Substituted bicyclic and tricyclic HSET inhibitors

Abstract

The present invention relates to substituted bicyclic and tricyclic systems of general formula I, and the use of the compounds of this invention for the treatment and / or prevention of hyperproliferative diseases and disorders in mammals, particularly humans, and pharmaceutical compositions containing such compounds.

Description

[Technical Field]

[0001] The present invention relates to compounds of general formula I, [ka] and uses of the compounds of this invention for the treatment and / or prevention of hyperproliferative diseases and disorders (such as cancer) in mammals, particularly humans, and pharmaceutical compositions containing such compounds. [Background technology]

[0002] Background of the Invention DNA replication, followed by equal chromosome segregation, ensures the 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 acts as the dominant site for spindle pole formation (Meunier and Vernos, 2012). Centrosome duplication is also tightly regulated and occurs concomitantly with DNA replication, ensuring the generation of two functional centrosomes that form the poles of the mitotic spindle (Sharp et al., 2000). Microtubule (MT) motor proteins play a central role in the assembly of a functional mitotic spindle (Cai et al., 2010; Ganem and Compton, 2004). One such protein, the minus-end MT motor HSET (encoded by KIFC1 in humans and Kifc5a in mice), has attracted attention in cancer due to its effects on cell division (Cai et al., 2010; Goshima et al., 2005). Although the importance of centrosomes, particularly HSET, for bipolar spindle formation has received considerable attention in recent years, the precise role of HSET in this process remains a topic of debate (Mahoney et al., 2006; Tillement et al., 2009). Recent reports have linked centrosome amplification and high HSET expression to chromosome missegregation and aneuploidy, hallmarks of human cancer (Marx et al., 2009). Centrosome amplification disrupts asymmetric cell division in neuroblastoma cells and drives tumorigenesis in fly models (Basto et al., 2008). Supernumerary centrosomes are also found in most solid tumor types and constitute a marker of malignancy in breast, brain, prostate, cervical, kidney, and bladder cancers (Chan, 2011). Thus, it is becoming increasingly clear that supernumerary centrosomes are not only a sign of malignancy but can also lead to neoplastic transformation (Ogden et al., 2013). However, not all cells with amplified centrosomes undergo multipolar mitosis, and centrosome clustering is a key mechanism by which cells with extra centrosomes acquire a pseudo-bipolar spindle (Basto et al., 2008; Ganem et al., 2009).

[0003] Although centrosome clustering prevents multipolar division and cell death, it prolongs mitosis and increases the frequency of chromosome missegregation as a result of merotelic kinetochore attachment (Ganem et al., 2009; Kwon et al., 2008; Yang et al., 2008). Based on previous studies, centrosome clustering may prove a weakness in cancer cells with supernumerary centrosomes (Basto et al., 2008), and growing evidence suggests that inhibiting centrosome clustering may offer a novel therapeutic strategy for tumors with a high incidence of centrosome amplification (Jordan and Wilson, 2004; Ogden et al., 2012).

[0004] A key protein known to be essential for centrosome clustering is HSET (Ncd in flies). HSET is required for tumor cell clustering of supernumerary centrosomes (Basto et al., 2008; Kwon et al., 2008). HSET is a member of the kinesin-14 family of MT motor proteins, a force-generating enzyme that facilitates movement along intracellular MTs (Mountain et al., 1999) and transports organelles, protein complexes, and mRNAs along microtubules in an ATP-dependent manner. HSET is a minus-end-directed kinesin motor that exerts inward force by cross-linking and sliding microtubules (Walczak et al., 1997; Cai et al., 2009; Rath et al., 2012). Although the exact role of HSET in cell division remains unclear, previous evidence suggests that HSET is essential for the survival of cancer cells but not for the survival of normal cells (Ganem et al., 2009; Kwon et al., 2008). High HSET expression levels are strongly correlated with brain metastasis of non-small cell lung cancer, suggesting a link between HSET, centrosome amplification, and tumorigenesis (Cai et al., 2010; Gordon et al., 2001; Grinberg-Rashi et al., 2009). Knockdown of HSET in normal retinal pigment epithelial 1 (RPE-1) cells or the breast cancer cell line MCF-7 (which do not have a high incidence of centrosome amplification) does not inhibit bipolar spindle 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, respectively, prevents centrosome clustering and induces cell death by multipolar anaphases (Kwon et al., 2008).Therefore, the above findings suggest HSET as a target of interest in cancer treatment (Basto et al., 2008; Kraljevic Pavelic et al., 2011; Kramer et al., 2011; Kwon et al., 2008).

[0005] Multiple studies have shown that HSET deficiency increases the frequency of cell death and multipolarization in cells with supernumerary centrosomes, but not in normal cells. For example, HSET deficiency induces spindle multipolarity and selectively sensitizes centrosome-amplified ER- breast cancer cell lines, including triple-negative breast cancer (TNBC), to cell death (Patel et al., 2018). HSET deficiency has been identified as a selective inducer of cytotoxicity in centrosome-amplified cancer cells (Drosopoulos et al., 2014). Additionally, HSET overexpression correlates with poor prognosis and resistance to docetaxel in breast cancer (De et al., 2009; Li et al., 2015), ovarian adenocarcinoma patients (Pawar et al., 2014), and numerous 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).

[0006] A wide range of tumors, including those with centrosome amplification, are treated with cytotoxic microtubule-targeting drugs (e.g., taxol, eribulin). Although these drugs induce temporary remissions, they typically exhibit severe side effects and the development of drug resistance, leading to early relapse. More recently, agents targeting kinesin motor proteins, such as Eg5 inhibitors, have been investigated to treat various human tumors (which induce monopolar spindles, a phenotype opposite to HSET inhibition) and to target all rapidly dividing cells (including myeloid cells). Consequently, they suffer from dose-limiting toxicity, similar to other antimitotic treatments. In contrast, HSET inhibitors are expected to exhibit reduced toxicity by selectively killing cells with centrosome amplification, while cells with a normal number of centrosomes would remain unaffected (Ganem et al., 2009; Patel et al., 2015). Together, these data provide support for developing drugs that selectively inhibit HSET to target centrosome-amplified tumors ( Myers and Collins, 2016 ).

[0007] Examples of small molecule HSET inhibitors have been described in the literature. AZ82 is an ADP / ATP-competitive inhibitor that has been shown to be selective for a panel of nine other kinesins, including Eg5 (Wu et al., 2013). AZ82 inhibits microtubule-stimulated HSET ATPase activity in biochemical assays (IC 50 = 0.3 μM), induced the formation of multipolar spindles and mitotic catastrophe in cells with amplified centrosomes. CW069 was an inhibitor of HSET (IC 50 = 75 μM) (Watts et al., 2013). SR31527 also inhibited HSET biochemically (IC 50 = 6.6 μM) (Zhang et al., 2016). More information can be found in WO09155025 and WO15085088.

[0008] Thus, there remains a need for therapies for the treatment and prevention of hyperproliferative diseases and disorders such as cancer. Therefore, the goal was to find HSET inhibitors that are potential therapeutic agents for the treatment of cancer diseases. Summary of the Invention

[0009] SUMMARY OF THE INVENTION It has surprisingly been found that the compounds according to the present invention are highly selective and effective inhibitors of HSET and thus the compounds of the present invention can be used in the treatment of hyperproliferative diseases and disorders such as cancer.

[0010] The present invention relates to compounds of general formula I, [ka] During the ceremony, W is [ka] wherein 1 to 4 H atoms may be replaced by D; R 1 displays Hal, A, or OA, R 2 teeth, [ka] X indicates CH or N, A is H, F, OH, NH2, or R 4 represents an unbranched or branched alkyl or cycloalkyl having 1 to 12 C atoms optionally substituted by, wherein two adjacent CH and / or CH groups may form a double or triple bond, and wherein one or two non-adjacent CH and / or CH groups may be replaced by an N atom, an O atom, and / or an S atom, and wherein 1 to 7 H atoms may be replaced by D, F or CI, R 3 displays H or A, R 4 denotes H or unbranched or branched alkyl with 1 to 4 C atoms, Hal denotes F, Cl, Br, or I; and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

[0011] A preferred embodiment of the present invention is a compound of formula I: During the ceremony, W is [ka] and R 1 , R 2 , R 3 , R 4 , X, and A have the meanings as disclosed above; and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

[0012] A preferred embodiment of the present invention is a compound of formula I: During the ceremony, W is [ka] and R 1 , R 2 , R 3 , R 4 , X, and A have the meanings as disclosed above; and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

[0013] A preferred embodiment of the present invention is a compound of formula I: During the ceremony, R 1 indicates OA, and R 1 , R 2 , R 3 , R 4 , X, and A have the meanings as disclosed above; and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

[0014] A preferred embodiment of the present invention is a compound of formula I: During the ceremony, R 1 represents OA, where A represents unbranched or branched alkyl, in which 1 to 3 H atoms may be replaced by D, F, or Cl, and R 1 , R 2 , R 3 , R 4 , X, and A have the meanings as disclosed above; and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

[0015] A preferred embodiment of the present invention is a compound of formula I: During the ceremony, R 2 teeth, [ka] and W.R. 1 , R 3 , R 4 , X, and A have the meanings as disclosed above; and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

[0016] A preferred embodiment of the present invention is a compound of formula I: During the ceremony, R 3 denotes 5-methyloxadiazole or 2-methyltretrazol, and W.R. 1 , R 2 , R 4 , X, and A have the meanings as disclosed above; and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

[0017] A preferred embodiment of the present invention is a compound of formula I: During the ceremony, R 3 represents 5-methyloxadiazole, and W.R. 1 , R 2 , R 4 , X, and A have the meanings as disclosed above; and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

[0018] A preferred embodiment of the present invention is a compound of formula I: During the ceremony, R 4 denotes methyl, and W.R. 1 , R 2 , R 3 , X, and A have the meanings as disclosed above; and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

[0019] The present invention preferably relates to a compound selected from the group consisting of: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any proportion.

[0020] Furthermore, the following abbreviations have the following meanings: Boc ter-butoxycarbonyl CBZ benzyloxycarbonyl DNP 2,4-dinitrophenyl FMOC 9-Fluorenylmethoxycarbonyl imi-DNP 2,4-dinitrophenyl at the 1-position of the imidazole ring OMe methyl ester POA Phenoxyacetyl DCCI Dicyclohexylcarbodiimide HOBt 1-hydroxybenzotriazole

[0021] The present invention further relates to pharmaceutical preparations comprising one or more compounds according to the invention and / or one of their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, as well as mixtures thereof in any ratio. The invention also relates to pharmaceutical preparations according to the invention of this type which contain further excipients and / or adjuvants. Additionally, the present invention also relates to the above pharmaceutical preparations according to the invention, which comprise at least one further medicament active compound. Pharmaceutically or physiologically acceptable derivatives are understood to mean, for example, salts of the compounds of the present invention, as well as so-called prodrug compounds. Prodrug compounds are understood to mean derivatives of the compounds of the present invention that are modified, for example, with alkyl or acyl groups (see also amino- and hydroxyl-protecting groups below), sugars, or oligopeptides, and that are rapidly cleaved or released in the organism to form active molecules. These also include biodegradable polymer derivatives of the compounds of the present invention, as described, for example, in Int. J. Pharm. 115 (1995), 61-67.

[0022] The compounds of the present invention can be used in their final non-salt form. On the other hand, the present invention also covers 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. Most of the pharmaceutically acceptable salt forms of the compounds of the present invention are prepared by conventional methods. When the compounds of the present invention contain a carboxyl group, a suitable salt can be formed by reacting the compounds of the present invention with a suitable base to give the corresponding base addition salt. Such bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline 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-methylglutamine. Aluminum salts of the compounds of the present invention are also included. Furthermore, base salts of the compounds of the present invention include, but are not intended to represent a limitation, aluminum, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese(III), manganese(II), potassium, sodium, and zinc salts.

[0023] Of the above salts, preferred are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium. Salts of the compounds of the present invention derived from pharmaceutically acceptable organic non-toxic bases include primary amines, secondary amines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethyl ... These include, but are not intended to represent a limitation, salts of diamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris(hydroxymethyl)methylamine (tromethamine).

[0024] As mentioned, pharmaceutically acceptable base addition salts of the compounds of the present invention are formed with 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.

[0025] Base addition salts of compounds of the invention are prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conventional manner. The free acid may be regenerated by bringing the salt form into contact with an acid and isolating the free acid in a conventional manner. The free acid forms differ in some respects from their corresponding salt forms with respect to certain physical properties, such as solubility in polar solvents; however, for purposes of this invention, the salts otherwise correspond to their respective free acid forms. In view of the above definition, it can be seen that in this context the term "pharmaceutically acceptable salt" is understood to mean the active compound of the present invention, including the compound of the present invention in one of its salt forms (especially when this salt form confers improved pharmacokinetic properties to the active compound compared to the free form of the active compound or any other salt form of the active compound previously used).The pharmaceutically acceptable salt form of the active compound can also provide the active compound with desired pharmacokinetic properties that it did not previously have, and can even have a positive effect on the pharmacodynamics of the active compound in relation to its therapeutic effectiveness in the body.

[0026] Solvates of the compounds of the invention are understood to mean adducts of the compounds of the invention with inert solvent molecules, which form owing to their mutual attractive force. Solvates are, for example, hydrates, such as mono- or dihydrates, or alcoholates, i.e., addition compounds with alcohols, such as, for example, methanol or ethanol. All physiologically acceptable salts, derivatives, solvates and stereoisomers of these compounds, as well as mixtures thereof in any proportion, also fall within the scope of the present invention.

[0027] Because the compounds of the present invention may contain one or more centers of chirality, all stereoisomers, enantiomers, diastereomers, etc. of the compounds of the present invention are also claimed in the present invention. The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.

[0028] The compounds of the present invention may be chiral due to their molecular structure and may consequently exist in various enantiomeric forms. They may therefore be in racemic or optically active form. Since the pharmaceutical efficacy of the racemates or stereoisomers of the compounds of the present invention may differ, it may be desirable to use enantiomers. In these cases, the final products, and even intermediates, may be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art or already employed as such in synthesis.

[0029] Pharmaceutically or physiologically acceptable derivatives are understood to mean, for example, salts of the compounds according to the invention, as well as so-called prodrug compounds. Prodrug compounds are understood to mean compounds of the invention that are modified, for example, with alkyl or acyl groups (see also amino- and hydroxyl-protecting groups below), sugars, or oligopeptides, and are rapidly cleaved or liberated in the organism to form effective 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.

[0030] Suitable acid addition salts are all physiologically or pharmacologically acceptable inorganic or organic salts of acids, such as halides, especially hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methylsulfonates or p-toluenesulfonates.

[0031] Very particular preference is given to the hydrochlorides, trifluoroacetates or bistrifluoroacetates of the compounds according to the invention. Solvates of the compounds of the invention are understood to mean adducts of inert solvent molecules onto the compounds of the invention, which form as a result of their mutual attractive force. Solvates are, for example, hydrates, such as mono- or dihydrates, or alcoholates, i.e., addition compounds with alcohols (such as, for example, methanol or ethanol).

[0032] Furthermore, the compounds of the present invention are intended to include isotopically labeled forms thereof. Isotopically labeled forms of the compounds of the present invention are identical to the compounds except for the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of most naturally occurring atoms. Examples of isotopes that are readily commercially available 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: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively. Compounds of the present invention, prodrugs thereof, or pharmaceutically acceptable salts of either thereof, that contain one or more of the above isotopes and / or other isotopes of other atoms are 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, 3 H or 14 Isotopically labeled compounds of the present invention incorporating radioactive isotopes such as C are suitable for use in medicament and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14C) are particularly preferred due to their simple preparation and excellent detectability. Heavier isotopes (e.g., deuterium ( 2 Incorporation of H) into compounds of the present invention has therapeutic advantages due to the higher metabolic stability of the isotopically labeled compounds. Higher metabolic stability translates directly into increased in vivo half-life or lower dosages, which will represent a preferred embodiment of the present invention under most circumstances. Isotopically labeled compounds of the present invention can generally be prepared by carrying out the procedures disclosed in the synthetic schemes and related descriptions herein, in the Examples section, and in the Preparations section, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0033] Deuterium ( 2 H) can also be incorporated into the compounds of the present invention. The primary kinetic isotope effect is the change in the rate of a chemical reaction due to the exchange of an isotope nucleus, which is caused secondarily by the change in the ground state energy required for covalent bond formation after this isotope exchange. The exchange of a heavier isotope usually results in a lowering of the ground state energy for the chemical bond, which in turn causes a reduction in the rate of rate-limiting bond breaking. If the bond breaking occurs in or near a saddle point region along the coordinate of a multi-product reaction, the product distribution ratio can be substantially altered. To illustrate: when deuterium is attached to a carbon atom at a non-exchangeable position, k M / k D A rate difference of 2 to 7 is typical. If this rate difference is successfully applied to an oxidation-prone compound of the present invention, the in vivo profile of the compound may thereby be dramatically altered, resulting in improved pharmacokinetic properties.

[0034] When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while retaining desired in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are prone to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information about the course of this type of oxidative metabolism, which in turn allows for the rational design of deuterated compounds of the present invention with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profiles of the compounds of the present invention are thereby obtained, improving in vivo half-life (T1 / 2), the concentration at maximum therapeutic effect (C max ), area under the dose-response curve (AUC), and F; and quantitatively in terms of reduced clearance, dose, and material cost.

[0035] The following is intended to illustrate what has been described above: Compounds of the present invention having multiple potential attack sites for oxidative metabolism (e.g., benzylic hydrogen atoms and hydrogen atoms attached to nitrogen atoms) are prepared as a series of analogs in which various combinations of hydrogen atoms are replaced with deuterium atoms (so that some, most, or all of these hydrogen atoms can be replaced with deuterium atoms). Determination of half-life allows for a convenient and accurate determination of the extent to which resistance to oxidative metabolism has been improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as a result of this type of deuterium-hydrogen exchange.

[0036] The replacement of hydrogen with deuterium in the compounds of the invention can also be used to achieve favorable modification of the metabolic spectrum of the starting compound to reduce or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (CH) bond cleavage, it can be reasonably expected that a deuterated analog will significantly reduce or eliminate the production of the undesired metabolite, even if the specific oxidation is not the rate-limiting step. Further state-of-the-art information on deuterium-hydrogen exchange is given, 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.

[0037] The present invention also relates to mixtures of the compounds of the present invention according to the present 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, 1:100 or 1:1000). These are particularly preferably mixtures of two stereoisomeric compounds. However, preference is also given to mixtures of two or more compounds of the present invention. Additionally, the present invention relates to a process for the preparation of the compounds of the invention, characterized in that a) a base of a compound of the invention is converted into one of its salts by treatment with an acid, or b) An acid of a compound of the invention is converted into one of its salts by treatment with a base. It is also possible in each case to carry out the reactions stepwise and to adapt the protecting group concept to modify the order of ligation of the building blocks.

[0038] The starting materials or compounds are generally known. If they are novel, they can be prepared by methods known per se. If desired, the starting materials can also be formed in situ not by isolating them from the reaction mixture, but instead by immediately converting them further to the compounds of the invention.

[0039] The compounds of the present invention are preferably obtained by liberating them from their functional derivatives by solvolysis, especially by hydrolysis or hydrogenolysis.Preferred starting materials for solvolysis or hydrogenolysis contain correspondingly protected amino, carboxyl, and / or hydroxyl groups in place of one or more free amino, carboxyl, and / or hydroxyl groups, preferably those bearing an amino-protecting group in place of the H atom connected to the N atom.Furthermore, preferred starting materials are those bearing a hydroxyl-protecting group in place of the H atom of the hydroxyl group.Preferred are also starting materials bearing a protected carboxyl group in place of a free carboxyl group.It is also possible for multiple identically or differently protected amino, carboxyl, and / or hydroxyl groups to be present in the starting material molecule.When the protecting groups present are different from each other, they can in many cases be selectively cleaved off.

