Substituted heterocycles as HSET inhibitors

Abstract

The present invention relates to substituted heterocycles of general formula I, where W is thiazole, thiophene, pyrazole, imidazole, or isoxazole, and to the use of the compounds of the invention for the treatment and / or prevention of hyperproliferative diseases and disorders in mammals, particularly humans, and to pharmaceutical compositions containing such compounds.

Description

[Technical Field]

[0001] The present invention relates to compounds of general formula I, [ka] the use 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).

[0003] 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).

[0004] 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).

[0005] 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).

[0006] 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 cytotoxicity inducer 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).

[0007] 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 (inducing 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 ).

[0008] 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.

[0009] Thus, there remains a need for therapies for the treatment and prevention of hyperproliferative diseases and disorders such as cancer. Therefore, the objective was to find HSET inhibitors that serve as potential therapeutic agents for the treatment of cancer diseases. Summary of the Invention

[0010] 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.

[0011] The present invention relates to compounds of general formula I, [ka] During the ceremony W is [ka] Display R 1 Hal, CN, A, COOR 7 , CON(R 7 )2, COA', or Het 1 Display R 2 displays H, Hal, or A', R 3 teeth, [ka] Display R 4 , R 8 are each independently H, unbranched or branched alkyl having 1 to 3 C atoms, R 5 represents H or one or more substituents selected from the group Hal, A, OH, OCH3, NH2, NHCH3, N(CH3)2, and CH2CN; R 6is unsubstituted or is selected from Hal, A, OH, N(R7)2, COOR7, CN, NO2, and / or Het 2 represents benzoyl, 2-isoquinolinyl, or 4-quinazolinyl, substituted 1-, 2-, or 3 times with A represents an unbranched or branched alkyl or cycloalkyl having 1 to 10 C atoms, wherein two adjacent CH and / or CH groups may form a double 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 an F or CI atom; A' represents unbranched or branched alkyl having 1 to 4 C atoms, in which 1 to 7 H atoms may be replaced by F or Cl, Het 1 denotes oxadiazolyl which is unsubstituted or substituted at its C atoms by 1 to 4 unbranched or branched alkyl, Het 2 denotes oxadiazolyl, tetrazolyl, pyrazolyl or oxazolyl which is unsubstituted or substituted at its C atoms by 1 to 4 unbranched or branched alkyl, R 7 displays H or A, Hal denotes F, Cl, Br, or I; and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

[0012] The present invention preferably provides a compound of formula I, wherein W is [ka] and R 1 , R 2 , R 3 , R 4 , R 5 , R 6, R 7 , R 8 ,A,A',Het 1 , and Het 2 relates to compounds according to which ##STR00001## has the meaning as in claim 1, and to their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in all proportions.

[0013] The present invention more preferably relates to a compound of formula I, wherein W is [ka] and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 ,A,A',Het 1 , and Het 2 relates to compounds according to which ##STR00001## has the meaning as in claim 1, and to their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in all proportions.

[0014] The present invention particularly preferably relates to a compound of formula I, wherein W is [ka] and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 ,A,A',Het 1 , and Het 2 relates to compounds according to which ##STR00001## has the meaning as in claim 1, and to their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in all proportions.

[0015] The present invention preferably comprises a compound of formula I, wherein R 2 indicates H or A', and W, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 ,A,A',Het 1 , and Het 2 relates to compounds according to which ##STR00001## has the meaning as in claim 1, and to their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in all proportions.

[0016] The present invention more preferably relates to a compound of formula I, wherein R 2 represents H or methyl, as well as W, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 ,A,A',Het 1 , and Het 2 relates to compounds according to which ##STR00001## has the meaning as in claim 1, and to their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in all proportions.

[0017] The present invention preferably comprises a compound of formula I, wherein R 3 teeth, [ka] and W, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 ,A,A',Het 1 , and Het 2relates to compounds according to which ##STR00001## has the meaning as in claim 1, and to their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in all proportions.

[0018] The present invention particularly preferably comprises a compound of formula I, wherein R 3 teeth, [ka] and W, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 ,A,A',Het 1 , and Het 2 relates to compounds according to which ##STR00001## has the meaning as in claim 1, and to their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in all proportions.

