide 73 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(4-methyl-7-propoxy-benzothiazol-2-yl)-propionamide 74 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-N-[2-(4-methyl-7-propoxy-benzothiazol-2-ylaminomethyl)-ethyl]-benzamide 75 3-(2-methyl-2H-tetrazolyl-5-yl)-N-[2-(7-propoxy-benzothiazol-2-ylaminomethyl)-ethyl]-benzamide 76 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[7-propoxy-4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propionamide 77 (2R)-2-amino-N-(4-fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 78 (S)-2-Hydroxy-3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(7-propoxy-benzothiazol-2-yl)-propionamide 79 N-(7-ethoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 80 (2S)-N-(7-ethoxy-1,3-benzothiazol-2-yl)-2-hydroxy-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 81 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-N-[2-(7-propoxy-benzothiazol-2-ylaminomethyl)-ethyl]-benzamide 82 (2R)-N-(7-ethoxy-1,3-benzothiazol-2-yl)-2-hydroxy-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 83 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(2-{10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl}ethyl)benzamide 84 2,2-Difluoro-N-(4-fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 85 3-{[7-(5-methyl-1,2,4-oxadiazole-3-yl)isoquinolin-1-yl]amino}-N-(1-methyl-7-propoxy-1H-1,3-benzodiazol-2-yl)propionamide 86 3-{[7-(5-methyl-1,2,4-oxadiazole-3-yl)isoquinolin-1-yl]amino}-N-(7-propoxy-1H-1,3-benzodiazol-2-yl)propionamide 87 8-(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl-1,1,2,2-d4)-1-(2,2,2-trifluoroethoxy-1,1-d2)-7,8-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrro-9(6H)-one-6,6,7,7-d4 88 3-(2-methyl-2H-tetrazolyl-5-yl)-N-(2-(9-oxo-1-(2,2,2-trifluoroethoxy-1,1-d2)-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrroline-8(9H)-yl-6,6,7,7-d4)ethyl-1,1,2,2-d4)benzamide

Example 90 : Testing the inhibitory activity of the compounds of the invention against HSET - HSET ADP-Glo assay S - 3 μM ATP Reagents: (stored at +4°C) - Paclitaxel Product No. TXD.01 2 mM in DMSO (from Universal Biologicals Cambridge). - Tubulin (preformed tubulin): Bovine brain Product No. MT001-XL Batch 025 10 mg/mL (from Universal Biologicals Cambridge).

Reagents: (stored at -80°C) - MT001-XL - Tubulin (preformed tubulin): bovine brain, reconstituted in the following buffer: 15 mM PIPES pH7, 1 mM MgCl ₂ , 20 μM paclitaxel (10 mg/mL aliquot) (from Universal Biologicals Cambridge). - HSET full length protein, current batch is FL HSET Prep1 (SEQ-000096_002-01_01) - Buffer is 20 mM Hepes pH 7.5, 200 mM NaCl, 2 mM TCEP, 5% glycerol (5 µL 10.2 µM aliquot)

Reagents: (stored at -20°C) - ADP-Glo Kinase Assay Kit (Promega Product No. V9102) 10,000 assay points - ADP-Glo Reagent (50 mL), Kinase Assay Reagent (100 mL), and Ultrapure ATP (10 mM) aliquots

Buffered stock solution (filtered and stored at room temperature for up to 1 month) - HEPES acid, 4-(2-hydroxyethyl)piperidinium-1-ethanesulfonic acid MW: 238, 238.3 mg/mL = 1M - 7149 mg/30 mL = 1M (with 5M NaOH, pH to 6.8) - PIPES, 1,4-piperidinium disodium ethanesulfonic acid MW: 302.4, 30.24 mg/mL = 100 mM; 907.2 mg/30 mL = 100 mM (with 5M NaOH, pH to 7, white cloudy suspension until pH changes) - EGTA, ethylene glycol-bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid MW: 380.35, 38.035 mg/mL = 100 mM - 1901.75 mg/50 mL = 100 mM (using 5M NaOH, pH to about 7), takes a long time to get the solution and pH stable - Triton-X-100, MW: 625, 62.5 mg/mL = 100 mM (6.25% w/v) (viscous, pipette Triton X-100 and Gilson, use trimmed pipette tip)

ECHO Protocol -Create an ECHO intermediate plate by adding 24.5 μL DMSO to rows 1 and 2 of an ECHO 384PP plate, and 40 μL DMSO to rows 23 and 24 -Add 100 nL compound/DMSO per well to a 384-well Proxi-Plate Plus (white) (Perkin Elmer Cat. No. 6008289) using the ECHO Dosing Protocol 100 nL Standard to proxi_8pt_200 μM.