[0040] The term "amino-protecting group" is generally known and refers to a group suitable for protecting (blocking) an amino group against chemical reaction, but which can be easily removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, inter alia, unsubstituted or substituted acyl groups, as well as unsubstituted or substituted aryl groups (e.g., 2,4-dinitrophenyl) or aralkyl groups (e.g., benzyl, 4-nitrobenzyl, triphenylmethyl). The type and size of the amino-protecting group, which is removed after the desired reaction or reaction sequence, are not critical, although preferred are those having 1 to 20, especially 1 to 8, carbon atoms. The term "acyl group" should be understood in the broadest sense in relation to the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic, or heterocyclic carboxylic or sulfonic acids, especially alkoxycarbonyl groups, aryloxycarbonyl groups, and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl, buturyl, aralkanoyl, such as phenylacetyl, aroyl, such as benzoyl or toluyl, aryloxyalkanoyl, such as phenoxyacetyl, alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, aralkoxycarbonyl, such as CBZ, 4-methoxybenzyloxycarbonyl, or FMOC. Preferred acyl groups are CBZ, FMOC, benzyl, and acetyl.

[0041] The terms "acid-protecting group" or "carboxy-protecting group" are also commonly known and refer to groups suitable for protecting (blocking) the -COOH group against chemical reaction, but which can be easily removed after the desired chemical reaction has been carried out elsewhere in the molecule. It is typical to use esters instead of free acids, for example substituted and unsubstituted alkyl esters (such as methyl, ethyl, tert-butyl, and their substituted derivatives), substituted and unsubstituted benzyl esters or silyl esters. The type and size of the acid-protecting group are not critical, but preferred are those having 1 to 20, especially 1 to 10, C atoms.

[0042] The term "hydroxyl protecting group" is also commonly known and refers to a group suitable for protecting (blocking) a hydroxyl group against chemical reaction, 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, as well as alkyl groups. The type and size of the hydroxyl protecting groups are not critical, but preferred are those having 1 to 20, especially 1 to 10, carbon atoms. Examples of hydroxyl protecting groups are, among others, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, and acetyl, where benzyl and acetyl are preferred. Further representative examples of amino-, acid-, and hydroxyl-protecting groups can be found, for example, in "Greene's Protective Groups in Organic Synthesis", fourth edition, Wiley-Interscience, 2007.

[0043] Functional derivatives of the compounds of the invention, which are to be used as starting materials, may be prepared by known methods of amino acid and peptide synthesis, for example as described in the standard works and patent applications.

[0044] The compounds of the present invention are liberated from their functional derivatives using, for example, strong acids, advantageously trifluoroacetic acid or perchloric acid, but also other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic acids such as trichloroacetic acid, or sulfonic acids such as benzoyl- or p-toluenesulfonic acid, depending on the protecting group used. The presence of additional inert solvents and / or catalysts is possible, but not necessarily required. Depending on the respective synthetic route, the starting materials may optionally be reacted in the presence of an inert solvent.

[0045] 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 due to substitution on the indole nitrogen), tetrahydrofuran (THF), or dioxane; glycol ethers, such as ethylene glycol monomethyl 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 acid anhydrides, such as acetic acid or acetic anhydride; nitro compounds, such as nitromethane or nitrobenzene, optionally in mixtures with each other or with water. The amount of solvent is not critical; 10 g to 500 g of solvent can preferably be added per 1 g of the compound of the invention to be reacted.

[0046] It may also be advantageous to add an acid-binding agent, such as an alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate, or other alkali or alkaline earth metal salt of a weak acid, preferably the potassium, sodium, or calcium salt, or an organic base, such as triethylamine, dimethylamine, pyridine, or quinoline, or an excess of an amine component.

[0047] The resulting compounds according to the present invention can be separated from the corresponding solution in which they were prepared (e.g., by centrifugation and washing) and stored in a separate composition after separation, or they can remain directly in the solution in which they were prepared. The resulting compounds according to the present invention can also be incorporated into a solvent desired for a particular application.

[0048] The reaction duration depends on the reaction conditions selected. Generally, the reaction duration is 0.5 hours to 10 days, preferably 1 to 24 hours. If microwaves are used, the reaction time can be reduced to 1 to 60 minutes.

[0049] The compounds of the present invention, as well as the starting materials for their preparation, are prepared by known methods, for example under known and suitable reaction conditions, as described in the literature (e.g., in standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). Variants that are known per se but are not described in more detail here can also be used here. Conventional work-up steps, such as adding water to the reaction mixture and extracting, make it possible to obtain the compound after removal of the solvent. Further purification of the product may be advantageously followed by distillation or crystallization, or by chromatographic purification.

[0050] The acids of the present invention can be converted to the relevant addition salts using a base, for example, by reaction (including evaporation) of an equal amount of acid and base in an inert solvent such as ethanol. Suitable bases for this reaction are, in particular, those that give physiologically acceptable salts. Thus, the acids of the present invention can be converted to the corresponding metal salts, in particular alkali metal salts or alkaline earth metal salts, or the corresponding ammonium salts using a base (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate). Organic bases that give physiologically acceptable salts, such as ethanolamine, are also suitable for this reaction.

[0051] On the other hand, the bases of the present invention can be converted into the related acid addition salts using an acid, for example by reaction of an equal amount of base with an acid in an inert solvent such as ethanol (followed by evaporation). Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, inorganic acids such as sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acid such as orthophosphoric acid, sulfamic acid, and also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic, or heterocyclic monobasic or polybasic carboxylic acids, sulfonic acids, or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxysulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acid, or lauryl sulfuric acid, can be used. Salts with physiologically unacceptable acids, such as picrates, can be used for the isolation and / or purification of the compounds of the present invention.

[0052] The compounds of the invention have been found to be well tolerated and to possess valuable pharmacological properties.

[0053] The present invention therefore also relates to the use of the compounds according to the invention for the preparation of a medicament for the treatment and / or prophylaxis of diseases which are caused, promoted and / or propagated by HSET. 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, as well as mixtures thereof in any ratio, for use in the treatment and / or prophylaxis of physiological and / or pathophysiological conditions. Especially preferred are physiological and / or pathophysiological conditions associated with HSET.

[0054] Physiological and / or pathophysiological conditions are understood to mean medically relevant physiological and / or pathophysiological conditions, such as diseases or illnesses, and medical disorders, complaints, symptoms, or complications of specific diseases, etc.

[0055] The present invention also 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, and mixtures thereof in any ratio, for use in the treatment and / or prophylaxis of physiological and / or pathophysiological conditions selected from the group consisting of hyperproliferative diseases and disorders. The present 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, and mixtures thereof in any ratio, for use in the treatment and / or prophylaxis of a physiological and / or pathophysiological condition selected from the group consisting of hyperproliferative and infectious diseases and disorders, wherein the hyperproliferative disease or disorder is cancer.

[0056] The present invention therefore particularly preferably 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, as well as mixtures thereof in any proportion, wherein 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 thrombocytosis, genitourinary cancer, glioma, glioblastoma, hairy cell leukemia, The cancer is selected from the group consisting of head and neck cancer, Hodgkin's disease, Kaposi's sarcoma, lung cancer, lymphoma, malignant carcinoid cancer, malignant hypercalcemia, malignant melanoma, malignant pancreatic insulinoma, medullary thyroid carcinoma, melanoma, multiple myeloma, mycosis fungoides, myeloid and lymphocytic leukemia, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, polycythemia vera, primary brain tumor, primary macroglobulinemia, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, skin cancer, small cell lung cancer, soft tissue sarcoma, squamous cell carcinoma, gastric 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, and mixtures thereof in any ratio, for use in the treatment and / or prophylaxis of physiological and / or pathophysiological conditions 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, liver cirrhosis, chronic inflammation-related disorders, proliferative diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, granulomatous diseases, immune hyperproliferation associated with organ or tissue transplantation, and immunoproliferative diseases or disorders selected from the group consisting of inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), retinal hypoxia and vascular hyperproliferation secondary to vasculitis.

[0057] The medicaments disclosed above are intended to include the corresponding uses of the compounds according to the invention for the preparation of medicaments for the treatment and / or prophylaxis of the above physiological and / or pathophysiological conditions. In addition, the medicaments disclosed above are intended to include corresponding methods for the treatment and / or prophylaxis of the above physiological and / or pathophysiological conditions, in which at least one compound according to the present invention is administered to a patient in need of such treatment.

[0058] The compounds according to the invention preferably exhibit advantageous biological activity that can be easily demonstrated in enzyme assays and animal experiments, as described in the examples. In such enzyme-based assays, the compounds according to the invention preferably exhibit and cause an inhibitory effect, which is usually an IC50 in the suitable range, preferably in the micromolar range, more preferably in the nanomolar range. 50 is evidenced by the values. The compounds according to the invention can be administered to humans or animals, especially mammals such as apes, dogs, cats, rats or mice, and used in the therapeutic treatment of the human or animal body and in combating the above-mentioned diseases. They can also be used as diagnostic agents or reagents.

[0059] Furthermore, the compounds according to the present invention can be used to isolate HSET and investigate the activity or expression of HSET. Furthermore, they are particularly suitable for use in diagnostic methods for diseases associated with impaired HSET activity. The present invention therefore also relates to the use of the compounds according to the present invention for the isolation of HSET and investigation of the activity or expression of HSET, or as binders and inhibitors of HSET.

[0060] The present invention therefore also relates to the use of the compounds according to the present invention for isolating HSET and investigating its activity or expression, or as binders and inhibitors of HSET. For diagnostic purposes, the compounds according to the present invention can be, for example, radiolabeled. A preferred labeling method is the iodogen method (Fraker et al., 1978). In addition, the compounds according to the present invention can be labeled with enzymes, fluorophores, and chemophores. Examples of enzymes are alkaline phosphatase, β-galactosidase, and glucose oxidase, examples of fluorophores are fluorescein, and examples of chemophores are luminol. For example, automated detection systems for fluorescent staining are described in, for example, US 4,125,828 and US 4,207,554.

[0061] The present invention further relates to pharmaceutical compositions containing the compounds of the present invention and their use for the treatment and / or prophylaxis of diseases and disorders in which partial or total inactivation of HSET may be beneficial. The compounds of the present invention can be used for the preparation of pharmaceutical preparations, especially by non-chemical methods, in which they are combined with at least one solid, liquid, and / or semi-liquid excipient or adjuvant, optionally with one or more additional active compound(s), to form a suitable dosage form. The present invention therefore also relates to pharmaceutical preparations comprising at least one compound of the invention and / or its physiologically acceptable salts, derivatives, solvates and stereoisomers, and mixtures thereof in any ratio. In particular, the present invention also relates to pharmaceutical preparations comprising further excipients and / or adjuvants, as well as to pharmaceutical preparations comprising at least one further pharmaceutically active compound.

[0062] In particular, the present invention also relates to a process for the preparation of pharmaceutical preparations, characterized in that the compound of the invention, and / or one of its physiologically acceptable salts, derivatives, solvates and stereoisomers, as well as mixtures thereof in any ratio, together with solid, liquid or semi-liquid excipients or adjuvants, and optionally together with further pharmaceutically active compounds, are brought into a suitable dosage form.

[0063] The pharmaceutical preparations according to the present invention can be used as human medicine and veterinary medicine. The patient or host can belong to any mammalian species, such as primate species, particularly humans; rodents, including mice, rats, and hamsters; rabbits; horses, cattle, dogs, cats, etc. Animal models are of interest for experimental investigations because they provide models for the treatment of human diseases. Suitable carrier substances are organic or inorganic substances that are suitable for enteral (e.g., oral), parenteral, or topical administration and that do not react with the novel compounds, such as 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. Those skilled in the art, thanks to their expertise, are well aware of which adjuvants are suitable for the desired pharmaceutical preparation. In addition to solvents such as water, physiological saline solution, or alcohols such as ethanol, propanol, or glycerol, sugar solutions such as glucose or mannitol solutions, or mixtures of such solvents, gel-forming agents, tablet assistants, and other active ingredient carriers, it is also possible to use, for example, lubricants, stabilizers and / or wetting agents, emulsifiers, salts for influencing osmotic pressure, antioxidants, dispersants, antifoaming agents, buffers, flavors and / or fragrances or flavor correctors, preservatives, solubilizers, or dyes. If desired, the preparations or medicaments according to the invention may also contain one or more further active compounds, for example one or more vitamins.

[0064] If desired, the preparations or medicaments according to the invention may also comprise one or more further active compounds and / or one or more action-enhancing agents (adjuvants).

[0065] The terms "pharmaceutical formulation" and "pharmaceutical preparation" are used synonymously for the purposes of this invention. As used herein, "pharmaceutically tolerated" refers to drugs, precipitating agents, excipients, adjuvants, stabilizers, solvents, and other agents that facilitate the administration of pharmaceutical preparations therefrom to mammals without undesirable physiological side effects, such as nausea, dizziness, dyspepsia, or the like.

[0066] Pharmaceutical preparations for parenteral administration require isotonicity, euhydration, tolerability and safety (low toxicity) of the formulation, of the adjuvants used and of the primary packaging. Surprisingly, the compounds according to the present invention preferably have the advantage that they can be used directly and therefore no further purification steps for the removal of toxicologically unacceptable agents (such as high concentrations of organic solvents) or other toxicologically unacceptable adjuvants are required before using the compounds according to the present invention in pharmaceutical formulations.

[0067] The present invention also particularly preferably relates to pharmaceutical preparations comprising at least one compound according to the invention in precipitated amorphous, precipitated crystalline or dissolved or suspended form, and optionally excipients and / or adjuvants and / or further pharmaceutical active compounds. The compounds according to the invention preferably allow for the preparation of highly concentrated formulations without causing unwanted or undesirable aggregation of the compounds according to the invention. Thus, ready-to-use solutions with high active ingredient contents can be prepared by utilizing the compounds according to the invention with or in aqueous media.

[0068] The compounds, and / or their physiologically acceptable salts and solvates, may also be lyophilized and the resulting lyophilizates may be used, for example, for the preparation of injectable preparations.

[0069] Aqueous preparations can be prepared by dissolving or suspending the compound according to the present invention in an aqueous solution, and optionally adding an adjuvant.To this end, a specified volume of stock solution containing the additional adjuvant at a specified concentration is advantageously added to a solution or suspension having a specified concentration of the compound according to the present invention, and the mixture is optionally diluted with water to a pre-calculated concentration.Alternatively, the adjuvant can be added in solid form.In each case, the required amount of stock solution and / or water can be added to the resulting aqueous solution or suspension.The compound according to the present invention can also advantageously be directly dissolved or suspended in a solution containing all additional adjuvants.

[0070] Solutions or suspensions containing the compounds according to the present invention and having a pH of 4 to 10, preferably 5 to 9, and an osmolality of 250 to 350 mosmol / kg can be advantageously prepared. The pharmaceutical preparations can thus be administered directly intravenously, intraarterially, intraarticularly, subcutaneously, or transdermally, virtually painlessly. In addition, the preparations can also be added to infusion solutions, such as glucose solution, isotonic saline, or Ringer's solution, which may also contain additional active compounds, thereby allowing relatively large amounts of the active compounds to be administered. Pharmaceutical preparations according to the invention may also contain mixtures of compounds according to the invention.

[0071] Preparations according to the invention are physiologically well tolerated, easy to prepare, can be accurately dispensed, and are preferably stable with respect to assay, decomposition products, and aggregates throughout storage and transport and during multiple freeze-thaw processes. They can preferably be stored in a stable manner at refrigerator temperature (2-8°C), rt (23-27°C), and 60% relative atmospheric humidity (RH) for periods of at least 3 months to 2 years. For example, the compounds according to the invention can be stored in a stable manner by drying and, if necessary, converted into ready-to-use pharmaceutical preparations by dissolution or suspension. Possible drying methods are, for example and without being limited to these examples, nitrogen gas drying, vacuum oven drying, freeze drying, washing with organic solvents followed by air drying, liquid bed drying, fluidized bed drying, spray drying, roller drying, layer drying, air drying at RT, and further methods.

[0072] The term "effective amount" refers to the amount of a drug or pharmaceutically active compound that elicits the biological or medical response sought or desired, for example, by a researcher or physician, in a tissue, system, animal, or human.

[0073] Additionally, the term "therapeutically effective amount" denotes an amount that has the following causal relationship: improved treatment, cure, prevention, or elimination of a disease, syndrome, condition, complaint, or disorder, or prevention of side effects, or also reduction in the progression of a disease, complaint, or disorder, compared to a corresponding subject not receiving this amount. The term "therapeutically effective amount" also encompasses amounts effective to increase normal physiological function.

[0074] When using the preparations or medicaments according to the present invention, the compounds according to the present invention and / or their physiologically acceptable salts and solvates are generally used in a dosage similar to known commercially available preparations or medicaments, preferably between 0.1 mg and 500 mg, particularly between 5 mg and 300 mg per unit of use. The daily dose is preferably between 0.001 mg / kg and 250 mg / kg of body weight, particularly between 0.01 mg / kg and 100 mg / kg of body weight. The preparations can be administered one or more times per day, for example, two, three, or four times per day. However, the individual dose for each patient depends on many individual factors, such as the effectiveness of the specific compound used, age, body weight, general health, sex, nutrition, the timing and method of administration, excretion rate, combination with other medications, and the severity and duration of the specific disease.

[0075] The measure of the uptake of a pharmaceutically active compound in an organism is its bioavailability.When a pharmaceutically active compound is delivered to an organism intravenously in the form of an injection solution, its absolute bioavailability, i.e., the proportion of the pharmaceutical that reaches the systemic blood (i.e., the general circulation) in its unchanged form, is 100%.In the case of oral administration of a therapeutically active compound, the active compound is generally in a solid form in the formulation, and therefore must first be dissolved so that it can overcome the barrier of entry, such as the gastrointestinal tract, oral mucosa, nasal mucosa, or skin, especially the stratum corneum, or be absorbed by the body.Pharmacokinetic, i.e., bioavailability, data can be obtained similarly to the method of J. Shaffer et al., J.Pharm.Sciences, 88 (1999), 313-318. Furthermore, a medicament of this type may be prepared using one of the processes generally known in the pharmaceutical art.

[0076] The medicament may be adapted for administration via any desired suitable route, for example, oral (including buccal or sublingual), rectal, pulmonary, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and especially intraarticular) routes. Medicaments of this type may be prepared using any process known in the pharmaceutical art, for example, by combining the active compound with excipient(s) or adjuvant(s).

[0077] Parenteral administration is preferably suitable for administering the medicaments according to the invention. In the case of parenteral administration, intra-articular administration is especially preferred.

[0078] The compounds according to the invention are also suitable for the preparation of medicaments to be administered parenterally, with slow, sustained, and / or controlled release of the active compound. They are therefore also suitable for the preparation of delayed-release formulations, which are advantageous for the patient, since only relatively long time intervals between administrations are required.

[0079] Pharmaceuticals suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats, and solutes (which make the preparation isotonic with the blood or synovial fluid of the recipient to be treated); and aqueous and non-aqueous sterile suspensions, which may contain suspension media and thickeners. The preparations can be delivered in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state, so that only the addition of a sterile carrier liquid (e.g., water for injection purposes) is required immediately before use. The injection solutions and suspensions prepared according to the formulations can be prepared from sterilized powders, granules, and tablets.

[0080] The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0081] The compounds of the present invention can also be coupled to soluble polymers as targeted pharmaceutical excipients. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl radicals. The compounds of the present invention can also be coupled to biodegradable polymers suitable for achieving sustained drug release, such as polymers such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, polylactic-co-glycolic acid, dextran-methacrylate conjugates, polyphosphoesters, various polysaccharides and polyamines, as well as poly-ε-caprolactone, albumin, chitosan, collagen, or modified gelatin, and crosslinked or amphiphilic block copolymers of hydrogels.

[0082] Suitable for enteral administration (oral or rectal) are, inter alia, tablets, dragees, capsules, syrups, juices, drops or suppositories, while 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-propanediol, or mixtures thereof with each other and / or with water) or powders. Also particularly suitable for topical use are liposomal preparations.

[0083] In the case of a formulation to give an ointment, the active compound can be employed with either a paraffin base or a water-miscible cream base. Alternatively, the active compound can be formulated into a cream with an oil-in-water cream base or a water-in-oil base. Medicaments adapted for transdermal administration can be delivered as separate patches for widespread contact with the recipient's epidermis. Thus, for example, the active compound can be dispensed from the patch using iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986). It goes without saying that in addition to the constituents specifically mentioned above, the medicaments according to the invention may also contain other agents as are customary in the art for particular types of pharmaceutical preparations.