Assay buffer (kept on ice): HEPES pH 6.8, MgCl ₂ , EGTA, Triton X-100, DTT, HPLC H ₂ O

Tubulin working solution (3.2): - 1 ml PM buffer: PIPES pH 7.0, MgCl ₂ , HPLC H ₂ O, paclitaxel, mix well and store at room temperature - Then add 26.4 μL 10 mg/ml tubulin to 724 μL of the above PM buffer to prepare 750 μL of tubulin working solution with 350 μg/mL tubulin (store at room temperature)

Prepare HSET enzyme solution (3.1) - Keep on ice - Add 1.33 μL 10.2 μM HSET Prep1 (SEQ-000096_002-01_01) to 1358 μL assay buffer to make a 10 nM stock solution for a 5 nM final assay concentration (1/1020 dilution).

HSET/Tubulin working solution (3.3) -Mix solutions 3.1 and 3.2 at a ratio of 2.5:1 (1214.3 μL 3.1 + 485.7 μL 3.2) and keep at room temperature for 15 minutes -3.2 is diluted 3.5 times and 3.1 is diluted 1.4 times

The blank solution is 357 μL 2XAB + 143 μL Tubulin working solution 3.2. (Same ratio as HSET/Tubulin working solution (3.3))

ATP working solution was 1 μL 10 mM ultrapure ATP (Promega kit) + 999 μL ddH ₂ O to give 10 μM ATP for a 3 μM final assay concentration, stored on ice.

Assay procedure in PROXIPLATE 384 PLUS White (Perkin Elmer) plates (Take 2.4 mL ADP Glo and 4.5 mL Kinase Assay Reagent from the refrigerator to warm to room temperature) - Add 3.5 μL of Blank Solution to the assay plate (row 12) - Add 3.5 μL of HSET/Tubulin Solution (3.3) (rows 1 to 11 and rows 13 to 24) - Centrifuge at 1000 rpm for 1 minute - (Pre-incubate enzyme and compound for 10 minutes)

The reaction was initiated by adding 1.5 μL of 10 μM ATP to give a final [HSET] of 5 nM, [ATP] of 3 nM and [Tubulin] of 70 μg/mL, centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 80 minutes.

After 80 minutes of incubation, the reaction was stopped by adding 5 μL of ADP-Glo reagent to all wells. Centrifugation was performed at 1000 rpm for 1 minute and incubation was performed at room temperature for 40 minutes.

In the dark/away from direct light, add 10 μL of Kinase Detection Reagent (KDR) to all wells, seal the plate with Topseal (Perkin Elmer Cat. No. 6050185) and centrifuge as above, and incubate covered with foil for 40 minutes at room temperature.

On New Envision, use the following protocol: US Luminescence 384, Read Luminescence.

result: Compound Example No. Combination HSET ADP GLO IC ₅₀ (µM) 1 0.13 2 0.074 3 0.06 4 0.14 5 0.064 6 0.01 7 0.067 8 0.034 9 0.012 10 0.008 11 0.008 12 0.008 13 0.016 14 0.016 15 0.003 16 0.002 17 0.006 18 0.003 19 0.007 20 6.5 twenty one 0.33 twenty two 0.23 twenty three 0.96 twenty four 0.24 25 0.002 26 0.002 27 0.002 28 0.003 29 0.001 30 0.005 31 0.001 32 0.002 33 0.001 34 0.002 35 ＜0.001 36 ＜0.001 37 0.003 38 0.008 39 0.009 40 1.346 41 0.016 42 0.017 43 0.004 44 0.002 45 0.007 46 0.001 47 0.001 48 0.043 49 0.654 50 1.214 51 0.503 52 0.036 53 0.014 54 0.008 55 0.006 56 0.008 57 0.012 58 0.005 59 0.193 60 0.33 61 0.358 62 0.008 63 0.014 64 0.015 65 0.024 66 0.094 67 0.045 68 0.203 69 0.835 70 0.104 71 1.079 72 1.216 73 0.008 74 0.048 75 0.017 76 0.105 77 0.048 78 0.002 79 0.007 80 0.011 81 0.027 82 0.006 83 0.011 84 0.022 85 0.169 86 0.027 87 0.001 88 0.003

Example 91 : Injection vials A solution of 100 g of the compound of the present invention and 5 g of sodium dihydrogen phosphate in 3 L of deionized water was adjusted to pH 6.5 using 2N hydrochloric acid, filtered under aseptic conditions, transferred to injection vials, freeze-dried under aseptic conditions and sealed under aseptic conditions. Each injection vial contained 5 mg of the compound of the present invention.