[0084] The present invention also relates to a set (kit) consisting of the following separate packs: a) an effective amount of a compound of the present invention, and / or its physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any ratio; and b) an effective amount of a further pharmaceutically active compound. The set comprises suitable containers, such as a box or carton, individual bottles, bags, or ampoules, etc. 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, and mixtures thereof in any ratio, and an effective amount of an additional pharmaceutically active compound in dissolved or lyophilized form.

[0085] Furthermore, the medicaments according to the present invention may be used to provide an additive or synergistic effect in a known treatment and / or to restore the effectiveness of an existing treatment. In addition to the compounds according to the invention, the pharmaceutical preparations according to the invention may also contain further pharmaceutically active compounds (e.g., for use in the treatment of cancer), other antitumor drugs. For the treatment of the other diseases mentioned, the pharmaceutical preparations according to the invention may also contain, in addition to the compounds according to the invention, further pharmaceutically active compounds known to those skilled in the art for their treatment.

[0086] In one principal embodiment, a method is provided for enhancing an immune response in a host in need thereof. The immune response can be enhanced by reducing T cell tolerance, including by increasing IFN-γ release, decreasing the production or activation of regulatory T cells, or increasing the production of antigen-specific memory T cells in the host. In one embodiment, the method comprises administering a compound of the present invention to a host in combination with or alternating with an antibody. In specific subembodiments, the antibody is a therapeutic antibody. In one specific embodiment, a method is provided for enhancing the effectiveness of passive antibody therapy, comprising administering a compound of the present invention in combination with or alternating with one or more passive antibodies. This method may enhance the effectiveness of antibody therapy for the treatment of abnormal cell proliferative disorders such as cancer, or may enhance the effectiveness of therapy in the treatment or prevention of infectious diseases. The compound of the present invention may be administered in combination with or alternating with an antibody, such as rituximab, Herceptin, or Erbitux.

[0087] In another principal aspect, there is provided a method of treating or preventing abnormal cell proliferation, the method comprising administering a compound of the present invention to a host in need thereof, substantially in the absence of another anti-cancer agent.

[0088] In another main embodiment, there is provided a method of treating or preventing abnormal cell proliferation in a host in need thereof, the method comprising administering to the host a first compound of the present invention substantially in combination with a first anti-cancer agent, followed by administering a receptor antagonist that is a second compound of the present invention. In one subembodiment, the second antagonist is administered substantially in the absence of another anti-cancer agent. In another main embodiment, there is provided a method of treating or preventing abnormal cell proliferation in a host in need thereof, the method comprising administering to the host a compound of the present invention substantially in combination with a first anti-cancer agent, followed by administering a second anti-cancer agent in the absence of an antagonist. Thus, the cancer treatments disclosed herein can be carried out as a treatment with the compounds of the present invention or in combination with surgery, radiation therapy, or chemotherapy. This type of chemotherapy can include the use of one or more active compounds from the following categories of antitumor active compounds:

[0089] (i) Antiproliferative / antineoplastic / DNA damaging active compounds and combinations thereof when used in medical oncology, such as alkylating active compounds (e.g., cisplatin, parvoplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, and nitrosoureas); antimetabolites (e.g., antifolates, such as fluoropyrimidines, e.g., 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, and gemcitabine); antitumor antibiotics (e.g., anthracyclines, e.g., adriamycin, benzodiazepines, benzocaine ... isin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotic active compounds (e.g., vinca alkaloids, such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids, such as taxol and taxotere); topoisomerase inhibitors (e.g., epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan, irinotecan, and camptothecin), and cell differentiation active compounds (e.g., all-trans retinoic acid, 13-cis-retinoic acid, and fenretinide);

[0090] (ii) cytostatically active compounds, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, and iodoxifene), estrogen receptor modulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin, and buserelin), progesterones (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and inhibitors of 5α-reductase, such as finasteride;

[0091] (iii) active compounds that inhibit cancer invasion, including metalloprotease inhibitors such as marimastat and inhibitors of urokinase-type plasminogen activator receptor function;

[0092] (iv) inhibitors of growth factor function, e.g., growth factor antibodies, growth factor receptor antibodies, e.g., the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbb1 antibody cetuximab [C225]), farnesyltransferase inhibitors, tyrosine kinase inhibitors, and serine / threonine kinase inhibitors, e.g., inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors), -, for example, 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, inhibitors of the platelet-derived growth factor family, and for example, inhibitors of the hepatocyte growth factor family;

[0093] (v) anti-angiogenic 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 antibodies, soluble VEGF receptor chimeric proteins, anti-VEGF receptor antibodies, anti-PDGF receptors, inhibitors of integrins, tyrosine kinase inhibitors, serine / threonine kinase inhibitors, antisense oligonucleotides, antisense oligodeoxynucleotides, siRNA, anti-VEGF aptamers, pigment epithelium-derived factors, and the like, as described in International Patent Applications WO 97 / 22596, WO 97 / 30035, WO 97 / 32856, and WO Compounds published in 98 / 13354;

[0094] (vi) vessel-destroying agents, such as combretastatin A4 and compounds published in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434, and WO 02 / 08213;

[0095] (vii) antisense therapy, e.g., directed against the targets mentioned above, e.g., ISIS 2503, an anti-Ras antisense;

[0096] (viii) Gene therapy approaches, such as replacement of abnormal modified genes, e.g., abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT approaches (gene-directed enzyme prodrug therapy), e.g., those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase enzymes, and approaches that increase a patient's resistance to chemotherapy or radiation therapy, e.g., multidrug resistance therapy; and

[0097] (ix) Immunotherapeutic approaches, including ex-vivo and in-vivo approaches to increase the immunogenicity of tumor cells in patients, such as transfection of cytokines, e.g., interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor, approaches to reduce T-cell anergy, approaches using transfected immune cells, e.g., cytokine-transfected dendritic cells, approaches for the use of cytokine-transfected tumor cells, and approaches for the use of anti-idiotypic antibodies.

[0098] (x) Chemotherapeutic agents, such as abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, live BCG (BCG live), bevacizumab, bexarotene, bleomycin, bortezomib, busulfan, calucelone, camptothecin, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cinacalcet, cisplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone, epirubicin, epoetin alfa, estramustine, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, and gemcitabine.

[0099] Medicaments from Table 1 may preferably, but not exclusively, be combined with compounds of the present invention.

[0100] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0101] It is assumed that, even without further embodiments, a person skilled in the art would be able to use the above description to the fullest extent, and the preferred embodiments should therefore be regarded merely as a descriptive disclosure that is in any way not limiting.

[0102] The following examples are therefore intended to illustrate the invention without limiting it. Unless otherwise indicated, percentage data are expressed as percentages by weight. All temperatures are indicated in degrees Celsius. "Conventional work-up" means: adding water if necessary, adjusting the pH if necessary to a value between 2 and 10, extracting the mixture with ethyl acetate or dichloromethane depending on the composition of the final product, separating the phases, drying the organic phase over sodium sulfate or magnesium sulfate, filtering and evaporating, and purifying the product by chromatography on silica gel and / or crystallization.

[0103] 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)

[0104] 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 Absorption rate 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 permeability glycoprotein PK (pharmacokinetics) po: by mouth (oral) rt room temperature t 1 / 2 Half-life t max The time when the maximum plasma concentration of the drug is reached UPLC Ultra High Performance Liquid Chromatography V ss Volume of distribution (at steady state) v / v volume to volume

[0105] Methods for preparing and analyzing compounds of the present invention The invention particularly relates to the following exemplary compounds, and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in all proportions.

[0106] All solvents used were commercially available and were used without further purification. Reactions were typically performed using anhydrous solvents under an inert atmosphere of nitrogen or argon. Flash column chromatography was performed using silica gel 60 (0.035-0.070 mm particle size). Flash column chromatography was also performed using a Biotage purification system using a SNAP KP-Sil cartridge or in reversed-phase mode using a SNAP Ultra C18 cartridge. Microwave-assisted reactions were performed using a Biotage Initiator microwave system.

[0107] 1 H 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 the internal reference.

[0108] Chemical shifts (δ) are reported in ppm relative to tetramethylsilane (TMS) referenced to the internal deuterated solvent. 1 1 H NMR data are reported as follows: chemical shifts (multiplicities, coupling constants, and hydrogen numbers). Multiplicities are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), sext (sext), hept (septet), m (multiplet), b (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) coupled to an Agilent 1100 mass spectrometer detector (positive mode). LC-MS analysis was carried out on a SHIMADZU LC-MS machine consisting of a UFLC 20-AD system and an LCMS 2020 MS detector.

[0109] Details of the conditions applied for HPLC / MS spectra recorded on a Shimadzu LCMS-2020 system or an Agilent 1100 system:

[0110] (A): Column: Kinetex EVO C18, 4.6x50mm, 5.0µm; 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: 3.3mL / min. (B): Column: Chromolith HR RP-18e, 4.6x50mm; 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: 3.3mL / min. (C): Column: Sunfire C18, 3.0x100mm, 5µm; 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 at min 2.0, hold to min 2.7, 99%B to 1%B until min 2.71, stop after 3.5; Flow: 1.4mL / min. (D): Column: Chromolith HR C18, 4.6x50mm; 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: 3.3mL / min.

[0111] (E): Column: Kinetex EVO C18, 2.1x30mm, 5.0µm, Mobile phase A: 0.0375% TFA (v / v) in water, Mobile phase B: 0.01875% TFA (v / v) in acetonitrile, Gradient: 5%B to 95%B in 0.8min, 95%B to min 1.2, 5%B to min 1.55, stopped after 1.55min, Flow: 1.5mL / min. (F): Column: Kinetex EVO C18, 2.1x30mm, 5.0µm, Mobile phase A: 0.0375% TFA (v / v) in water, Mobile phase B: 0.01875% TFA (v / v) in acetonitrile, Gradient: 0%B to 60%B in 0.8min, 60%B to min 1.2, stopped after 1.55min, 0%B, Flow: 1.5mL / min. (G): Column: Kinetex EVO C18, 2.1x30mm, 5.0µm; Mobile phase A: 0.025% NH₃·H₂O in water (v / v); Mobile phase B: acetonitrile; Gradient: 5% B to 95% B in 0.8 min, 95% B to min 1.2, stopped after 1.55 min, 5% B; Flow: 1.5mL / min. Details of the conditions applied to HPLC / MS spectra on an Agilent 1200 Series HPLC and diode array detector coupled to a 6210 time-of-flight mass spectrometer with dual multimode APCI / ESI sources.

[0112] (P): Analytical separation was performed on a Merck Chromolith Flash column (RP-18e, 25x2 mm) at 40°C using a flow rate of 1.5 mL / min with a 2-min gradient elution 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 elution was as follows: 5:95 (A / B) to 100:0 (A / B) over 1.25 min, 100:0 (A / B) for 0.5 min, then reversed to 5:95 (A / B) over 0.05 min, and finally 5:95 (A / B) for 0.2 min. (Q): Analytical separation was performed on a Merck Chromolith Flash column (RP-18e, 25x2 mm) at 30°C using a flow rate of 0.75 mL / min with a 4-minute gradient elution 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 elution was as follows: 5:95 (A / B) to 100:0 (A / B) over 2.5 min, 100:0 (A / B) for 1 min, then back to 5:95 (A / B) over 0.1 min, and finally 5:95 (A / B) for 0.4 min. Details of the conditions applied to HPLC / MS spectra on a Waters Acquity UPLC and diode array detector coupled to a Waters G2 QToF mass spectrometer with a multimode ESI / APCI source.

[0113] (R): Analytical separation was performed on a Phenomenex Kinetex C18 column (30x2.1 mm, 2.6 u, 100 A) at 30°C using a 2-minute gradient elution 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 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, then reversed to 10:90 (A / B) over 0.15 min, and finally 10:90 (A / B) for 0.1 min. (S): Analytical separation was performed on a Phenomenex Kinetex C18 column (30x2.1 mm, 2.6 u, 100 A) at 30°C using a 4-minute gradient elution 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 elution was as follows: 10:90 (A / B) to 90:10 (A / B) over 3 min, 90:10 (A / B) for 0.5 min, then back to 10:90 (A / B) over 0.3 min, and finally 10:90 (A / B) for 0.2 min.

[0114] (T): Analytical separation was performed on an Agilent Poroshell C18 column (30x2.1mm, 2.6u, 100A) at 30°C using a 2 minute gradient elution at a flow rate of 0.5mL / min and detection at 254nm. 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, then back to 10:90 (A / B) over 0.15 min, and finally 10:90 (A / B) for 0.1 min.

[0115] (U): Analytical separation was performed on an Agilent Poroshell C18 column (30x2.1mm, 2.6u, 100A) at 30°C using a flow rate of 0.3mL / min with a 4 minute gradient elution and detection at 254nm. 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 3 min, 90:10 (A / B) for 0.5 min, then back to 10:90 (A / B) over 0.3 min, and finally 10:90 (A / B) for 0.2 min. Details of the conditions applied to HPLC / MS spectra on an Agilent 1260 Infinity II Series UPLC and diode array detector coupled to a 6530 quadrupole time-of-flight mass spectrometer with an Agilent Jet Stream ESI source. (V): Analytical separation was performed on an Agilent Poroshell C18 column (30x2.1mm, 2.6u, 100A) at 40°C using a flow rate of 0.6mL / min with a 2 minute gradient elution and detection at 254nm, 280nm, and 214nm. 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 1.25min, 90:10 (A / B) for 0.5min, then back to 10:90 (A / B) over 0.15min, and finally 10:90 (A / B) for 0.1min.

[0116] (X): Analytical separation was performed on an Agilent Poroshell C18 column (30x2.1mm, 2.6u, 100A) at 40°C using a flow rate of 0.4mL / min with a 4 minute gradient elution and detection at 254nm, 280nm, and 214nm. 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 2.5min, 90:10 (A / B) for 1min, then back to 10:90 (A / B) over 0.3min, and finally 10:90 (A / B) for 0.2min. (Y): Analytical separation was performed on a Phenomenex Kinetex C18 column (30x2.1 mm, 2.6 u, 100 A) at 40°C using a flow rate of 0.6 mL / min with a 2-minute gradient elution and detection at 254 nm, 280 nm, 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, then back to 10:90 (A / B) over 0.15 min, and finally 10:90 (A / B) for 0.1 min. (Z): Analytical separation was performed on a Phenomenex Kinetex C18 column (30x2.1 mm, 2.6 u, 100A) at 40°C using a 4-minute gradient elution with a flow rate of 0.4 mL / min and detection at 254 nm, 280 nm, 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, then back to 10:90 (A / B) over 0.3 min, and finally 10:90 (A / B) for 0.2 min.

[0117] Synthesis of intermediates: A1: 5-methyl-3-(2-oxideisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [ka]

[0118] 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 continued to stir at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature and thoroughly mixed 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 MgSO4, filtered, and concentrated under reduced pressure to afford 3.70 g (76%) of N'-hydroxyisoquinoline-7-carboxamidine as an off-white solid. HPLC / MS m / z: 188.0829 [M+H]+, Rt (S): 0.37 min.

[0119] A1.2: Four 20 mL microwave vials were each charged with one-quarter of the following: N'-hydroxyisoquinoline-7-carboxamidine (3.67 g, 19.6 mmol) was mixed with acetonitrile (40 mL) and acetic anhydride (2.2 mL, 23.5 mmol) under an argon atmosphere. Portions of the reaction mixture were each heated at 180 °C for 10 min under microwave irradiation. The combined reaction mixtures were evaporated onto silica gel and purified by flash chromatography (20-80% ethyl acetate in cyclohexane) to yield 3.59 g (87%) of 3-(7-isoquinolyl)-5-methyl-1,2,4-oxadiazole as an off-white solid. HPLC / MS m / z: 212.1 [M+H]+, Rt (R): 0.88 min.

[0120] A1.3: 3-(7-Isoquinolyl)-5-methyl-1,2,4-oxadiazole (3.59 g, 17.0 mmol) was suspended in anhydrous chloroform (57 mL) under an argon atmosphere 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 continued stirring overnight. Potassium carbonate (9.40 g, 68.0 mmol) was added. The mixture was stirred at room temperature for 4 h and then filtered through a pad of anhydrous MgSO4. The filtrate was concentrated under reduced pressure to produce 5-methyl-3-(2-oxidoisoquinolin-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.

[0121] A2: 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole [ka]

[0122] A2.1: Nitrogen gas 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 at 100 °C in a sealed vial 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-absorbed onto silica, and purified by column chromatography (eluent: methanol / dichloromethane - 0-10% gradient) to yield 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).

[0123] A2.2: 1-Hydroxyisoquinoline-7-carbonitrile (0.215 g, 1.26 mmol) and hydroxylamine hydrochloride (0.176 g, 2.52 mmol) in 1-butyl-3-methylimidazolium acetate (1.3 mL) were heated at 80° C. for 30 min. 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-carboxamidine. HPLC / MS m / z: 204.07 [M+H]+, Rt (R): 0.36 min.

[0124] A2.3.: N',1-Dihydroxyisoquinoline-7-carboxamidine (0.235 g, 1.16 mmol) and acetic anhydride (0.13 mL, 1.39 mmol) in acetonitrile (4.6 mL) were heated by microwave irradiation at 180 °C for 10 min. 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.

[0125] A2.4: 7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-ol (50 mg, 0.22 mmol) in phosphorus oxychloride (2 mL) was heated at 100° C. for 1 h. The mixture was concentrated to give 0.054 g (100%) of 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole. HPLC / MS m / z: 246 / 248 Cl split [M+H]+, Rt (R): 1.32 min.

[0126] B1: 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propanoic acid [ka]

[0127] B1.1: 3-(5-Methyl-1,2,4-oxadiazol-3-yl)benzoic acid (147.0 mg, 0.720 mmol) and methyl 3-aminopropanoate dihydrochloride (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 h. The reaction was concentrated in vacuo, and the residue was purified by RP-flash chromatography. The fractions were combined, diluted with saturated aqueous NaHCO3 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.

[0128] 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). Lithium hydroxide (85.5 mg, 3.569 mmol) was added with stirring, 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 yield 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.

[0129] B2: 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propanoic acid [ka]

[0130] 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 oven. 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, and the combined product fractions were diluted with saturated aqueous NaHCO3 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.

[0131] 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), trifluoroacetic acid (788.5 μL, 10.235 mmol) was added, and the yellow solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, 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.

[0132] B3: (1S,3S)-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}cyclobutane-1-carboxylic acid [ka]

[0133] B3.1: 7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-2-ium-2-olate [Intermediate A1] (500.0 mg, 2.201 mmol) and cis-methyl 3-aminocyclobutanecarboxylate hydrochloride (355.3 mg, 2.751 mmol) were dissolved in dry dichloromethane (11.0 mL) under an argon atmosphere. 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 yield 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.

[0134] 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 yield 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.

[0135] B4: (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid [ka]

[0136] B4.1: To a solution of methyl (2S)-3-amino-2-hydroxy-propanoate hydrochloride (342.36 mg, 2.2005 mmol) in dry DCM, DIPEA (1.30 mL, 7.4817 mmol) was added, followed by 5-methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Intermediate A1] (1.76 mL, 1.7604 mmol), followed by bromotri(pyrrolidino)phosphonium hexafluorophosphate (1066.87 mg, 2.2885 mmol). The mixture was stirred for 42 hours. The mixture was diluted with water and extracted with DCM (2 x 70 mL). The organic phase was dried over Na2SO4. Purification by NP silica column chromatography (eluent: 25-100% EtOAc in cyclohexane) yielded methyl (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoate (230 mg). HPLC / MS m / z: 329.126 [M+H]+, Rt (T): 0.79 min.

[0137] B4.2: Methyl (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoate (215.00 mg, 0.6548 mmol) was dissolved in a 3:1 mixture of MeOH and HO (1.06 mL). Lithium hydroxide monohydrate (56.28 mg, 1.3097 mmol) was added. The solution was stirred briefly, then diluted with water (2 mL) and acidified with 1 M HCl (pH = 1). The product precipitated out to give (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid (100 mg, 49%, 0.3182 mmol). HPLC / MS m / z: 315.111 [M+H]+, Rt (T): 0.80 min.

[0138] 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}propanamide [ka]

[0139] 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 dry ethanol (15.0 mL) in a microwave tube. The reaction mixture was heated to 150° C. in a microwave reactor for 7 h. 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 afford 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.

[0140] 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 min the reaction mixture was allowed to warm to room temperature and stirred for 45 min. 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.

[0141] Example 1.3: A solution of 3-bromo-2-ethoxypyridin-4-amine (789.0 mg, 3.635 mmol) and benzoyl isothiocyanate (1.78 g, 10.907 mmol) in acetone (4.0 mL) was stirred overnight at room temperature. A yellow precipitate formed, which was suction filtered, washed with heptane, and dried to yield 1.23 g (89%) of 1-benzoyl-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.

[0142] 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 to room temperature, and treated with saturated aqueous NH4Cl until a precipitate formed. The precipitate was filtered off with 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.

[0143] 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 dry DMSO (7.5 mL). The reaction mixture was heated to 70° C. under an argon atmosphere, stirred overnight, cooled to room temperature, and stirred for 2 d. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The crude product was purified by RP flash chromatography to yield 688 mg (33%) of ammonium 4-ethoxy-[1,3]thiazolo[5,4-c]pyridine-2-formate as a pale green solid. HPLC / MS m / z: 195.9 [M+H] + , Rt (B): 1.13 min.

[0144] 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'-tetramethylformamidinium hexafluorophosphate (68.0 mg, 0.230 mmol) were added, and the reaction was stirred at room temperature for 1 h, heated to 60°C, and stirred for 5 h. The reaction mixture was cooled to room temperature and diluted with water (5 mL). A precipitate formed, which was suction filtered, 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-d6): 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).

[0145] The following examples were prepared in a similar manner. Example 2: 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamide}-N-[4-(propan-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl]propenamide [ka] 29 mg colorless solid. HPLC / MS m / z: 466.8 [M+H] + , Rt (C): 2.40 min. 1 H NMR (700 MHz, DMSO-d6): 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).

[0146] 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}propenamide [ka] 17 mg colorless solid. HPLC / MS m / z: 478.8 [M+H] + , Rt (A): 0.96 min. 1H NMR (400 MHz, DMSO-d6): 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).

[0147] Example 4: N-[4-(butan-2-yloxy)-[1,3]thiazolo[5,4-c]pyridin-2-yl}-3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}propenamide [ka] 56 mg colorless solid. HPLC / MS m / z: 480.8 [M+H] + , Rt (C): 2.50 min. 1H NMR (700 MHz, DMSO-d6): 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).

[0148] 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}propenamide [ka] 34 mg colorless solid. HPLC / MS m / z: 488.8 [M+H] + , Rt (C): 2.33 min. 1 H NMR (700 MHz, DMSO-d6): 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).

[0149] 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]propenamide [ka] 14 mg colorless solid. HPLC / MS m / z: 506.7 [M+H] + , Rt (A): 0.95 min. 1 H NMR (700 MHz, DMSO-d6): 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).

[0150] 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]formamide}propenamide [ka] 31.5 mg colorless solid. HPLC / MS m / z: 514.7 [M+H] + , Rt (C): 2.43 min. 1H NMR (500 MHz, DMSO-d6): 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).

[0151] 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}propenamide [ka] 36 mg of colorless solid. HPLC / MS m / z: 520.7 [M+H] + , Rt (C): 2.52 min. 1 H NMR (700 MHz, DMSO-d6): 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), 2.68 (s, 3H), 1.53 (d, J = 6.5 Hz, 3H).

[0152] 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}propenamide [ka] Intermediate B2 (170.0 mg, 0.570 mmol) was dissolved in dry 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 a nitrogen atmosphere and stirred for 1 d. 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 under suction. Further product was isolated from the filtrate by RP flash chromatography to give 139 mg (51%) of the title compound as a pale yellow solid. HPLC / MS m / z: 475.8 [M+H] + , Rt (C): 1.84 min. 1 H NMR (700 MHz, DMSO-d6): 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.

[0153] 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}propenamide [ka] 15 mg colorless solid. HPLC / MS m / z: 490.1 [M+H] + , Rt (D): 1.47 min. 1 H NMR (400 MHz, DMSO-d6): 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).

[0154] 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]propanamide [ka] 19 mg of colorless solid. HPLC / MS m / z: 489.8 [M+H] + , Rt (C): 1.90 min. 1H NMR (700 MHz, DMSO-d6): 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).

[0155] Example 12: N-[4-(butan-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}propanamide [ka] 112 mg of colorless foam. HPLC / MS m / z: 503.8 [M+H] + , Rt (C): 1.96 min. 1H NMR (700 MHz, DMSO-d6): 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).

[0156] 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}propanamide [ka] 33mg colorless solid. HPLC / MS m / z: 501.8 [M+H] + , Rt (A): 0.79 min. 1H NMR (700 MHz, DMSO-d6): 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).

[0157] 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}propanamide [ka] 23mg colorless solid. HPLC / MS m / z: 537.8 [M+H] + , Rt (C): 1.95 min. 1H NMR (500 MHz, DMSO-d6): 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).

[0158] 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}propanamide [ka] 13 mg colorless solid. HPLC / MS m / z: 507.8 [M+H] + , Rt (A): 0.76 min. 1H NMR (700 MHz, DMSO-d6): 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 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 5.7 Hz, 1H), 6.97 (d, J = 5.5 Hz, 1H), 4.66 (t, J = 5.8 Hz, 1H), 4.59 (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).

[0159] 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}propanamide [ka] 6 mg brown solid. HPLC / MS m / z: 525.9 [M+H] + , Rt (A): 0.78 min. 1H NMR (700 MHz, DMSO-d6): 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).

[0160] 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}propanamide [ka] 46 mg of colorless solid. HPLC / MS m / z: 511.7 [M+H] + , Rt (A): 0.77 min. 1H NMR (700 MHz, DMSO-d6): 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).

[0161] 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]propanamide [ka] 15 mg of pale yellow solid. HPLC / MS m / z: 529.7 [M+H] + , Rt (A): 0.80 min. 1 H NMR (700 MHz, DMSO-d6): 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).

[0162] 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}propanamide [ka] 34 mg colorless solid. HPLC / MS m / z: 543.7 [M+H] + , Rt (A): 0.81 min. 1 H NMR (700 MHz, DMSO-d6): 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).

[0163] 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 [ka] Intermediate B3 (25.0 mg, 0.077 mmol) was dissolved in dry 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 d. 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, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 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-d4): 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).

[0164] 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 [ka] 29mg brown oil. HPLC / MS m / z: 502.2 [M+H] + , Rt (C): 2.00 min.1 H NMR (700 MHz, DMSO-d6): 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).

[0165] 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 [ka] 12 mg brown oil. HPLC / MS m / z: 516.2 [M+H] + , Rt (D): 1.52 min. 1H NMR (700 MHz, DMSO-d6): 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, 2H), 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).

[0166] Example 23: N-{1-ethoxypyrrolo[1,2-a]pyrazin-7-yl}-3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}propanamide [ka]

[0167] Example 23.1: 1-Chloro-7-nitropyrrolo[1,2-a]pyrazine (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, yielding 172.5 mg (87%) of 1-ethoxy-7-nitropyrrolo[1,2-a]pyrazine as a reddish-brown solid. HPLC / MS m / z: 208.1 [M+H] + , Rt (D): 1.54 min.

[0168] Example 23.2: 1-Ethoxy-7-nitropyrrolo[1,2-a]pyrazine (172.5 mg, 0.833 mmol), zinc dust (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 min. 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]pyrazin-7-amine as a brown gum. HPLC / MS m / z: 178.1 [M+H] + , Rt (D): 0.82 min.

[0169] Example 23.3: 3-{[(tert-butoxy)carbonyl]amino}propanoic acid (63.4 mg, 0.335 mmol), 1-ethoxypyrrolo[1,2-a]pyrazin-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 h. 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 yield 76.5 mg (72%) of tert-butyl N-[2-({1-ethoxypyrrolo[1,2-a]pyrazin-7-yl}carbamoyl)ethyl]carbamate as an off-white solid. HPLC / MS m / z: 349.2 [M+H] + , Rt (D): 1.28 min.

[0170] Example 23.4: Intermediate 23.3 (76.5 mg, 0.220 mmol) was dissolved in 1,4-dioxane (1.0 mL) and treated with a solution of 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]pyrazin-7-yl}propanamide dihydrochloride as a pale orange solid. HPLC / MS m / z: 249.1 [M+H] + , Rt (D): 0.86 min.

[0171] Example 23.5: The amide coupling reaction was carried out as described in Intermediate B3.1. Yield: 11 mg (13%) of N-{1-ethoxypyrrolo[1,2-a]pyrazin-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-d6): 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), 3.81 (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).

[0172] Example 24: 3-{[7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl]amino}-N-{1-propoxypyrrolo[1,2-a]pyrazin-7-yl}propanamide [ka] Prepared as described in Example 23. Yield: 16 mg of a pale yellow solid. HPLC / MS m / z: 472.1 [M+H] + , Rt (D): 1.33 min. 1 H NMR (700 MHz, DMSO-d6): 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).

[0173] Example 25: 11-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]ethyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one [ka]

[0174] Example 25.1: 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 4A MS (1600 mg) in toluene (4.00 mL, 0.3600 M) and THF (4.00 mL, 0.3600 M) were heated in a sealed vial at 80° C. for 22 h. The reaction mixture was filtered and washed with EtOAc (100 mL). Purification by NP silica column chromatography (eluent: 20-80% EtOAc in cyclohexane) afforded methyl 4-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (658.4 mg, 79%, 2.2571 mmol) as a cream-colored 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).

[0175] 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 material was evaporated and subjected to NP silica column chromatography (0-60% EtOAc:cyclohexane) to afford 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.

[0176] 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 4 N HCl in dioxane (20.78 mL, 83.109 mmol) and 1,4-dioxane (20.78 mL, 0.1000 M) under argon at RT and stirred for 2 h. The volatiles were removed under reduced pressure. The crude solid was washed with chloroform to give 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 pale yellow solid. HPLC / MS m / z 318.1071 [M+H-HCl] + , Rt (Y): 1.13 min. 1 H NMR (600 MHz, DMSO-d6): 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-d6): 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.

[0177] 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 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. This 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-d6): 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-d6): 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.

[0178] 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 to 0° C. in an ice bath, followed by the addition of NaH (168.29 mg, 4.2073 mmol). The reaction mixture was allowed to stir 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, which was then allowed to warm to RT. The reaction mixture was allowed to stir at RT for 2 d. 0.6 equivalents of N-Boc-2-chloroethylamine reagent was added to the reaction cooled to 0 °C, followed by another 1 equivalent of NaH, and the reaction was left stirring at RT overnight. Water was added, and the reaction was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, and evaporated under reduced pressure. The crude material was subjected to NP chromatography (0-100% EtOAc:cyclohexane) to yield 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 (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).

[0179] 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 4 N HCl in 1,4-dioxane (5.60 mL, 22.408 mmol) and 1,4-dioxane (5.60 mL, 0.1000 M) under argon at RT 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, passed through an SCX-II column, and released with 2N NH 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.

[0180] 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-oxideisoquinolin-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 h. The reaction was evaporated in vacuo and subjected to RP column chromatography (10-80% MeOH:water + 0.1% formic acid) to afford partially pure product. Pure fractions were passed through an SCX-II column, released using 2N NH3 in methanol, and evaporated. Subsequent RP column run yielded 11-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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. 1H NMR (600 MHz, DMSO-d6): 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.

[0181] The intermediates in the following examples were also prepared in an analogous 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]trideca-2,4,6,8-tetraen-11-yl]ethyl]benzamide [ka]

[0182] 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, after which saturated aqueous NaHCO was added. This was extracted with DCM, filtered over MgSO, and evaporated. The compound was subjected to RP column chromatography (10-80% MeOH:water + 0.1% formic acid) to yield 3-(2-methyltetrazol-5-yl)-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]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-d6): 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, 3H), 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). 13C NMR (151 MHz, DMSO-d6): 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.

[0183] Example 27: 3-(2-methyltetrazol-5-yl)-N-[1,1,2,2-tetradeuterio-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 [ka]

[0184] 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) in portions at RT, followed by stirring for 30 min at 60° C. The reaction was cooled to RT, and to this solution was added 1,2-dibromoethane-d4 (1.06 mL, 12.271 mmol) and stirred at RT overnight. The reaction mixture was poured into water and the precipitated product was collected by filtration to give 11-(2-bromo-1,1,2,2-tetradeuterio-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. After filtration, the solvent was removed under reduced pressure to give 11-(1,1,2,2-tetradeuterio-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).

[0185] 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-tetradeuterio-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 x 5 mL), washed with brine, dried over MgSO4, and concentrated in vacuo to give 11-(2-azido-1,1,2,2-tetradeuterio-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, which was used directly without further purification. Rt (Y): 1.40 min

[0186] Example 27.3: To a solution of 11-(2-azido-1,1,2,2-tetradeuterio-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 HO (1.84 mL, 0.0800 M) was added and the reaction was heated to 60 °C and stirred for 4 h. The solvent was removed under reduced pressure, and the resulting residue was purified by a very short silica gel column (eluted with 1:10 to 1:5 methanol-DCM) to give 11-(2-amino-1,1,2,2-tetradeuterio-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-d6): 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).

[0187] 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-tetradeuterio-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, and then saturated aqueous NaHCO was added. This was extracted with DCM, filtered over MgSO4, and evaporated. Silica gel chromatography using DCM and MeOH (100:0 to 96:4) as eluents yielded slightly impure product by NMR. The compound was subjected to RP column chromatography (10 to 80% MeOH:water + 0.1% formic acid), and fractions were passed through an SCX-II column and released with 2N NH3 in methanol to give 3-(2-methyltetrazol-5-yl)-N-[1,1,2,2-tetradeuterio-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 (28.7 mg, 41%, 0.0554 mmol) as a fine white solid after evaporation. HPLC / MS m / z 519.1961 [M+H] + , Rt (Z): 2.50 min. 1H NMR (600 MHz, DMSO-d6): 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-d6): 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.

[0188] Example 28: 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-[1,1,2,2-tetradeuterio-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 [ka] 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-tetradeuterio-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 adding saturated aqueous NaHCO3. This was extracted with DCM, filtered over MgSO4, and evaporated. Silica gel chromatography using DCM and MeOH (100:0 to 96:4) as eluent yielded slightly impure product by NMR. The compound was subjected to RP column chromatography (10 to 80% MeOH:water + 0.1% formic acid) and clean fractions were collected and evaporated to give 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-[1,1,2,2-tetradeuterio-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. 1H NMR (600 MHz, DMSO-d6): 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-d6): 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.

[0189] Example 29: 11-[1,1,2,2-tetradeuterio-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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 [ka]

[0190] Example 29.1: To a dry 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-tetradeuterio-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 stirred overnight. The solution was then washed with saturated aqueous NaHCO (120 mL) and HO (120 mL). The combined aqueous layer was extracted with DCM (120 mL), and the combined organic layer was dried over NaSO, decanted, and concentrated in vacuo. The residue was purified by flash column chromatography (0–80% EtOAc:cyclohexane) to afford 11-(2-chloro-1,1,2,2-tetradeuterio-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).

[0191] 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-tetradeuterio-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), washed with brine, dried over MgSO4, and concentrated in vacuo to give 11-(2-azido-1,1,2,2-tetradeuterio-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, which was used directly without further purification. HPLC / MS m / z 359.1377 [M+H] + , Rt (R): 1.25 min.

[0192] Example 29.3: To a solution of 11-(2-azido-1,1,2,2-tetradeuterio-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 PPh (329.41 mg, 1.2559 mmol). The mixture was stirred at RT for 48 h, then HO (1.84 mL, 0.0600 M) was added and the reaction was heated to 60 °C and stirred for 4 h. The solvent was removed under reduced pressure, and the resulting residue was purified by a very short silica gel column (eluted with 1:10 to 1:5 methanol-DCM) to give 11-(2-amino-1,1,2,2-tetradeuterio-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.

[0193] Example 29.4: DIPEA (0.14 mL, 0.7899 mmol) was added dropwise to a suspension of 11-(2-amino-1,1,2,2-tetradeuterio-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-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole (57.44 mg, 0.2528 mmol), and PyBrop (117.84 mg, 0.2528 mmol) in DCM (1.76 mL, 0.1200 M). The tube was sealed and heated to 60 °C in a microwave for 1 h. Water was added and extracted with DCM. The organic layer was dried over MgSO4 and evaporated in vacuo. NP silica column chromatography (0–7% MeOH in DCM) afforded nearly pure product. A second NP column run (0–4% MeOH in DCM) afforded pure 11-[1,1,2,2-tetradeuterio-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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-colored solid. HPLC / MS m / z 542.2065 [M+H] + , Rt (Z): 2.32 min. 1H NMR (600 MHz, DMSO-d6): 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-d6): 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.

[0194] 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]trideca-2,4,6,8-tetraen-11-yl]ethyl]benzamide [ka]

[0195] Example 30.1.: Ethyl 3-aminobenzoate (0.81 mL, 5 mmol) was dissolved in a mixture of water (1.00 mL) and 50% aqueous hydrofluoric 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 pale pink solid was observed. The reaction was filtered and the solid was washed with EtO. The solid was transferred to a flask and dried in vacuo for 30 min to give 3-ethoxycarbonylbenzenediazonium tetrafluoroboron (1.1 g, 83%, 4.167 mmol) as a pale pink powder. Rt (T): 1.36 min

[0196] 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-ethoxycarbonylbenzenediazonium; 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. A solution of brine and Na2S2O3 was added to the mixture. The product was extracted with EtOAc, and the organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by NP silica column chromatography (eluent: 5-30% EtOAc in cyclohexane) to give 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. 1H NMR (500 MHz, DMSO-d6): 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).

[0197] Example 30.3: Ethyl 3-(5-methyltetrazol-2-yl)benzoate (150.00 mg, 0.6459 mmol) was dissolved in THF (3.23 mL) and HO (1.00 mL, 0.1500 M). 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 3, and the product was extracted with EtOAc (60 mL). After phase separation, the organic layer was dried over MgSO, 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 on to the next step without further purification. HPLC / MS m / z 205.0723 [M+H] + , Rt (R): 1.09 min.

[0198] 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 adding saturated aqueous NaHCO3. This was extracted with DCM, filtered over MgSO4, and evaporated. Silica gel chromatography using DCM and MeOH (100:0 to 96:4) as eluent yielded slightly impure product by NMR. The compound was subjected to RP column chromatography (10 to 80% MeOH:water + 0.1% formic acid), and fractions were passed through an SCX-II column and released with 2N NH3 in methanol to give 3-(5-methyltetrazol-2-yl)-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]benzamide (34.3 mg, 56%, 0.0650 mmol) as a fine white solid after evaporation. HPLC / MS m / z 515.1768 [M+H] + , Rt (S): 2.84 min. 1H NMR (600 MHz, DMSO-d6): 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-d6): 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.

[0199] Example 31: 11-[2-[[7-(2-methyltetrazol-5-yl)-1-isoquinolyl]amino]ethyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one [ka]

[0200] 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), and sodium carbonate (73.16 mg, 0.6903 mmol) in a 4:1 mixture of DME (1.84 mL, 0.2000 M) / water (0.46 mL, 0.2000 M) was added Pd(PPh3)4 (53.18 mg, 0.0460 mmol) under an argon atmosphere. The solution was stirred at 90 °C for 18 h and then treated with water. Using standard procedures, the mixture was extracted with DCM, and the organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by NP column chromatography (20-100% EtOAc:cyclohexane) to afford 7-(2-methyltetrazol-5-yl)isoquinoline (72.74 mg, 75%, 0.3444 mmol) as a pale 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).