Example 92 : Solution A solution was prepared from 1 g of the compound of the invention, 9.38 g NaH ₂ PO ₄ . 2H ₂ O, 28.48 g Na ₂ HPO ₄ . 12 H ₂ O and 0.1 g benzyl ammonium chloride in 940 mL of deionized water. The pH was adjusted to 6.8, and the solution was made up to 1 L and sterilized by irradiation.

Example 93 : Ampoules A solution of 1 kg of the compound of the present invention in 60 L of deionized water was filtered under sterile conditions, transferred into ampoules, freeze-dried under sterile conditions and sealed under sterile conditions. Each ampoule contained 10 mg of the compound of the present invention.

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Claims (19)

A compound of formula I, Where W represents wherein 1 to 4 H atoms may be replaced by D; R ¹ represents Hal, A or OA, R ² represents X represents CH or N, A represents H, F, OH, _NH2 or an unbranched or branched alkyl or cycloalkyl group having 1 to 12 C atoms, the unbranched or branched alkyl or cycloalkyl group may be substituted by ^R4 and wherein two adjacent CH- and/or _CH2- groups may form a double bond or a triple bond, and wherein one or two non-adjacent CH- and/or _CH2- groups may be replaced by N-, O- and/or S-atoms and wherein 1 to 7 H atoms may be replaced by D, F or Cl, ^R3 represents H or A, ^R4 represents H or an unbranched or branched alkyl group having 1 to 4 C atoms, Hal represents F, Cl, Br or I and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios. For the compound of claim 1, W represents and R ¹ , R ² , R ³ , R ⁴ , X and A have the meanings as in claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios. The compound of claim 1 or 2, wherein W represents and R ¹ , R ² , R ³ , R ⁴ , X and A have the meanings as in claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios. The compound of any of the preceding claims, wherein R ¹ represents OA and W, R ² , R ³ , R ⁴ , X and A have the meanings as in claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios. A compound as in any of the preceding claims, wherein R ¹ represents OA, wherein A represents an unbranched or branched alkyl group, wherein 1 to 3 H atoms may be replaced by D, F or Cl and W, R ² , R ³ , R ⁴ , X and A have the meanings as in claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios. A compound as claimed in any of the preceding claims, wherein R ² represents and W, R ¹ , R ³ , R ⁴ , X and A have the meanings as in claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios. A compound as claimed in any of the preceding claims, wherein R ³ represents 5-methyloxadiazole or 2-methyltetrazolyl and W, R ¹ , R ² , R ⁴ , X and A have the meanings as in claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios. A compound as claimed in any of the preceding claims, wherein R ³ represents 5-methyloxadiazole and W, R ¹ , R ² , R ⁴ , X and A have the meanings as in claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios. A compound as claimed in any of the preceding claims, wherein R ⁴ represents methyl and W, R ¹ , R ² , R ³ , X and A have the meanings as in claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios. A compound selected from the group consisting of: 1 N-{4-ethoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 2 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-[4-(propan-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propanamide 3 N-{4-cyclobutoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 4 N-[4-(But-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 5 N-[4-(2,2-difluoroethoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 6 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-[4-(2,2,2-trifluoroethoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propanamide 7 N-[4-(3,3-difluorocyclobutoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 8 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-{4-[(1,1,1-trifluoropropan-2-yl)oxy]-[1,3]thiazolo[5,4-c]pyridin-2-yl}propanamide 9 N-{4-ethoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 10 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-propoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}propionamide 11 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[4-(propan-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propionamide 12 N-[4-(But-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 13 N-{4-cyclobutoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 14 N-[4-(3,3-difluorocyclobutoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 15 N-[4-(3-fluoropropoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 16 N-[4-(2,2-difluoropropoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 17 N-[4-(2,2-difluoroethoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 18 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[4-(2,2,2-trifluoroethoxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propionamide 19 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-[(1,1,1-trifluoropropan-2-yl)oxy]-[1,3]thiazolo[5,4-c]pyridin-2-yl}propionamide 20 (1s,3s)-N-{4-methoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}cyclobutane-1-carboxamide twenty one (1s,3s)-N-{4-ethoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}cyclobutane-1-carboxamide twenty two (1s,3s)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-propoxy-[1,3]thiazolo[5,4-c]pyridin-2-yl}cyclobutane-1-carboxamide twenty three N-{1-ethoxypyrrolo[1,2-a]pyrrol-7-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide twenty four 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{1-propoxypyrrolo[1,2-a]pyrrol-7-yl}propanamide 25 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 26 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 27 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-11-yl](1,1,2,2-2H4)ethyl}benzamide 28 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-11-yl](1,1,2,2-2H4)ethyl}benzamide 29 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}(1,1,2,2-2H4)ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 30 3-(5-methyl-2H-1,2,3,4-tetrazolyl-2-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 31 11-(2-{[7-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 32 11-(2-{[7-(5-methyl-2H-1,2,3,4-tetrazolyl-2-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 33 11-(2-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 34 3-Fluoro-5-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 35 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)(12,12,13,13-2H4)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-11-yl]ethyl}benzamide 36 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-6-(2,2,2-trifluoroethoxy)(12,12,13,13-2H4)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 37 11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-6-propoxy-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 38 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-(2-{10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-11-yl}ethyl)benzamide 39 1-(Dodeca-11-yn-1-yloxy)-8-(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)-7,8-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrroline-9(6H)-one 40 N-(2-{6-chloro-10-oxo-1,5,11-triazatricyclo[7.4.0.0^{2,7}]tridec-2,4,6,8-tetraen-11-yl}ethyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide 41 N-{2-[6-(3-fluoropropoxy)-10-oxo-1,5,11-triazatricyclo[7.4.0.0^{2,7}]tridec-2,4,6,8-tetraen-11-yl]ethyl}-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide 42 N-{2-[6-(2,2-difluoroethoxy)-10-oxo-1,5,11-triazatricyclo[7.4.0.0^{2,7}]tridec-2,4,6,8-tetraen-11-yl]ethyl}-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide 43 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-{2-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.0^{2,7}]tridec-2,4,6,8-tetraen-11-yl]ethyl}benzamide 44 6-(3-Fluoropropoxy)-11-(2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}ethyl)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-10-one 45 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-(2-{10-oxo-6-[(1,1,2,2,3,3,3-2H7)propoxy]-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-11-yl}ethyl)benzamide 46 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-(2-{10-oxo-6-[2,2,2-trifluoro(1,1-2H2)ethoxy]-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl}ethyl)benzamide 47 N-(2-(1-(Dodeca-11-yn-1-yloxy)-9-oxo-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrrol-8(9H)-yl)ethyl)-3-(2-methyl-2H-tetrazol-5-yl)benzamide 48 11-(3-amino-2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propyl)-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 49 (S)-3-(2-methyl-2H-tetrazol-5-yl)-N-(6-(methylamino)-1-(9-oxo-1-(2,2,2-trifluoroethoxy)-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrrol-8(9H)-yl)hexan-2-yl)benzamide 50 3-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)-N-[6-(methylamino)-1-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2(7),3,5,8-tetraen-11-yl]hexan-2-yl]benzamide 51 N-{6-[methyl(prop-2-yn-1-yl)amino]-1-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02.7]tridec-2,4,6,8-tetraen-11-yl]hex-2-yl}-3-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)benzamide 52 11-[(2S)-6-[methyl(prop-2-yn-1-yl)amino]-2-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}hexyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7[7.4.0.02.7]trideca-2,4,6,8-tetraen-10-one 53 N-{(S)-4-methylamino-1-[(7-propoxy-benzothiazol-2-ylaminomethyl)-methyl]-butyl}-3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzamide 54 (3S)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-6-(methylamino)-N-(7-propoxy-1,3-benzothiazol-2-yl)hexanamide 55 (3S)-N-(4-Fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-6-(methylamino)hexanamide 56 N-[4-Fluoro-7-(3-fluoropropoxy)-1,3-benzothiazol-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 57 N-[4-Fluoro-7-(2-fluoroethoxy)-1,3-benzothiazol-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 58 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(7-propoxy-benzothiazol-2-yl)-propionamide 59 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (7-propoxy-benzothiazol-2-yl)-amide 60 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (7-methoxy-4-methyl-benzothiazol-2-yl)-amide 61 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (7-methoxy-benzothiazol-2-yl)-amide 62 N-(4-Fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 63 N-(4-chloro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 64 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{4-propoxypyrazolo[1,5-a]pyridin-2-yl}propionamide 65 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(4-propoxypyrazolo[1,5-a]pyrrolidone-2-yl)-propionamide 66 N-{4-ethoxypyrazolo[1,5-a]pyrrolidone-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 67 N-[4-(3-fluoropropoxy)pyrazolo[1,5-a]pyrrolidone-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 