[0201] 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 RT overnight. K2CO3 (183.22 mg, 1.3256 mmol) was added. This was stirred at RT for 4 h and then filtered through a pad of anhydrous MgSO4. The filtrate was concentrated in vacuo to yield 7-(2-methyltetrazol-5-yl)-2-oxide-isoquinolin-2-ium (78.5 mg, 104%, 0.3455 mmol) as an off-white powder. Significant triphenylphosphine oxide impurity from the ligand. Carried on 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).

[0202] Example 31.3: 7-(2-methyltetrazol-5-yl)-2-oxide-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) were stirred at 40° C. in a microwave vial under nitrogen atmosphere 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) was added in DCM (0.70 mL, 0.1200 M), and the reaction was heated by microwave irradiation at 60 °C for 1 h. Water was added, and it was extracted with DCM. The organic layer was dried over MgSO and evaporated in vacuo. The product was purified using normal phase chromatography (0-5% MeOH in DCM) followed by two additional RP columns (10-80% MeOH:water + 0.1% formic acid), and fractions were passed through an SCX-II column and released with 2N NH3 in methanol to give 11-[2-[[7-(2-methyltetrazol-5-yl)-1-isoquinolyl]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. 1H NMR (600 MHz, DMSO-d6): 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), 7.29 (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-d6): 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.

[0203] Example 32: 11-[2-[[7-(5-methyltetrazol-2-yl)-1-isoquinolyl]amino]ethyl]-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one [ka]

[0204] 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 h, diethyl ether (10 mL) was added to precipitate the diazonium compound, which was filtered and washed with diethyl ether (3 × 5 mL). The desired compound, isoquinoline-7-diazonium tetrafluoroboron (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-d6): 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-d6): δ 154.52, 149.72, 139.29, 138.64, 130.36, 127.53, 125.83, 121.10, 114.12.

[0205] 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 isoquinoline-7-diazonium tetrafluoroboron (1.40 g, 5.762 mmol) in portions. After stirring at RT for 1.5 h, LC / MS indicated complete addition of the acetamidine moiety, and 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 NaSO was added to the mixture. The product was extracted with EtOAc (7 x 100 mL), and the organic layer was dried over MgSO and concentrated in vacuo. The crude material was purified by NP column chromatography (eluent: 0-70% EtOAc in 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.

[0206] Example 32.3: 7-(5-Methyltetrazol-2-yl)isoquinoline (155.00 mg, 0.7338 mmol) was dissolved in CHCl3 (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. K2CO3 (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 CHCl3, washed with a saturated solution of NaHCO3, dried over MgSO4, and concentrated in vacuo to give 7-(5-methyltetrazol-2-yl)-2-oxide-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.

[0207] Example 32.4: 7-(5-methyltetrazol-2-yl)-2-oxide-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) were stirred at 40° C. in a microwave vial under nitrogen atmosphere 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) was added in DCM (1.00 mL, 0.1200 M) and the reaction was heated by microwave irradiation at 60 °C for 1 h. The reaction was evaporated in vacuo and subjected to RP column chromatography (10-80% MeOH:water + 0.1% formic acid). The pure fractions were passed through an SCX-II column, released using a 2N NH3 in methanol solution, and evaporated to give 11-[2-[[7-(5-methyltetrazol-2-yl)-1-isoquinolyl]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-d6): 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). 13C NMR (151 MHz, DMSO-d6): 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.

[0208] 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 [ka]

[0209] Example 33.1: 4-Hydroxyquinazoline-6-carbonitrile (500 mg, 2.92 mmol) and triethylamine (0.41 mL, 2.92 mmol) were heated in [bmim]OAc (2.9 mL) at 80° C. Hydroxylamine hydrochloride (406 mg, 5.84 mmol) was added, after which some effervescence was observed. The reaction mixture was continued to stir at 80° C. for 30 min. The reaction mixture was cooled to room temperature and water was added (50 mL). The precipitate was filtered off, washed with water (50 mL) and dried under reduced pressure to yield 536 mg (90%) of N,4-dihydroxyquinazoline-6-carboxamidine. HPLC / MS m / z: 205.1 [M+H] + , Rt (U): 0.46 min.

[0210] Example 33.2: A suspension of N,4-dihydroxyquinazoline-6-carboxamidine (480 mg, 2.35 mmol) and acetic anhydride (0.27 mL, 2.82 mmol) in anhydrous ACN (4.70 mL) under an argon atmosphere was heated at 180° C. for 10 min under microwave irradiation. The reaction mixture was cooled to room temperature and cold water was added (50 mL). The precipitate was filtered off, washed with water (50 mL) and diethyl ether (10 mL), and dried under reduced pressure to yield 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.

[0211] 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) under argon at RT. 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 × 10 mL), dried over anhydrous MgSO, filtered, and concentrated in vacuo. The crude material was first purified by NP flash chromatography (0–5% MeOH in DCM) to give the semi-pure product. Fractions were combined, evaporated, and subjected to RP column chromatography (0–80% MeOH:water with 0.1% formic acid) to yield 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. 1H NMR (600 MHz, DMSO-d6): 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-d6): 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.

[0212] 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]trideca-2,4,6,8-tetraen-11-yl]ethyl]benzamide [ka]

[0213] 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 mixture of DME / water (4:1, concentration 0.2000 M), (3-fluoro-5-methoxycarbonyl-phenyl)boronic acid (110.53 mg, 0.5584 mmol) in DME (0.36 mL, 0.2000 M) was added under an argon atmosphere at 60 °C, and the reaction was heated at 90 °C for 18 h and then treated with water. In a standard workup, the mixture was extracted with DCM, and the organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-80% EtOAc:cyclohexane) to afford methyl 3-fluoro-5-(2-methyltetrazol-5-yl)benzoate (43.6 mg, 43%, 0.1846 mmol) as a pale yellow solid. HPLC / MS m / z 237.0783 [M+H] + , Rt (Y): 1.41 min. 1 H NMR (600 MHz, DMSO-d6): 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).

[0214] 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 HO (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 h. The reaction was quenched with 2 N HCl, and DCM was added. The aqueous layer was extracted with DCM (3 x 20 mL), dried over MgSO, 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. Used in the next step without further purification. HPLC / MS m / z 223.0627 [M+H] + , Rt (Y): 1.25 min.

[0215] 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 the mixture was stirred at RT overnight, followed by the addition of saturated aqueous NaHCO. The mixture was extracted with DCM, filtered over MgSO, and evaporated. The compound was subjected to RP column chromatography (10-80% MeOH:water) to yield 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]trideca-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-d6): 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), 4.42-4.37 (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-d6): 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.

[0216] Example 35: 12,12,13,13-tetradeuterio-11-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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 [ka]

[0217] 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-tetradeuterio-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 (0-60% EtOAc:cyclohexane), and the containing fractions were combined and evaporated under reduced pressure to give methyl 1-(2-bromo-1,1,2,2-tetradeuterio-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.

[0218] 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 methyl 1-(2-bromo-1,1,2,2-tetradeuterio-ethyl)-4-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxylate (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 × 5 mL), washed with brine, dried over MgSO4, and concentrated in vacuo to give methyl 1-(2-azido-1,1,2,2-tetradeuterio-ethyl)-4-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxylate (506.4 mg, 97%, 1.4581 mmol) as a yellow solid, which was used directly without further purification. HPLC / MS m / z 348.1229 [M+H] + , Rt (R): 1.44 min.

[0219] Example 35.3: To a solution of methyl 1-(2-azido-1,1,2,2-tetradeuterio-ethyl)-4-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxylate (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 stirred for 4 h. The solvent was removed under reduced pressure, and the resulting residue was purified by RP column chromatography (0-5% methanol in DCM) to give 12,12,13,13-tetradeuterio-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-d6): 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 = 9.1Hz, 2H).

[0220] Example 35.4: 12,12,13,13-tetradeuterio-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 to 0° C. in an ice bath, followed by the addition of NaH (115.6 mg, 2.8902 mmol). The reaction mixture was allowed to stir 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, which was then allowed to warm to RT. The reaction mixture was allowed to stir at RT for 5 d. Water was added, and the reaction was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, and evaporated under reduced pressure. The crude material was subjected to NP chromatography (0-100% EtOAc:cyclohexane) to yield tert-butyl N-[2-[12,12,13,13-tetradeuterio-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 (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.

[0221] Example 35.5: tert-Butyl N-[2-[12,12,13,13-tetradeuterio-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 4 N HCl in 1,4-dioxane (3.33 mL, 13.32 mmol) and 1,4-dioxane (3.33 mL, 0.1000 M) at RT under argon and stirred for 2 h. The volatiles were removed under reduced pressure to give 11-(2-aminoethyl)-12,12,13,13-tetradeuterio-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 (10-80% MeOH:water with 0.1% formic acid). Pure fractions were passed through an SCX-II column and released with 2N NH3 in methanol, yielding 11-(2-aminoethyl)-12,12,13,13-tetradeuterio-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-d6): 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). 13C NMR (151 MHz, DMSO-d6): 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.

[0222] Example 35.6: DIPEA (0.13 mL, 0.7335 mmol) was added dropwise to a suspension of 11-(2-aminoethyl)-12,12,13,13-tetradeuterio-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-oxidoisoquinolin-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 heated to 60 °C in a microwave for 1 h. The reaction was evaporated in vacuo and subjected to RP column chromatography (10–80% MeOH:water + 0.1% formic acid). Pure fractions were passed through an SCX-II column, released using a 2N NH3 in methanol solution, and evaporated to yield 12,12,13,13-tetradeuterio-11-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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. 1H NMR (600 MHz, DMSO-d6): 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-d6): 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.

[0223] Example 36: 3-(2-methyltetrazol-5-yl)-N-[2-[12,12,13,13-tetradeuterio-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 [ka] 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-tetradeuterio-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-10-one (22.00 m, 0.0662 mmol) in DCM (0.66 mL, 0.1000 M). This was stirred for 2 h before adding saturated aqueous NaHCO3. This was extracted with DCM, filtered over MgSO4, and evaporated. The compound was subjected to RP column chromatography (10-80% MeOH:water + 0.1% formic acid). Pure fractions were passed through an SCX-II column, released using a 2N NH3 in methanol solution, and evaporated to yield 3-(2-methyltetrazol-5-yl)-N-[2-[12,12,13,13-tetradeuterio-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. 1H NMR (600 MHz, DMSO-d6): 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, 3H), 3.73 (t, J = 6.0 Hz, 2H), 3.58 (q, J = 6.0 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6): 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.

[0224] 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]pyrazin-9(6H)-one [ka]

[0225] 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.), CsCO (1.20 g, 3.68 mmol, 1.4 eq.), tBuBrettPhos Pd G (90 mg, 0.11 mmol, 4 mol%), tBuBrettPhos (102 mg, 0.21 mmol, 8 mol%), and 4A molecular sieves (1.0 g) in THF (6.56 mL, 0.4 M) was heated in a sealed vial at 80° C. overnight. Silica was added and the solvent was evaporated. Normal phase column chromatography (0-80% EtOAc in cyclohexane) afforded pure methyl 4-propoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (442 mg, 72% yield) as a yellowish powder. HPLC / MS m / z: 235.1 [M+H] + , Rt (Y): 1.188 min.

[0226] Example 37.2: 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) was added aqueous NaOH (3N, 11.8 mL), which was heated to 45 °C for 45 min, then the solvent was evaporated and the crude solid was triturated with Et O. The solid was filtered, washed with more Et 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.

[0227] 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, followed by the addition of a solution of tert-butyl N-{2-[(2-hydroxyethyl)amino]ethyl}carbamate (19 mg, 90 μmol, 1.05 eq.) in DCM (200 μL). After 5 min, the reaction was quenched with saturated aqueous NaHCO3, extracted with DCM, dried over MgSO4, and then evaporated under vacuum. The crude product was precipitated with water, and the aqueous phase was discarded. The product was used in the next step without purification (26.3 mg, crude yield 73%). Rf (EtOAc:DCM, 9:1) = 0.34; HPLC / MS m / z: 407.2 [M+H] + , Rt (Y): 1.154 min.

[0228] 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 allowed to warm to RT and stirred for 2 h. After removing the solvent under reduced pressure, the residue was diluted with EtOAc and extracted with aqueous HCl (1 M) (×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 over a pad of MgSO4 and silica to afford tert-butyl (2-(9-oxo-1-propoxy-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrazin-8(9H)-yl)ethyl)carbamate as a clear oil. HPLC / MS m / z: 398.2 [M+H] + , Rt (Y): 1.319 min.

[0229] Example 37.5: To the crude solid was added aqueous HCl (1 M) (1.63 mL, 1.63 mmol, 3.0 eq.), which was stirred for 10 min until all material was dissolved, then evaporated to dryness. The solid was triturated with DCM, the solvent filtered off, and washed with more DCM to afford 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 two steps) as a white solid. HPLC / MS m / z: 289.2 [M+H] + , Rt (Y): 0.547 min.

[0230] Example 37.6: DIPEA (67.03 μL, 0.3848 mmol) was added to a mixture of 5-methyl-3-(2-oxideisoquinolin-2-ium-7-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), which was heated via microwave irradiation (60° C.; 1 h). The solvent was evaporated and the residue was subjected to AccQ Prep reverse-phase HPLC (20-30% MeCN in HO) followed by normal-phase preparative TLC (5% MeOH in DCM) to yield 11-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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; 1H NMR (500 MHz, Methanol-d4 / 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), 7.89 (d, J = 5.9 Hz, 1H), 7.78 (d, J = 6.1 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 1.1 Hz, 1H), 6.93 (ddd, J = 6.1, 2.2, 0.9 Hz, 2H), 4.34 (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 (dtd, J = 14.0, 7.4, 6.5 Hz, 2H), 1.05 (t, J = 7.4 Hz, 3H).

[0231] 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]pyrazin-8(9H)-yl)ethyl)benzamide [ka] Obtained 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 using the procedure of Example 54.3 at 60° C., yielded 3-(2-methyltetrazol-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 (7.1 mg, 0.0149 mmol) as a white solid. HPLC / MS m / z: 475.221 [M+H] + , Rt (Z): 2.18 min. 1 H NMR (600 MHz, DMSO-d6): 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).

[0232] Example 39: 1-(dodec-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]pyrazin-9(6H)-one [ka] Synthesized in a manner similar to Example 37 using dodec-11-yn-1-ol as the starting alcohol. Preparative TLC (5% MeOH in 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-d4 / 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), 1.33-1.26 (m, 3 x 2 H).

[0233] Example 40: N-(2-(1-chloro-9-oxo-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrazin-8(9H)-yl)ethyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide [ka]

[0234] Example 40.1: 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) was added aqueous NaOH (3N, 21 mL), which was heated to 45 °C for 1 h, after which the solvent was evaporated and the crude solid was triturated with Et O. The solid was filtered, washed with more Et O, and 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 used in the next step without further purification (crude mass 1.2 g, quantitative). HPLC / MS m / z: 197.0 [M+H] + , Rt (Y): 0.947 min.

[0235] Example 40.2: DMF (9.72 mL) was added dropwise to a mixture of 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), which was stirred for 30 min, and then 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, then water was added and the solvent was evaporated to dryness. Reverse-phase chromatography (0-100% MeOH in HO) to remove the major impurity afforded the crude product (crude mass 2.535 g), which was carried on to the next step. HPLC / MS m / z: 383.1 [M+H] + , Rt (R): 1.083 min.

[0236] Example 40.3: 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) was added DIAD (3.91 mL, 19.868 mmol) over 40 min at 0° C. After 1 h, the resulting mixture was allowed to warm to RT and stirred for an additional 3 h. After removing the solvent under reduced pressure, the residue was diluted with EtOAc and 10% aqueous Na2CO3, extracted with EtOAc, and filtered over MgSO4 to give crude tert-butyl 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.

[0237] Example 40.4: The crude material was diluted in DCM (30 mL) and TFA (30 mL) was added at 0° C., at which point the solution turned red. This was stirred at RT for 30 min, then the solvent was evaporated and the mixture was added back into aqueous HCl (3N). After concentration, the residue was washed several times with DCM and then purified by reverse phase chromatography (5-25% MeOH in HO) to give 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: no ionization, Rt (Y): 0.522 min.

[0238] Example 40.5: 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]trideca-2,4,6,8-tetraen-11-yl)ethylammonium chloride (150.00 mg, 0.4981 mmol) in DCM (3.32 mL, 0.1500 M) was added DIPEA (0.35 mL, 1.9922 mmol). This was stirred for 2 h before adding saturated aqueous NaHCO3. This was extracted with DCM, filtered over MgSO4, and evaporated. Slow silica gel chromatography using DCM and MeOH (100:0 to 96:4) as eluents afforded 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 (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-d4): 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).

[0239] Example 41: N-(2-(1-(3-fluoropropoxy)-9-oxo-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrazin-8(9H)-yl)ethyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide [ka] 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 (gentle gradient elution from 100:0 to 96:4) using DCM and MeOH as eluents afforded N-[2-[6-(3-fluoropropoxy)-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 (5.42 mg, 12%, 0.0110 mmol) as a white solid. HPLC / MS m / z: 493.2 [M+H] + , Rt (Y): 1.31 min; 1H NMR (600 MHz, Methanol-d4): 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, 1H), 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).

[0240] Example 42: N-(2-(1-(2,2-difluoroethoxy)-9-oxo-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrazin-8(9H)-yl)ethyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide [ka] Obtained from 2,2-difluoroethanol 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. Preparative TLC using DCM and MeOH (94:6) as eluent. (11.4 mg, 20% yield). HPLC / MS m / z: 497.2 [M+H] + , Rt (Z): 2.44 min; 1H NMR (600 MHz, Methanol-d4 / 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 (dt, 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, 4.2Hz, 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), 2.65 (s, 3H).

[0241] 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]pyrazin-8(9H)-yl)ethyl)benzamide [ka] Cs2CO3 (98.3 mg, 0.3 mmol, 2.7 eq.), 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 (51 mg, 0.11 mmol, 1.0 eq.), BrettPhos (10 m g, 18.6 μmol, 16 mol%), crotyl(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl)palladium(II) triflate (10 mg, 11.8 μmol, 10 mol%), molecular sieves 4A (130.00 mg), and 2,2,2 trifluoroethanol (16.4 μL, 0.23 mmol, 2.0 eq.) were heated to 0° C. overnight. Water was added, and the mixture was filtered over cotton and evaporated. Normal-phase silica gel chromatography (gentle gradient elution from 100:0 to 98:2) using DCM and MeOH as eluents afforded 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-2,4,6,8-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; 1H NMR (600 MHz, Methanol-d4): 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).

[0242] 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]pyrazin-9(6H)-one [ka] 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]pyrazin-9(6H)-one and 3-fluoropropan-1-ol using the conditions of Example 37.1. Preparative TLC (5% MeOH in DCM) (4.6 mg, 9% yield). HPLC / MS m / z: 516.2 [M+H] + , Rt (Y): 1.18 min; 1H NMR (600 MHz, Methanol-d4): 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), 3.89 (dd, J = 6.6, 5.0 Hz, 2H), 2.59 (s, 3H), 2.25-2.15 (m, 2H).

[0243] 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]pyrazin-8(9H)-yl)ethyl)benzamide [ka]

[0244] Example 45.1: Using the conditions of Example 40.5, N-(2-(1-chloro-9-oxo-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrazin-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. Purification by column chromatography (eluent: 0-4% MeOH in DCM) afforded N-(2-(1-chloro-9-oxo-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrazin-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.

[0245] 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 was purified by preparative TLC (6% MeOH in DCM) to give 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]pyrazin-8(9H)-yl)ethyl)benzamide as a white powder (5.0 mg, 9% yield). HPLC / MS m / z: 482.3 [M+H] + , Rt (R): 1.09 min; 1H NMR (600 MHz, Methanol-d4 / 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).

[0246] 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]pyrazin-8(9H)-yl)ethyl)benzamide [ka] 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]trideca-2,4,6,8-tetraen-11-yl)ethyl]-3-(2-methyltetrazol-5-yl)benzamide using the conditions of Example 37.1. Silica gel chromatography (0-2% MeOH in DCM) (15.99 mg, 31% yield). White powder. HPLC / MS m / z: 517.2 [M+H] + , Rt (R): 1.270 min; 1H NMR (600 MHz, Methanol-d4 / 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).

[0247] Example 47: N-(2-(1-dodec-11-yn-1-yloxy)-9-oxo-6,7-dihydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrazin-8(9H)-yl)ethyl)-3-(2-methyl-2H-tetrazol-5-yl)benzamide [ka] Obtained from 3-(2-methyl-2H-tetrazol-5-yl)-benzoic acid and 11-(2-aminoethyl)-6-dodec-11-ynoxy-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 (0-3.25% MeOH in DCM) followed by preparative TLC (10% MeOH in DCM) and then trituration with EtOAc. (72.1 mg, 50% yield). White solid. HPLC / MS m / z: 597.3 [M+H] + , Rt (R): 1.56 min; 1H NMR (600 MHz, Methanol-d4 / 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 2 H).

[0248] 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]pyrazin-9(6H)-one [ka]

[0249] Example 48.1: 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) was added DIPEA (1029.54 μL, 5.9109 mmol). This was heated at 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, at which point a precipitate formed, which was stirred at this temperature for 2 h. The mixture was washed with HO, aqueous HCl (1 N), and extracted with DCM. The solvent was dried over MgSO4 and evaporated. Normal phase column chromatography (0-5% MeOH in DCM) afforded 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.

[0250] Example 48.2: To a solution of tert-butyl N-[(1S)-1-(benzyloxycarbonylaminomethyl)-2-(2-hydroxyethylamino)-2-oxo-ethyl]carbamate (23 mg, 60.3 μmol) in THF (600 μL) was added BF3.OEt2 (7.4 μL, 60.3 μmol, 1.0 eq.) dropwise at 0 °C, followed immediately by BH3·THF (1 M 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 (0-20% MeOH in 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.

[0251] Example 48.3: A 15 min pre-stirred yellow solution of 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) 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 MgSO4 and evaporated. Normal phase chromatography (20-90% EtOAc in DCM) afforded 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.

[0252] Example 48.4: 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 PPh3 (397.96 mg, 1.5172 mmol) in THF (5.06 mL, 0.1000 M) was added dropwise DIAD (298.74 μL, 1.5172 mmol) at 0 °C. After 1 h, the ice bath was removed and the mixture was stirred overnight. The reaction was quenched with water, the mixture was extracted with DCM, and the organic phase was dried over MgSO4 and evaporated in vacuo. Normal phase chromatography (0-100% EtOAc in DCM) afforded a mixture of Ph3P=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]trideca-2,4,6,8-tetraen-11-yl]ethyl]carbamate, which was carried on to the next step without further purification. HPLC / MS m / z: 592.2 [M+H] + , Rt (Y): 1.608 min.

[0253] 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. Elution through an SCX-2 column with MeOH to remove impurities, then NH in MeOH (2M) afforded benzyl N-[(2S)-2-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 (229.1 mg, 92% yield over two steps). HPLC / MS m / z: 492.2 [M+H] + , Rt (Y): 1.253 min.

[0254] Example 48.6: To a suspension of benzyl N-[(2S)-2-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 (229.10 mg, 0.4662 mmol), 5-methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole (127.11 mg, 0.5594 mmol), and PyBrop (260.78 mg, 0.5594 mmol) in DCM (4.66 mL, 0.1000 M) was added DIPEA (304.48 μL, 1.7481 mmol) dropwise. The tube was sealed and heated to 60 °C for 1 h. Water was added and extracted with DCM. The organic layer was dried over MgSO4 and evaporated in vacuo. Normal phase chromatography (1-1.5% MeOH in DCM) (140.2 mg, 43% yield). Orange oil. HPLC / MS m / z: 701.2509 [M+H] + , Rt (R): 1.32 min.

[0255] Example 48.7: To a solution of Pd(OAc)2 (5.6 mg, 24.9 μL, mmol, 23 mol%) in DCM (543 μL) were added Et3N (13 μL, 95.3 μmol, 0.9 eq) and Et3SiH (38 μL, 0.24 mmol, 2.2 eq) successively at RT. The dark mixture was stirred for 5 min, followed by the addition of benzyl N-[(2S)-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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). The vial was sealed and stirred for 18 h. The black precipitate was washed with saturated aqueous NaHCO3, extracted with DCM (3 × 2 mL), and passed through an SCX-2 column eluting with MeOH and then NH3 (2 M in MeOH) to give the crude amine. Normal phase silica gel chromatography (0-20% NH in DCM (2M in MeOH)) afforded 11-[(2S)-3-amino-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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; 1H NMR (600 MHz, Methanol-d4 / 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).

[0256] 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]pyrazin-8(9H)-yl)propan-2-yl)-3-(2-methyl-2H-tetrazol-5-yl)benzamide [ka]

[0257] Example 49.1: 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) was added DIPEA (142 μL, 0.8 mmol, 4.0 eq.) and stirred at 40° C. for 30 min before adding benzyl N-[(2S)-2-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 (100 mg, 0.2 mmol, 1.0 eq.) in DCM (1.0 mL) at RT. The mixture was stirred for 4 h, then washed with water, extracted with DCM, filtered over MgSO4, and evaporated. Silica gel chromatography (70-100% EtOAc in cyclohexane) afforded 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 (96.9 mg, 70% yield). HPLC / MS m / z: 678.2 [M+H] + , Rt (Y): 1.57 min.

[0258] Example 49.2: 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.) in EtOH (552 μL, 0.1 M) and Pd / C (35 mg, 100% wt / wt) was added EtSiH (50 μL, 0.3 mmol, 5.7 eq.) at RT. The mixture was passed through an SCX-2 column and eluted successively with MeOH and DCM, followed by 10% NH in DCM (2 M in MeOH) to collect the expected free amine. Further purification was carried out by preparative TLC (10% NH3 in DCM (2M in MeOH)). HPLC / MS m / z: 544.2 [M+H] + , Rt (Y): 1.21 min; 1 H NMR (600 MHz, Methanol-d4 / 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 (ddd, 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).

[0259] 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]pyrazin-8(9H)-yl)hexan-2-yl)benzamide [ka]

[0260] Example 50.1: 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, 0.1000 M) was added DIPEA (721.88 μL, 4.1445 mmol). The mixture was heated at 50° C. for 15 min until it 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, at which point a precipitate formed, which 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 (0-7% MeOH in DCM) gave tert-butyl N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-(2-hydroxyethylamino)-6-oxo-hexyl]-N-methyl-carbamate (5.45 g, quantitative) as a white solid. HPLC / MS m / z: 526.3 [M+H] + , Rt (R): 1.477 min.

[0261] 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 MeOH at 0 °C and the solvent was evaporated. Normal phase chromatography (0-20% MeOH in DCM) afforded tert-butyl N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-(2-hydroxyethylamino)hexyl]-N-methyl-carbamate (3.43 g, 65% yield). HPLC / MS m / z: 512.3 [M+H] + , Rt (Y): 1.401 min.

[0262] Example 50.3: 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) was added dropwise a 15 min pre-stirred 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). 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 MgSO4 and evaporated. Normal phase chromatography (0-5% MeOH in DCM) followed by reverse phase chromatography (20-100% MeOH in HO) afforded 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-methylcarbamate (1.37 g, 51% yield). f (DCM:EtOAc, 1:1) = 0.13; HPLC / MS m / z: 754.3 [M+H] + , Rt (R): 1.59 min.

[0263] Example 50.4: 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) was added a solution of PPh3 (1.56 g, 6.0 mmol, 3.0 eq.) in THF (9.9 mL) at −40° C. to prevent Fmoc removal. Immediately thereafter, DIAD (1.2 mL, 6.0 mmol, 3.0 eq.) was added dropwise, allowing the yellow color to fade between each addition. After 30 seconds of vigorous stirring at −40° C., the reaction was quenched with water. The mixture was extracted with DCM, and the organic phase was dried over MgSO4 and evaporated in vacuo. Normal phase chromatography (0-70% EtOAc in DCM) afforded a mixture of triphenylphosphine oxide and 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]trideca-2,4,6,8-tetraen-11-yl]hexyl]-N-methyl-carbamate, which was carried on to the next step without further purification. HPLC / MS m / z: 736.3 [M+H] + , Rt (Y): 1.862 min.

[0264] Example 50.5: To 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]trideca-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) was added piperidine (392 μL, 3.97 mmol, 2.0 eq). After 30 min, water was added and the solvent was evaporated. Normal phase chromatography (0-15% MeOH in DCM) afforded tert-butyl N-[(5S)-5-amino-6-[10-oxo-6-(2,2,2-trifluoroethoxy)-1,5,11-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-11-yl]hexyl]-N-methyl-carbamate (824 mg, 81% yield over two steps). HPLC / MS m / z: 514.3 [M+H] + , Rt (R): 1.17.

[0265] Example 50.6: 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 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 (44.70 mg, 0.0870 mmol) in DCM (870.41 uL, 0.1000 M) was added DIPEA (60.64 μL, 0.3482 mmol). After stirring for 2 h, the solution was washed once with water, then extracted with DCM, filtered over MgSO4, and evaporated. Silica gel chromatography (70-100% EtOAc in cyclohexane) (51.4 mg, 84%, 0.0735 mmol) was performed. The product was carried on to the next step without further purification. HPLC / MS m / z: 700.3 [M+H] +, Rt (R): 1.47 min.

[0266] 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 and re-evaporated (×2) with aqueous HCl (3N). The solid was washed with DCM, re-added to MeOH, filtered through an SCX-2 column, and washed with MeOH. The free amine was recovered by washing the column with NH3 in MeOH (2 M). 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, quantitative over two steps). HPLC / MS m / z: 600.3 [M+H] + , Rt (Y): 1.248 min; 1H NMR (600 MHz, Methanol-d4): 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, 1H), 3.60 (dd, J = 13.9, 4.2 Hz, 1H), 2.93 (ddd, J = 8.6, 6.5, 3.5 Hz, 2H), 2.64 (s, 3H), 1.79 (quint, J = 7.6 Hz, 2H), 1.84-1.75 (m, 1H), 1.75-1.67 (m, 1H), 1.67-1.49 (m, 2H).

[0267] 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]pyrazin-8(9H)-yl)hexan-2-yl)-3-(2-methyl-2H-tetrazol-5-yl)benzamide [ka] 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]trideca-2,4,6,8-tetraen-11-yl]methyl]pentyl]-3-(2-methyltetrazol-5-yl)benzamide (154 mg, 0.26 mmol, 1.0 eq.) and CsCO (336.8 mg, 1.03 mmol, 4.0 eq.) in DMF (1.3 mL, 0.2 M) was added a solution of propargyl bromide (80% in toluene) (26 μL, 0.27 mmol, 1.05 eq.) at 0 °C and stirred at RT for 18 h. Water was added and the solvent was evaporated. Silica gel chromatography (0-6% MeOH in DCM) afforded 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]trideca-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; 1H NMR (600 MHz, Methanol-d4): 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, 2H), 1.63 (tdd, J = 11.8, 6.5, 3.8 Hz, 1H), 1.59-1.45 (m, 2H + 1H).

[0268] 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]pyrazin-9(6H)-one [ka]

[0269] Example 52.1: To a suspension 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-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole (53.09 mg, 0.2337 mmol), and PyBrop (108.93 mg, 0.2337 mmol) in DCM (1.62 mL, 0.1200 M) was added DIPEA (0.13 mL, 0.7302 mmol) dropwise. The tube was sealed and heated to 60 °C in a microwave for 1 h. Water was added and extracted with DCM. The organic layer was dried over MgSO4 and evaporated in vacuo. Normal phase chromatography (50-100% EtOAc in cyclohexane) (140 mg, 99% yield). HPLC / MS m / z: 723.3 [M+H] + , Rt (R): 1.36 min.

[0270] Example 52.2: tert-Butyl N-methyl-N-[(5S)-5-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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 and the residue was returned to MeOH and filtered through an SCX-2 column, washing with MeOH. The free amine was recovered by washing the column with NH3 in MeOH (2M). (76.9 mg, 80% yield). HPLC / MS m / z: 300.6 [M+2H] + , Rt (Y): 1.248 min.

[0271] Example 52.3: To a mixture of 11-[(2S)-6-(methylamino)-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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 CsCO (162 mg, 0.49 mmol, 4.0 eq.) in DMF (0.62 mL, 0.2 M) was added a solution of propargyl bromide (80% in toluene) (12 μL, 0.13 mmol, 1.05 eq.) at 0 °C and stirred at RT for 18 h. Water was added and the solvent was evaporated. Preparative TLC (5% MeOH in DCM) afforded 11-[(2S)-2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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); 1H NMR (500 MHz, Methanol-d4): 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).

[0272] 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 [ka]

[0273] 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 dry DMF (7.70 mL) was added T3P and triethylamine (0.67 mL, 4.7402 mmol) in DMF (3.72 mL, 3.1602 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 phase was washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NH4Cl (75 mL), then dried over Na2SO4 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 pale yellow oil. HPLC / MS m / z: 503.3 [M+H] + , Rt (R): 1.47 min.

[0274] 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), water (0.5 mL, sufficient 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 the mixture was acidified to pH 3 with 2 M aqueous HCl. This was extracted twice with EtOAc, and the combined organics were dried over NaSO and then concentrated under reduced pressure to give 381 mg of a pale yellow foam / solid. Purification by reverse-phase flash chromatography (eluent: 0-80% MeOH / HO + 0.1% formic acid) afforded 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.

[0275] 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 dry 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 (eluent: 10-80% MeOH / HO + 0.1% formic acid) afforded 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.

[0276] Example 53.4: To a flask containing 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 4 M 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 pale yellow solid. The crude material was dissolved in MeOH and purified using a 1 g SCX-2 column, first flushed with MeOH and then eluted with a 2 N solution of NH3 in MeOH. The basic eluent 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 pale 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).

[0277] Example 54: (3S)-6-(methylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-N-(7-propoxy-1,3-benzothiazol-2-yl)hexanamide [ka]

[0278] Example 54.1: To a solution of tert-butyl 3-amino-6-[tert-butoxycarbonyl(methyl)amino]hexanoate (522.25 mg, 1.6504 mmol) in dry DCM (8.63 mL) was added 5-methyl-3-(2-oxidoisoquinolin-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). The mixture was stirred under N at room temperature for 16 h. An additional 300 mg of PyBroP (0.644 mmol) was added, and the mixture was stirred under N for an additional 18 h. The mixture was concentrated under reduced pressure and purified by silica column chromatography (eluent: 20-50% EtOAc in cyclohexane) to yield tert-butyl (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]hexanoate, 522 mg (75%) as a green gum. HPLC m / z: 526.3 [M+H] + , Rt (R): 1.24 min.

[0279] 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-isoquinolyl]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 enough to dissolve the KOH), followed by 8 drops of MeOH. The mixture was stirred at 50° C. for 18 h. An additional 557.21 mg (9.9308 mmol) of potassium hydroxide was added, and stirring was continued at 50° C. for 13 d. Additional addition of MeOH (1 mL) and water (1 mL) was required for complete conversion. The mixture was allowed to cool, and the volatiles were removed under reduced pressure. Water (20 mL) was added, and the mixture was acidified to pH 3 with 2 M aqueous HCl. Extraction with EtOAc (3x) was performed, and the combined organics were dried over Na2SO4. They were then concentrated under reduced pressure to give a pale yellow solid. Purification by reverse-phase flash chromatography (eluent: 10-100% MeOH / HO + 0.1% formic acid) afforded (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]hexanoic acid, 177 mg (38%), as a pale yellow glassy solid. HPLC m / z: 470.2 [M+H] + , Rt (R): 1.12 min.

[0280] Example 54.3: To a mixture of (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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) was added triethylamine (0.03 mL, 0.1917 mmol) followed by 1-propanephosphonic anhydride (50% in DMF) (0.08 mL, 0.1278 mmol) under N. The mixture was stirred at 70 °C for 5 d under N, followed by an additional 3 d at 60 °C. Purification by reverse-phase flash chromatography (eluent: 20-80% MeOH / HO + 0.1% formic acid) afforded tert-butyl N-methyl-N-[(4S)-4-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-6-oxo-6-[(7-propoxy-1,3-benzothiazol-2-yl)amino]hexyl]carbamate, 31 mg (73%), as a pale yellow solid. HPLC / MS m / z: 452.2 [M+H] + , Rt (R): 1.40 min.

[0281] Example 54.4: To a flask containing tert-butyl N-methyl-N-[(4S)-4-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-6-oxo-6-[(7-propoxy-1,3-benzothiazol-2-yl)amino]hexyl]carbamate (34.00 mg, 0.0515 mmol) was added 4 M 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 10.5 mg (36%) of (3S)-6-(methylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-N-(7-propoxy-1,3-benzothiazol-2-yl)hexanamide as an off-white amorphous solid. HPLC / MS m / z: 560.2 [M+H] + , Rt (S): 2.28 min. 1 H NMR (600 MHz, Methanol-d4): 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).

[0282] The following examples were also synthesized by similar procedures: 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 [ka] 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] gave (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) as a white solid. HPLC / MS m / z: 578.234 [M+H] + , Rt (AE): 2.33 min. 1 H NMR (600 MHz, DMSO-d6): 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 (td, 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).

[0283] Example 56: N-[4-fluoro-7-(3-fluoropropoxy)-1,3-benzothiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide [ka]

[0284] 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) was added potassium carbonate (120.06 mg, 0.8687 mmol) while stirring under N at RT. This was stirred for 30 min before adding 1-iodo-3-fluoropropane (0.04 mL, 0.4343 mmol). This was then stirred under N for 7 h. The mixture was diluted with water (2 mL) and acidified to pH 6 with 2N HCl solution, followed by the addition of MeOH (20 mL). This was loaded onto a 5 g SCX-2 column, washed with MeOH, and then eluted with 2N NH in MeOH solution. The basic flash was concentrated under reduced pressure to give 70 mg (66%) of 4-fluoro-7-(3-fluoropropoxy)-1,3-benzothiazol-2-amine as a dark gray solid. HPLC / MS m / z: 245.1 [M+H] + , Rt (R): 1.11 min.

[0285] Example 56.2: To a mixture of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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), followed by 1-propanephosphonic anhydride (50% in DMF) (0.10 mL, 0.1676 mmol). The mixture was stirred at 70° C. under N for 3 d. An additional 2 eq of 1-propanephosphonic anhydride (50% in DMF) (0.10 mL, 0.1676 mmol) was added, and the mixture was stirred at 70° C. under N for 18 h. An additional 2 eq of 1-propanephosphonic anhydride (50% in DMF) (0.10 mL, 0.1676 mmol) was added, and the mixture was stirred under N at 70 °C for 4 h. The crude material was purified by preparative HPLC to give 8.5 mg (19%) of N-[4-fluoro-7-(3-fluoropropoxy)-1,3-benzothiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide as a white solid. HPLC / MS m / z: 525.2 [M+H] + , Rt (Z): 2.41 min. 1H NMR (500 MHz, DMSO-d6): 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).

[0286] Example 57: N-[4-fluoro-7-(3-fluoroethoxy)-1,3-benzothiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide [ka]

[0287] 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) was added potassium carbonate (120.06 mg, 0.8687 mmol) while stirring under N at RT. This was stirred for 30 min before adding 1-iodo-3-fluoroethane (0.05 mL, 0.4343 mmol). This was then stirred under N for 25 h. The mixture was diluted with water (2 mL) and acidified to pH 6 with 2N aqueous HCl, followed by the addition of MeOH (20 mL). This was loaded onto a 5 g SCX-2 column, washed with MeOH, and then eluted with a 2N solution of NH in MeOH. The basic flash was concentrated under reduced pressure to give 93 mg (93%) of 4-fluoro-7-(2-fluoroethoxy)-1,3-benzothiazol-2-amine as a dark gray solid. HPLC / MS m / z: 231.0 [M+H] + , Rt (R): 0.96 min.