68 N-[4-(2-Fluoroethoxy)pyrazolo[1,5-a]pyrroline-2-yl]-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 69 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[4-(oxacyclobutane-3-yloxy)pyrazolo[1,5-a]pyrrolidone-2-yl]propanamide 70 N-{4-cyclopropoxypyrazolo[1,5-a]pyrrolidone-2-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 71 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{1-methyl-4-propoxy-1H-pyrrolo[3,2-c]pyridin-2-yl}propionamide 72 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-cyclobutanecarboxylic acid (4-methoxy-pyrazolo[1,5-a]pyridin-2-yl)-amide 73 3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(4-methyl-7-propoxy-benzothiazol-2-yl)-propionamide 74 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-N-[2-(4-methyl-7-propoxy-benzothiazol-2-ylaminocarbonyl)-ethyl]-benzamide 75 3-(2-Methyl-2H-tetrazol-5-yl)-N-[2-(7-propoxy-benzothiazol-2-ylaminomethyl)-ethyl]-benzamide 76 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-[7-propoxy-4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propionamide 77 (2R)-2-amino-N-(4-fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 78 (S)-2-Hydroxy-3-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-isoquinolin-1-ylamino]-N-(7-propoxy-benzothiazol-2-yl)-propionamide 79 N-(7-ethoxy-1,3-benzothiazol-2-yl)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 80 (2S)-N-(7-ethoxy-1,3-benzothiazol-2-yl)-2-hydroxy-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 81 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-N-[2-(7-propoxy-benzothiazol-2-ylaminomethyl)-ethyl]-benzamide 82 (2R)-N-(7-ethoxy-1,3-benzothiazol-2-yl)-2-hydroxy-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propionamide 83 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(2-{10-oxo-6-propoxy-1,5,11-triazatricyclo[7.4.0.02.7]trideca-2,4,6,8-tetraen-11-yl}ethyl)benzamide 84 2,2-Difluoro-N-(4-fluoro-7-propoxy-1,3-benzothiazol-2-yl)-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propionamide 85 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-(1-methyl-7-propoxy-1H-1,3-benzodiazol-2-yl)propionamide 86 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-(7-propoxy-1H-1,3-benzodiazol-2-yl)propionamide 87 8-(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl-1,1,2,2-d4)-1-(2,2,2-trifluoroethoxy-1,1-d2)-7,8-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrroline-9(6H)-one-6,6,7,7-d4 88 3-(2-methyl-2H-tetrazol-5-yl)-N-(2-(9-oxo-1-(2,2,2-trifluoroethoxy-1,1-d2)-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrrol-8(9H)-yl-6,6,7,7-d4)ethyl-1,1,2,2-d4)benzamide and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios. A pharmaceutical preparation comprising at least one compound according to any one of claims 1 to 10 and/or its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios. The pharmaceutical preparation of claim 11, which comprises additional excipients and/or adjuvants. A pharmaceutical preparation comprising at least one compound according to any one of claims 1 to 10 and/or its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios), and at least one additional pharmaceutically active compound. A method for preparing a pharmaceutical preparation, wherein a compound as claimed in any one of claims 1 to 10 and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios) is formulated into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant. A medicament comprising at least one compound according to any one of claims 1 to 10 and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios), for use in the treatment and/or prevention of physiological and/or pathological conditions. A medicament comprising at least one compound according to any one of claims 1 to 10 and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios) for use in the treatment and/or prevention of physiological and/or pathological conditions selected from the group consisting of hyperproliferative diseases and disorders. The medicament for use as claimed in claim 16, wherein the hyperproliferative disease or condition is cancer. The medicament for use of claim 17, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute granulocytic leukemia, adrenocortical carcinoma, bladder cancer, brain cancer, breast cancer, cervical hyperplasia, cervical cancer, choriocarcinoma, chronic granulocytic leukemia, chronic lymphocytic leukemia, colon cancer, endometrial cancer, esophageal cancer, essential thrombocythemia, genitourinary tract cancer, neuroglioma, neuroglioblastoma, hairy cell leukemia, head and neck cancer, Hodgkin's disease disease), Kaposi's sarcoma, lung cancer, lymphoma, malignant carcinoid tumor, malignant hypercalcemia, malignant melanoma, malignant insulinoma, medullary thyroid carcinoma, melanoma, multiple myeloma, mycosis fungoides, myeloid and lymphocytic leukemia, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, polycythemia vera, primary brain cancer, essential macroglobulinemia, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, skin cancer, small cell lung cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, testicular cancer, thyroid cancer, and Wilms' tumor. A set consisting of the following individual packages: a) an effective amount of a compound as claimed in any one of claims 1 to 10 and/or its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, and b) an effective amount of another pharmaceutically active compound.