[0288] Example 57.2: To a mixture of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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). The mixture was stirred at 70° C. under N for 3 d. Additional 1-propanephosphonic anhydride (50% in DMF) (0.06 mL, 0.2347 mmol) was added, and the mixture was stirred at 70° C. under N for 3 d. Purification by NP silica column chromatography (eluent: 0-10% MeOH / DCM) followed by reverse-phase flash chromatography (eluent: 20-100% MeOH / HO) afforded 22 mg (36%) of N-[4-fluoro-7-(3-fluoroethoxy)-1,3-benzothiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide as a white solid. HPLC / MS m / z: 511.2 [M+H] + , Rt (Z): 2.25 min. 1 H NMR (600 MHz, DMSO-d6): 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).

[0289] The following examples followed 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)propanamide [ka] Obtained using 7-propoxy-1,3-benzothiazol-2-amine [Example 73.1] and 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid B2. 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-d6): 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).

[0290] 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 [ka] 3-[[7-(5-Methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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, 0.1800 M) under argon at RT. 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 (eluent: 20-70% MeOH / HO + 0.1% formic acid) followed by ion-exchange SCX-2 chromatography eluting with 2M NH in MeOH afforded 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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. 1H NMR (600 MHz, DMSO-d6): 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).

[0291] The following examples followed 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 [ka] White powder, 10mg, 0.0190mmol. HPLC / MS m / z: 501.168 [M+H] + , Rt (S): 2.34 min. 1H NMR (600 MHz, DMSO-d6): 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).

[0292] 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 [ka] Off-white solid, 32 mg, 0.0645 mmol. HPLC / MS m / z: 487.154 [M+H] + , Rt (X): 2.68 min. 1H NMR (600 MHz, DMSO-d6): 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), 3.95 (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).

[0293] 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)propanamide [ka]

[0294] Example 62.1: A mixture of 2-amino-4-fluorobenzo[d]thiazol-7-ol (200 mg, 1.09 mmol, 1.00 eq), potassium carbonate (59.9 mg, 4.33 mmol, 3.99 eq), and 1-iodopropane (22.2 mg, 1.30 mmol, 1.20 eq) in acetonitrile (2.00 mL) was stirred at 50 °C for 12 h. After the reaction was completed, the mixture was filtered. The filtrate was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 4-fluoro-7-propoxybenzo[d]thiazol-2-amine (160 mg, 707 umol, 65% yield) as a white solid. 1H 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).

[0295] 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 umol, 1.00 eq), 4-fluoro-7-propoxybenzo[d]thiazol-2-amine (50.0 mg, 221 umol, 1.10 eq), and propylphosphonic anhydride (256 mg, 402 umol, 239 uL, 50% purity in dimethylformamide, 2.00 eq) in dimethylformamide (0.500 mL) was stirred at 50°C for 2 h. After the reaction was complete, the mixture was poured into saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 20%~50%, 10min) 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 (25.37mg, 45.4umol, yield 22%, purity 99%) as a white solid. HPLC / MS m / z: 507.1 [M+H] + , Rt (E): 0.87 min. 1H NMR (400 MHz, DMSO-d6): 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).

[0296] 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)propanamide [ka]

[0297] Example 63.1: To a solution of potassium thiocyanate (1.36 g, 14.0 mmol, 1.10 eq) in acetone (20 mL) was added a solution of acetyl chloride (1.10 g, 14.0 mmol, 0.996 mL, 1.10 eq) in acetone (10 mL) at 20° C. The mixture was stirred at 50° C. for 0.2 h. Then, to the mixture was 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. Then, the mixture was poured into water (200 mL) and filtered. The filter cake was dried under reduced pressure to obtain a residue. The residue was diluted with methanol (10 mL), and to the mixture was added potassium carbonate (3.51 g, 25.4 mmol, 2.00 eq). The mixture was stirred at 25° C. for 12 h. 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-d6): 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).

[0298] 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) was added bromine (608 mg, 3.81 mmol, 196 uL, 0.55 eq) at 0° C. The mixture was stirred at 20° C. for 2 h. The mixture was filtered and the filter cake was dried under reduced pressure to afford 4-chloro-7-methoxybenzo[d]thiazol-2-amine (1.50 g, crude) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): 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).

[0299] 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) was added boron tribromide (9.92 g, 39.6 mmol, 3.82 mL, 5.00 eq) at 0 °C. 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-d6): 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).

[0300] 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 uL, 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 umol, 49% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 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).

[0301] Example 63.5: To a solution of 4-chloro-7-propoxybenzo[d]thiazol-2-amine (100 mg, 412 umol, 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) was added 1-methylimidazole (67.7 mg, 0.824 mmol, 65.7 uL, 2.00 eq) and N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (347 mg, 1.24 mmol, 3.00 eq). The mixture was stirred at 30° C. for 4 h. The mixture was then filtered. The filtrate was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 58%~88%, 9min) 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 (24mg, 45.43umol, yield 11%, purity 99%) as a white solid. HPLC / MS m / z: 523.1 [M+H] + , Rt (E): 0.87 min. 1H NMR (400 MHz, DMSO-d6): 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).

[0302] 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)propanamide [ka]

[0303] 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. To the mixture was added 1-iodopropane (21.1 g, 124 mmol, 1.80 eq). 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 (3×80 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 2-bromo-3-propoxypyridine (14.0 g, 64.8 mmol, 93% yield) as a brown oil. 1H 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).

[0304] Example 64.2: To a solution of acetonitrile (3.06 g, 74.5 mmol, 2.80 eq) in tetrahydrofuran (100 mL) was added n-butyllithium (2.5 M in hexane, 74.5 mmol, 29.8 mL, 2.80 eq) dropwise at −78° C. 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 solution (20 mL) and extracted with ethyl acetate (3×50 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 (SiO2, 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-d6): 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).

[0305] Example 64.3: To a solution of ethyl (1E)-N-(2,4,6-trimethylphenyl)sulfonyloxyethanimidate (10.0 g, 35.0 mmol, 1.00 eq) in dioxane (20 mL) was added perchloric acid (9.32 g, 64.9 mmol, 5.61 mL, 70% purity, 1.85 eq) at 0 ° C. 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 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.

[0306] Example 64.4: To a solution of amino 2,4,6-trimethylbenzenesulfonic acid (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, which was used directly in the next step.

[0307] Example 64.5: To a solution of 1-amino-2-(cyanomethyl)-3-propoxypyridin-1-ium 2,4,6-trimethylbenzenesulfonate 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, 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. 1H 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).

[0308] 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 uL, 4.00 eq) in DMF (1 mL) was added N,N,N,N-tetramethylchloroformamidonium hexafluorophosphate (132 mg, 0.471 mmol, 3.00 eq). The mixture was stirred at 20° C. for 12 h. 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*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 21%~51%, 10min), 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 (9.78mg, 18.52umol, yield 3.93%, purity 98%, formate) as a white solid. HPLC / MS m / z: 472.2 [M+H] + , Rt (E): 0.83 min. 1H NMR (400 MHz, DMSO-d6): 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).

[0309] Example 65: 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(4-propoxypyrazolo[1,5-a]pyrazin-2-yl)propanamide [ka]

[0310] Example 65.1: To a solution of 3-nitro-1H-pyrazole-5-carboxylic acid (6.00 38.2 mmol, 1.00 eq) in acetonitrile (60 mL) was added 1,1-carbonyldiimidazole (7.43 g, 45.8 mmol, 1.20 eq). The mixture was stirred at 60° C. for 3 h. To the mixture was added 2,2-dimethoxyethanamine (4.02 g, 38.2 mmol, 1.00 eq) and the mixture was stirred at 60° C. for 12 h. 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 afford N-(2,2-dimethoxyethyl)-3-nitro-1H-pyrazole-5-carboxamide (6.00 g, 24.6 mmol, 64% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 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).

[0311] 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-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (5.00 g, crude) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 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, 1H), 3.67-3.42 (m, 1H).

[0312] Example 65.3: To a solution of 7-hydroxy-2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2.00 g, 10.1 mmol, 1.00 eq) in toluene (50 mL) was added thionyl 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]pyrazin-4-ol (1.60 g, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 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).

[0313] Example 65.4: To a solution of 2-nitropyrazolo[1,5-a]pyrazin-4-ol (0.800 g, 4.44 mmol, 1.00 eq) in phosphoryl 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 (3×20 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]pyrazine (0.600 g, crude) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): 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).

[0314] Example 65.5: To a solution of propan-1-ol (363 mg, 6.04 mmol, 2.00 eq) in tetrahydrofuran (20 mL) was added sodium hydride (266 mg, 6.65 mmol, 60% purity, 2.20 eq) at 0° C. The mixture was stirred at 20° C. for 0.5 h. To the mixture was added 4-chloro-2-nitropyrazolo[1,5-a]pyrazine (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 (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-nitro-4-propoxypyrazolo[1,5-a]pyrazine (0.6 g, 2.70 mmol, 89% yield) as a yellow solid.1 H NMR (400 MHz, DMSO-d6): 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).

[0315] Example 65.6: To a solution of 2-nitro-4-propoxypyrazolo[1,5-a]pyrazine (300 mg, 1.35 mmol, 1.00 eq) in methanol (8 mL) and water (8 mL) was 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]pyrazin-2-amine (200 mg, 1.04 mmol, 77% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): 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), 0.98 (t, J = 7.4 Hz, 3H).

[0316] Example 65.7: To 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanoic acid B2 (15.5 mg, 52.0 umol, 1.00 eq), 4-propoxypyrazolo[1,5-a]pyrazin-2-amine (10 mg, 52.02 umol, 1.00 eq), and 1-methylimidazole (12.8 mg, 156 umol, 3.00 eq) in DMF (1 mL) was added N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (29.2 mg, 104.05 umol, 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*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 19%~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]pyrazin-2-yl)propanamide (9.47 mg, 19.0 umol, yield 9%, purity 95%) as a white solid. HPLC / MS m / z: 473.1 [M+H] + , Rt (E): 0.82 min. 1H NMR (400 MHz, DMSO-d6): 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).

[0317] Example 66: N-(4-ethoxypyrazolo[1,5-a]pyrazin-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide [ka] 4-Ethoxypyrazolo[1,5-a]pyrazin-2-amine (0.16 g, 898 μmol) was prepared by a procedure similar to Example 65 using ethanol. To a solution of 4-ethoxypyrazolo[1,5-a]pyrazin-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 h. 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 obtain 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%~43%, 10 min) and lyophilized to give N-(4-ethoxypyrazolo[1,5-a]pyrazin-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide (66.32 mg, 143 μmol, yield 36%, purity 99%) as a white solid. HPLC / MS m / z: 459.2 [M+H] + , Rt (E): 0.77 min. 1H NMR (400 MHz, DMSO-d6): 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).

[0318] Example 67: N-(4-(3-fluoropropoxy)pyrazolo[1,5-a]pyrazin-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide [ka]

[0319] Example 67.1: A mixture of 4-chloro-2-nitro-pyrazolo[1,5-a]pyrazine [Example 65] (300 mg, 1.51 mmol, 1.00 eq), cesium carbonate (98.5 mg, 3.02 mmol, 2.00 eq), and 3-fluoropropan-1-ol (142 mg, 1.81 mmol, 1.20 e) in acetonitrile (6.00 mL) was stirred at 50 °C for 2 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 6 / 1 to 2 / 1) to give 4-(3-fluoropropoxy)-2-nitropyrazolo[1,5-a]pyrazine (180 mg, 749 µmol, 49% yield) as a yellow solid. 1H 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).

[0320] Example 67.2: A mixture of 4-(3-fluoropropoxy)-2-nitro-pyrazolo[1,5-a]pyrazine (170 mg, 708 umol, 1.00 eq) and palladium on activated carbon (17.0 mg, 10% purity, wet) in ethyl acetate (10.0 mL) was stirred under a hydrogen atmosphere (15 psi) at 25° C. for 2 h. After the reaction was complete, the mixture was filtered and the filtrate was concentrated to give 4-(3-fluoropropoxy)pyrazolo[1,5-a]pyrazin-2-amine (140 mg, 666 umol, 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).

[0321] 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 umol, 1.00 eq), propylphosphonic anhydride (213 mg, 335 umol, 50% in DMF, 2.00 eq), and 4-(3-fluoropropoxy)pyrazolo[1,5-a]pyrazin-2-amine (38.8 mg, 184 umol, 1.10 eq) in DMF (0.500 mL) was stirred at 40° C. for 2 h. After the reaction was complete, the mixture was poured into saturated aqueous sodium bicarbonate solution (6 mL) and extracted with ethyl acetate (3×4 mL). The combined organic layers were concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 42%~72%, 10min) and lyophilized to give N-(4-(3-fluoropropoxy)pyrazolo[1,5-a]pyrazin-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide (42.53mg, 85.8umol, yield 51%, purity 99%) as a yellow solid. HPLC / MS m / z: 494.4 [M+H] + , Rt (G): 0.90 min. 1H NMR (400 MHz, DMSO-d6): 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).

[0322] The following examples were also prepared by similar procedures. Example 68: N-(4-(2-fluoroethoxy)pyrazolo[1,5-a]pyrazin-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide [ka] White solid, 41.12 mg, 77.1 umol, 98% purity, formate salt. HPLC / MS m / z: 477.2 [M+H] + , Rt (E): 0.80 min. 1H NMR (400 MHz, DMSO-d6): 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).

[0323] Example 69: 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(4-(oxetan-3-yloxy)pyrazolo[1,5-a]pyrazin-2-yl)propanamide [ka] White solid, 3.29mg, 6.70umol, 99% purity. HPLC / MS m / z: 487.4 [M+H] + , Rt (G): 0.86 min. 1 H NMR (400 MHz, DMSO-d6): 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).

[0324] Example 70: N-(4-cyclopropoxypyrazolo[1,5-a]pyrazin-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide [ka] 4-(Cyclopropoxy)pyrazolo[1,5-a]pyrazin-2-amine (20.00 mg, 0.1052 mmol), 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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) at ambient temperature under argon. The reaction mixture was heated at 70 °C for 24 h. The crude reaction mixture was directly purified by preparative HPLC (AccqPrep, focused gradient, 34-44% MeOH in water, pH 3) to afford N-[4-(cyclopropoxy)pyrazolo[1,5-a]pyrazin-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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. 1H NMR (600 MHz, DMSO-d6): 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).

[0325] 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)propanamide [ka]

[0326] 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 (72.8 mg, 5.13 mmol, 1.20 eq). The mixture was stirred at 25 °C for 2 h. After the reaction was complete, the mixture was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 × 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 afford 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).

[0327] 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 the reaction was complete, 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-d6): 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).

[0328] 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 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO, 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).

[0329] Example 71.4: 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 uL) and water (200 uL) were stirred at 30° C. for 12 h. The mixture was concentrated to remove tetrahydrofuran and diluted with water (10 mL). The pH of the aqueous phase was adjusted to approximately 4 by adding hydrochloric acid (1 M). A white solid precipitated and was 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. 1H NMR (400 MHz, DMSO-d6): 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).

[0330] Example 71.5: A mixture of 1-methyl-4-propoxy-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (200 mg, 854 umol, 1.00 eq), diphenylphosphoryl 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 that was purified by flash silica gel chromatography (eluent: 0-45% ethyl acetate / petroleum ether, gradient 25 mL / min) to afford tert-butyl (1-methyl-4-propoxy-1H-pyrrolo[3,2-c]pyridin-2-yl)carbamate (140 mg, 458 umol, 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).

[0331] Example 71.6: tert-Butyl (1-methyl-4-propoxy-1H-pyrrolo[3,2-c]pyridin-2-yl)carbamate (140 mg, 458 umol, 1.00 eq) in hydrochloric acid / ethyl acetate (4 M, 500 uL) 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 salt) as a white solid. HPLC / MS m / z: 206.2 [M+H] + , Rt (F): 0.75 min.

[0332] 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 umol, 1.00 eq), 1-methyl-4-propoxy-pyrrolo[3,2-c]pyridin-2-amine (58.5 mg, 285 umol, 1.00 eq), and propylphosphonic anhydride (181 mg, 285 umol, 169 uL, 50% in DMF, 1.00 eq) in DMF (2.00 mL) was stirred at 30° C. for 2 h. After the reaction was complete, the mixture was poured into saturated aqueous sodium bicarbonate (7 mL) and extracted with ethyl acetate (3 × 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*30mm*3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 32%~62%, 8min) 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 (18.75mg, 38.2umol, yield 13%, purity 99%) as a pink solid. HPLC / MS m / z: 486.2 [M+H] + , Rt (E): 0.74 min. 1H NMR (400 MHz, DMSO-d6): 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).

[0333] 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 [ka]

[0334] Example 72.1: To a solution of acetonitrile (769 mg, 18.7 mmol, 4.40 eq) in tetrahydrofuran (10 mL) was added n-butyllithium (2.50 M, 6.81 mL, 17.0 mmol, 4.00 eq) dropwise at −78° C. 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 (3×20 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 column chromatography (SiO, petroleum ether / ethyl acetate=10 / 1~0 / 1) and preparative HPLC (column: Phenomenex Gemini-NX C75*30mm*3um; mobile phase: [water (10mM NHHCO)-ACN]; B%: 6%~36%, 8min) to give 2-(3-methoxypyridin-2-yl)acetonitrile (0.300g, 2.02mmol, yield 47%) 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).

[0335] Example 72.2: To a solution of O-(mesitylsulfonyl)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-pyridyl)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, which was used directly in the next step. HPLC / MS m / z: 164.0 [M+H] + , Rt (G): 0.67 min.

[0336] 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, 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-d6): 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).

[0337] 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 umol, 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 umol, 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*50mm*3um; mobile phase: [water (0.225% formic acid)-ACN]; B%: 25%-45%, 10min), preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: Purification by HPLC (30%-60%, 8 min) and lyophilization afforded (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) as a pink solid. HPLC / MS m / z: 470.3 [M+H] + , Rt (G): 1.00 min. 1H NMR (400 MHz, DMSO-d6): 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).

[0338] 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)propanamide [ka]

[0339] Example 73.1: 2-Amino-4-methyl-1,3-benzothiazol-7-ol (100.00 mg, 0.5548 mmol) and K2CO3 (153.36 mg, 1.1097 mmol) were mixed in anhydrous DMF (0.55 mL, 1 M) 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 1 M HCl, diluted with MeOH (20 mL), and filtered through a 2 g SCX2 column. The product was released with 2 M 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. 1H NMR (600 MHz, DMSO-d6): 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), 1.68-1.76 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

[0340] Example 73.2: 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-isoquinolyl]amino]propanoic acid B2 (50.00 mg, 0.1676 mmol) were mixed in anhydrous DMF (0.34 mL, 0.5000 M) at ambient temperature under argon. 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-isoquinolyl]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. 1H NMR (600 MHz, DMSO-d6): 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 = 6.4Hz, 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).

[0341] 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 [ka] Prepared in a similar manner to Examples 73 and 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. 1H 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).

[0342] Example 75: 3-(2-methyl-2H-tetrazol-5-yl)-N-(3-oxo-3-((7-propoxybenzo[d]thiazol-2-yl)amino)propyl)benzamide [ka]

[0343] 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 combined organics were washed with saturated aqueous bicarbonate (150 mL) and brine (200 mL) and then dried over MgSO4. 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 pale yellow film, which was used without further purification. HPLC / MS m / z: 290.13 [M+H] + , Rt (P): 1.15 min.

[0344] 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 MgSO4 to afford 3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propanoic acid (137 mg, 85%, 0.4977 mmol) as a white solid. HPLC / MS m / z: 276.12 [M+H] + , Rt (P): 1.03 min.

[0345] Example 75.3: 2-Amino-1,3-benzothiazol-7-ol (79.00 mg, 0.4753 mmol) and K2CO3 (78.83 mg, 0.5704 mmol) were dissolved in dry DMF (3.17 mL), and the mixture was stirred at RT for 30 min. Then, at 0 °C, 1-iodopropane (0.05 mL, 0.4753 mmol) was added. The mixture was stirred at 0 °C for 1 h 30 min. Then, the ice bath was removed, and the reaction mixture was stirred for 2 d. Additional K2CO3 (24 mg) was added and stirred for 20 min. At 0 °C, 1-iodopropane (14 mL) was added. The mixture was stirred at 0 °C for 1 h, then at RT for 30 min. A few drops of water were added to the reaction mixture. Purification by reverse-phase flash chromatography (eluent: 10-80% MeOH / HO + 0.1% formic acid), followed by ion-exchange SCX-2 chromatography eluting with 2M NH 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.

[0346] 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]propanoic 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 argon atmosphere. The resulting solution was stirred at 70° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with DMSO, and directly purified by preparative HPLC (AccqPrep, focused gradient, ACN in water, pH 3) to give 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-d6): 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).

[0347] 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)propanamide [ka]

[0348] Example 76.1: 3-Nitro-4-(trifluoromethyl)phenol (410.00 mg, 1.9796 mmol), potassium carbonate (300.96 mg, 2.1776 mmol), and 1-iodopropane (0.21 mL, 2.1776 mmol) were combined in anhydrous acetone (3.96 mL, 0.5000 M) in a microwave vial under argon. The reaction mixture was heated at 100 °C under microwave irradiation for 2 h. Purification by NP flash chromatography (eluent: 0-10% EtOAc in cyclohexane) afforded 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-d6): 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).

[0349] 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 material was purified directly by NP chromatography (0-20% EtOAc in cyclohexane) to give 5-propoxy-2-(trifluoromethyl)aniline (272 mg, 68%, 1.2409 mmol) as a clear oil. 1H NMR (500 MHz, DMSO-d6): 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).

[0350] 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. A solution of 5-propoxy-2-(trifluoromethyl)aniline (265.00 mg, 1.2089 mmol) in acetone (2.00 mL) was then added and the reaction mixture was continued to stir at 50° C. for 15 min. The reaction mixture was stirred for a further 15 min before the heating was removed. 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 h. Water (50 mL) was added, and 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-d6): 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).

[0351] Example 76.4: To a solution of [5-propoxy-2-(trifluoromethyl)phenyl]thiourea (220.00 mg, 0.7905 mmol) in AcOH (3.95 mL) kept 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 continued to stir for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in MeOH and filtered through an SCX-2 ion exchange column. The product was released with 2 M 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-d6): 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).

[0352] Example 76.5: 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-isoquinolyl]amino]propanoic acid (30.00 mg, 0.1006 mmol) were mixed in anhydrous DMF (0.20 mL, 0.5000 M) at ambient temperature under argon. 1-Propanephosphonic anhydride (50% in DMF) (0.12 mL, 0.2011 mmol) and TEA (0.04 mL, 0.3017 mmol) were added sequentially, and the reaction mixture was stirred for 30 min. The reaction mixture was heated at 60 °C for 1 h and then at 80 °C for 1 h. 2 × 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 h. The reaction mixture was cooled to ambient temperature, quenched with a few drops of water, diluted with DMSO, and directly purified by preparative HPLC (AccqPrep, focused gradient, 35.2–45.2% ACN in water, pH 3). The product-containing fractions were filtered through a 2 g SCX2 ion-exchange column. The product was released with 2 M 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. 1H NMR (500 MHz, DMSO-d6): 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).

[0353] 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)propanamide [ka]

[0354] 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) was added dropwise a solution of BBr in DCM (1 M) (9.23 mL, 9.2322 mmol) at 0 °C, and the mixture was allowed to warm to RT and stirred overnight. MeOH was then added at 0 °C and stirred for an additional 10 min, after which the solvent was evaporated in vacuo. Two additional cycles of dissolution / evaporation with MeOH gave 2-amino-4-fluoro-1,3-benzothiazol-7-ol (929 mg, 100%, 5.0437 mmol) as a dark powder. The product was carried on to the next step without further purification. 1H NMR (500 MHz, DMSO-d6): δ 7.00 (dd, J = 10.7, 8.8 Hz, 1H), 6.53 (dd, J = 8.8, 3.3 Hz, 1H).

[0355] 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), DMF (1.00 mL) and 1-bromopropane (454.59 μL, 5.0046 mmol) were added sequentially. This was stirred at 65° C. for 2 h. The solvent was evaporated, and the residue was reconstituted in EtOAc and water, extracted with EtOAc, dried over MgSO4, and evaporated. Purification by NP silica column chromatography (0-40% EtOAc in cyclohexane) afforded 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.

[0356] Example 77.3: Ethyl (2R)-3-amino-2-(benzyloxycarbonylamino)propionate (367 mg, 1.38 mmol), 5-methyl-3-(2-oxideisoquinolin-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 placed in a microwave vial at RT under argon. The reaction mixture was heated at 60 °C by microwave irradiation for 1 h. The volatiles were removed, and the crude material was purified by RP flash chromatography (30-60% MeOH in water). The product-containing fractions were filtered through a 1 g SCX-2 ion exchange column. The product was released with 2M ammonia in MeOH to give ethyl (2R)-2-(benzyloxycarbonylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoate (409 mg, 62%, 0.8601 mmol) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6): 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), 1.04 (t, J = 7.1 Hz, 3H).

[0357] Example 77.4: Ethyl (2R)-2-(benzyloxycarbonylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoate (200.00 mg, 0.4206 mmol) was dissolved in THF (2.10 mL) at ambient temperature. EtOH (0.42 mL) and aqueous 2 M NaOH (0.42 mL, 0.8412 mmol) were added, and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was neutralized with 2 M aqueous HCl and concentrated under reduced pressure. The crude material was directly purified by RP flash column chromatography (20-80% MeOH in water) to give (2R)-2-(benzyloxycarbonylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid (94 mg, 50%, 0.2101 mmol) as an off-white powder. 1 H NMR (500 MHz, DMSO-d6): 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).

[0358] Example 77.5: (2R)-2-(benzyloxycarbonylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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 (in 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 (eluent: 0-100% EtOAc in cyclohexane) afforded 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-isoquinolyl]amino]methyl]-2-oxo-ethyl]carbamate (55 mg, 75%, 0.0839 mmol) as an off-white solid. 1H NMR (500 MHz, DMSO-d6): 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).

[0359] 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-isoquinolyl]amino]methyl]-2-oxo-ethyl]carbamate (50.00 mg, 0.0763 mmol) was suspended in acetic acid (1.80 mL, 0.0400 M) under an argon atmosphere at room temperature. 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, 72.3-82.3% MeOH in water [+ 0.1% NH]) 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-isoquinolyl]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-d6): 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).

[0360] 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)propenamide [ka] To a mixture of (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid B4 (15.0 mg, 0.048 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18.3 mg, 0.096 mmol), and 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 a nitrogen atmosphere. The resulting solution was stirred at 45° C. overnight. Purification by reverse-phase flash chromatography (eluent: 20-80% MeOH / HO + 0.1% formic acid), followed by ion-exchange SCX-2 chromatography eluting with 2M NH in MeOH, afforded (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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. 1H NMR (600 MHz, DMSO-d6): 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).

[0361] Example 79: N-(7-ethoxybenzo[d]thiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propenamide [ka]

[0362] Example 79.1: 2-Amino-1,3-benzothiazol-7-ol (94.0 mg, 0.56 mmol) and K2CO3 (93.8 mg, 0.68 mmol) were dissolved in dry DMF (3.8 mL), and the resulting mixture was stirred at room temperature for 40 min. Iodoethane (51 μL, 0.56 mmol) was then added at 0 °C. The mixture was stirred at 0 °C for 1 h. The ice bath was then removed, and the reaction mixture was stirred at room temperature for 3 d. Water (~1 mL) was then added to the reaction mixture. The crude solution was purified by reverse-phase column chromatography eluting with 10-80% MeOH in water (both + 0.1% formic acid). Pure fractions were combined and concentrated, followed by purification using an SCX-II ion exchange cartridge (2 g, 15 mL), eluting with MeOH and 2 M NH3 in MeOH. The combined basic fractions were 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-d6): 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).

[0363] 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) was added 1-hydroxybenzotriazole (22.6 mg, 0.17 mmol) under N. The resulting solution was stirred at 60 °C overnight. The crude reaction was purified by reverse-phase column chromatography eluting with 20–100% MeOH in water (both + 0.1% formic acid). Fractions containing the pure compound were combined, evaporated to dryness, and further purified by SCX-II ion exchange cartridge (2 g, 15 mL) using MeOH and 2 M NH in MeOH as eluents. The combined basic fractions were evaporated to dryness to give N-(7-ethoxy-1,3-benzothiazol-2-yl)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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-d6): 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), 3.85 (q, 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).

[0364] 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)propenamide [ka] To a mixture of (2S)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid [B4] (25.0 mg, 0.08 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg, 0.16 mmol), and 7-ethoxy-1,3-benzothiazol-2-amine (Example 79.1) (18.5 mg, 0.096 mmol) in anhydrous DMF (0.5 mL) was added 1-hydroxybenzotriazole (21.5 mg, 0.16 mmol) under a nitrogen atmosphere. The resulting solution was stirred at 60 °C overnight. The crude product was purified by reverse-phase column chromatography (eluent: 20–100% MeOH in water (both + 0.1% formic acid)). The pure product fractions were combined, 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 required product, which was impure (8.5 mg, 88%). The impure product was further purified by preparative TLC (500 microns) using 5% MeOH in DCM as eluent to give (2S)—N-(7-ethoxy-1,3-benzothiazol-2-yl)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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. 1H NMR (600 MHz, DMSO-d6): 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).

[0365] 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 [ka] 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 a nitrogen atmosphere. The resulting solution was stirred at 60 °C for 19 h. The crude material was purified by reverse-phase column chromatography eluting with 20–100% MeOH in water (both with 0.1% formic acid) to afford 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. 1H NMR (600 MHz, DMSO-d6): 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).

[0366] 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)propenamide [ka]

[0367] Example 82.1: A1 (200.0 mg, 0.88 mmol) and methyl (2R)-3-amino-2-hydroxy-propanoate 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 d. The volatiles were evaporated and the crude material was purified by RP column chromatography (eluent: 0-70% MeOH in water (both + 0.1% formic acid modifier)) to afford the desired product, methyl (2R)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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-d4): 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).

[0368] Example 82.2: Methyl (2R)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoate (107.5 mg, 0.33 mmol) was dissolved in anhydrous THF (0.82 mL) and water (0.82 mL). Lithium hydroxide monohydrate (30.2 mg, 0.72 mmol) was added and the resulting mixture was stirred at RT for 21 h. The volatiles were removed in vacuo, and the crude material was dissolved in DMSO (2 mL) and purified by reverse-phase column chromatography (eluent: 5-80% MeOH in water (both + 0.1% formic acid modifier)) to afford (2R)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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-d6): 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).

[0369] Example 82.3: To (2R)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic 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) was added 1-hydroxybenzotriazole (25.8 mg, 0.19 mmol) under a nitrogen atmosphere. The resulting solution was stirred at 60 °C overnight. The crude product was purified by reverse-phase column chromatography (eluent: 20-100% MeOH in water (both + 0.1% formic acid modifier)). The pure product fractions 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 eluents. Further purification by preparative TLC (500 microns) using 5% MeOH in DCM as eluent afforded (2R)-N-(7-ethoxy-1,3-benzothiazol-2-yl)-2-hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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. 1H NMR (500 MHz, DMSO-d6): 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, 1H), 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).

[0370] 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]pyrazin-8(9H)-yl)ethyl)benzamide [ka] 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 dry DMF (0.46 mL). Triethylamine (40 μL, 0.28 mmol) and T3P (0.11 mL, 0.18 mmol) were then added. After 4 h, more T3P (109 μL) and TEA (39 μL) were added to the reaction mixture, which was left stirring at RT for 2 d. The crude material was purified by reverse-phase column chromatography (eluent: 20-90% MeOH in water (both + 0.1% formic acid)). Fractions containing pure product were combined and concentrated, followed by purification via an 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]trideca-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. 1H NMR (600 MHz, DMSO-d6): 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), 7.84 (d, J = 6.0 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.15 (dd, J = 6.1, 0.9 Hz, 1H), 6.97 (d, J = 0.9 Hz, 1H), 4.35 (td, J = 6.5, 2.9 Hz, 4H), 3.94-3.79 (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).

[0371] 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 [ka]

[0372] Example 84.1: 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) was added DIPEA (0.70 mL, 4.00 mmol). The yellow reaction mixture was stirred at room temperature for 2 d. 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 resulting crude material was purified by NP flash silica column chromatography using a gradient of 0-10% MeOH in DCM as eluent to give 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).

[0373] Example 84.2: 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) was added lithium hydroxide (47.4 mg, 1.98 mmol). The reaction mixture was left stirring 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-d4): 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).

[0374] 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 μL, 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 to room temperature, quenched with water (0.2 mL), diluted with DMSO (0.5 mL), and directly loaded onto a Biotage C18 SNAP Ultra column and purified by reverse phase chromatography. The 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-d6): 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, 1H), 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).

[0375] 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)propenamide [ka]

[0376] 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, which was stirred overnight. The volatiles were evaporated, and the crude material was dissolved in ethyl acetate (30 mL), which was washed with an aqueous saturated solution of sodium bicarbonate (30 mL), water (30 mL), and brine (30 mL). The organic layer was then dried over MgSO4, filtered, and evaporated to dryness. The resulting crude material (58 mg) was purified by normal phase silica column chromatography (eluent: 0-20% gradient of MeOH in DCM) to yield the desired regioisomer, 1-methyl-7-propoxy-1H-benzo[d]imidazol-2-amine (9.2 mg). Fractions with the mixture of regioisomers were combined and further purified by preparative TLC (500 microns) using 10% MeOH in DCM as the eluent to yield an additional 4.6 mg of pure desired product. The pure product obtained from column chromatography and preparative TLC was combined to yield 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-d4): 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).

[0377] 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 d. The reaction was diluted with DMSO (0.3 mL) and purified by reverse-phase column chromatography (eluent: 20–100% MeOH in water (both + 0.1% formic acid)). Pure fractions were combined, evaporated to dryness, and further purified by SCX-II ion exchange column (2 g, 15 mL) using MeOH and 2 M NH3 in MeOH solution as eluents. The basic fractions were combined and concentrated under reduced pressure to produce 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)propenamide (5 mg, 31%, 0.01 mmol) as a pale pink solid. HPLC / MS m / z: 486.2 [M+H] + , Rt (T): 1.11 min. 1 H NMR (600 MHz, DMSO-d6): 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].

[0378] 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)propenamide [ka]

[0379] 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 an aqueous saturated solution of sodium bicarbonate (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), an aqueous saturated solution of sodium bicarbonate (80 mL), brine (50 mL), dried over MgSO4, filtered, and evaporated to dryness. The crude was purified by SCX-II ion exchange column using MeOH and a 2M NH3 solution in MeOH as eluents. After evaporation of the solvent, the resulting crude material (0.99 g) was purified by NP silica column chromatography (eluent: 0-10% EtOAc in cyclohexane) to give 2-nitro-6-propoxy-aniline (576 mg, 90%, 2.94 mmol) as a bright orange solid. HPLC / MS m / z: 197.1 [M+H] + , Rt (Y): 1.44 min. 1H NMR (500 MHz, Chloroform-d): δ 7.74 (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).

[0380] 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 placed 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 the microwave vial was resealed, after which the reaction mixture was further heated at 135° C. for 5 min. After cooling, the reaction mixture was poured into an aqueous saturated solution of sodium bicarbonate (75 mL). The bicarbonate phase was extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with an aqueous saturated solution of sodium bicarbonate (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).

[0381] Example 86.3: 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) was added bromine cyanide 5M in MeCN (0.19 mL, 0.97 mmol). The reaction mixture was stirred at RT overnight. The volatiles were evaporated to dryness and the resulting crude was purified by normal phase silica column chromatography (eluent: 2-15% gradient of MeOH in DCM) to yield 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].

[0382] 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 uL, 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 minutes. The reaction mixture was left stirring at 70° C. for 18 h. More T3P (92 uL) and TEA (28 uL) were added to the reaction mixture, which was further stirred at 70° C. for 18 h. The reaction was quenched with water (0.3 mL) and stirred for 5 min before diluting with DMSO (0.4 mL) and purifying by reverse-pha...

Claims

1. Formula I, 【Chemistry 1】 During the ceremony, W is 【Chemistry 2】 wherein 1 to 4 H atoms may be replaced by D, R 1 displays Hal, A, or OA, R 2 teeth, 【Transformation 3】 X indicates CH or N, A is H, F, OH, NH 2 , or R 4 represents an unbranched or branched alkyl or cycloalkyl having 1 to 12 C atoms, optionally substituted by two adjacent CH groups and / or CH 2 The groups may form a double or triple bond and wherein one or two non-adjacent CH groups and / or CH 2 the group may be replaced by N, O, and / or S atoms, and wherein 1 to 7 H atoms may be replaced by D, F, or CI; R 3 displays H or A, R 4 denotes H or unbranched or branched alkyl with 1 to 4 C atoms, Hal denotes F, Cl, Br, or I; and physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers thereof, and mixtures thereof in any proportion.

2. W is 【Chemistry 4】 and R 1 , R 2 , R 3 , R 4 , X, and A have the meanings as in claim 1; 10. The compound of claim 1, and its physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

2. W is 【Transformation 5】 and R 1 , R 2 , R 3 , R 4 , X, and A have the meanings as in claim 1; 10. Compounds according to claim 1 or 2, and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any proportion.

3. R 1 indicates OA, and W.R. 2 , R 3 , R 4 , X, and A have the meanings as in claim 1; Compounds according to any one of claims 1 to 2, and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any proportion.

4. R 1 represents OA, where A represents unbranched or branched alkyl, in which 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; Compounds according to any one of claims 1 to 3, and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any proportion.

5. R 2 teeth, 【Transformation 6】 and W.R. 1 , R 3 , R 4 , X, and A have the meanings as in claim 1; Compounds according to any one of claims 1 to 4, and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any proportion.

6. R 3 denotes 5-methyloxadiazole or 2-methyltretrazol, and W.R. 1 , R 2 , R 4 , X, and A have the meanings as in claim 1; Compounds according to any one of claims 1 to 5, and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio.

7. R 3 represents 5-methyloxadiazole, and W.R. 1 , R 2 , R 4 , X, and A have the meanings as in claim 1; Compounds according to any one of claims 1 to 6, and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio.

8. R 4 denotes methyl, and W.R. 1 , R 2 , R 3 , X, and A have the meanings as in claim 1; Compounds according to any one of claims 1 to 7, and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio.

9. A compound selected from the group consisting of: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

10. 10. Pharmaceutical preparations comprising at least one compound according to any one of claims 1 to 9, and / or their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio.

11. 11. The pharmaceutical preparation of claim 10, further comprising an excipient and / or an adjuvant.

12. 12. A pharmaceutical preparation comprising at least one compound according to any one of claims 1 to 11, and / or their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio, and at least one further pharmaceutically active compound.

13. A process for the preparation of pharmaceutical preparations, characterized in that the compound according to any one of claims 1 to 9, and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio, are brought into a suitable dosage form together with solid, liquid or semi-liquid excipients or adjuvants.

14. A medicament comprising at least one compound according to any one of claims 1 to 9, and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio, for use in the treatment and / or prophylaxis of physiological and / or pathophysiological conditions.

15. A medicament comprising at least one compound according to any one of claims 1 to 9, and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio, for use in the treatment and / or prophylaxis of physiological and / or pathophysiological conditions selected from the group consisting of hyperproliferative diseases and disorders.

16. 16. The medicament for use according to claim 15, wherein the hyperproliferative disease or disorder is cancer.

17. Cancers include 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 thrombocytosis, genitourinary cancer, glioma, glioblastoma, hairy cell leukemia, head and neck cancer, Hodgkin's disease, Kaposi's sarcoma, lung cancer, lymphoma, malignant carcinoid cancer, malignant hypercalcemia, malignant melanoma, malignant pancreatic insulinoma, and medullary thyroid cancer.

17. The medicament for use according to claim 16, wherein the cancer is selected from the group consisting of carcinoma, melanoma, multiple myeloma, mycosis fungoides, myeloid and lymphocytic leukemia, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, polycythemia vera, primary brain tumor, primary macroglobulinemia, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, skin cancer, small cell lung cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, and Wilms' tumor.

18. The following separate packs: a) an effective amount of a compound according to any one of claims 1 to 9, and / or their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio, and b) an effective amount of a further pharmaceutically active compound; A set (kit) consisting of:

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