[0019] The present invention particularly preferably comprises a compound of formula I, wherein R 6 represents benzoyl or 2-isoquinolinyl, and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 ,A,A',Het 1 , and Het 2 relates to compounds according to which ##STR00001## has the meaning as in claim 1, and to their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in all proportions.

[0020] The present invention preferably relates to compounds according to formula I, wherein Het 2 denotes oxadiazolyl or tetrazolyl, and W, R 1 , R 2 , R 3, R 4 , R 5 , R 6 , R 7 , R 8 , A, A', and Het 1 has the meaning as in claim 1, and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in all proportions.

[0021] The present invention particularly preferably relates to compounds of formula I, wherein Het 2 denotes methyl-oxadiazolyl or methyl-tetrazolyl, and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', and Het 1 relates to compounds according to which ##STR00001## has the meaning as in claim 1, and to their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in all proportions.

[0022] The present invention preferably relates to a compound selected from the group consisting of: [Table A-1]

[0023] [Table A-2]

[0024] [Table A-3]

[0025] [Table A-4]

[0026]

Table A-5

[0027]

Table A-6

[0028]

Table A-7

[0029]

Table A-8

[0030]

Table A-9

[0031]

Table A-10

[0032]

Table A-11

[0033]

Table A-12

[0034]

Table A-13

[0035]

Table A-14

[0036] [Table A-15]

[0037] [Table A-16]

[0038] [Table A-17]

[0039] [Table A-18]

[0040] [Table A-19]

[0041] [Table A-20]

[0042] [Table A-21] and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

[0043] 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

[0044] 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.

[0045] 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.

[0046] 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.

[0047] The compounds of the present invention can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of the compounds of the present invention in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic bases by procedures known in the art. 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 encompassed.

[0048] 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.

[0049] 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).

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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. 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.

[0055] The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.

[0056] 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.

[0057] Pharmaceutically or physiologically acceptable derivatives are understood to mean, for example, salts of the compounds according to the present invention, as well as so-called prodrug compounds. Prodrug compounds are understood to mean 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 are rapidly cleaved or liberated in the organism to form effective compounds according to the present invention. These also include biodegradable polymer derivatives of the compounds according to the present invention, as described, for example, in Int. J. Pharm. 115 (1995), 61-67.

[0058] 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. Very particular preference is given to the hydrochlorides, trifluoroacetates or bistrifluoroacetates of the compounds according to the invention.

[0059] 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).

[0060] Furthermore, the compounds of the present invention are intended to encompass 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-mentioned 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 14Isotopically 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 ( 14 C) 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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. The starting materials or compounds are generally known. If they are novel, they can be prepared by methods known per se.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] Depending on the respective synthetic route, the starting materials may optionally be reacted in the presence of an inert solvent.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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 a microwave is used, the reaction time can be reduced to 1 to 60 minutes.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] The compounds of the invention have been found to be well tolerated and to possess valuable pharmacological properties. 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.

[0087] 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.

[0088] Especially preferred are physiological and / or pathophysiological conditions associated with HSET. 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.

[0089] 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.

[0090] 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.

[0091] 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 and chronic 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, and the like. The cancer is selected from the group consisting of hematologic malignancies, 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.

[0092] 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.

[0093] The medicaments disclosed above are intended to encompass 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.

[0094] In addition, the medicaments disclosed above are intended to encompass 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.

[0095] 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.

[0096] The compounds according to the present 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 the fight against the above-mentioned diseases. They can also be used as diagnostic agents or reagents.

[0097] 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.

[0098] For diagnostic purposes, the compounds according to the invention may be, for example, radiolabeled. Examples of radiolabels are: 3 H, 14C. 231 I, and 125 I. 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 US 4,125,828 and US 4,207,554.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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). The terms "pharmaceutical formulation" and "pharmaceutical preparation" are used synonymously for the purposes of this invention.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] Pharmaceutical preparations according to the invention may also contain mixtures of compounds according to the invention.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] Furthermore, a medicament of this type may be prepared using one of the processes generally known in the pharmaceutical art.

[0121] 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).

[0122] 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.

[0123] 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.

[0124] 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 may be delivered in single-dose or multi-dose containers, such as sealed ampoules and vials, and may 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. Injectable solutions and suspensions prepared according to the formulation may be prepared from sterilized powders, granules, and tablets.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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).

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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: (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);

[0139] (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;

[0140] (iii) active compounds that inhibit cancer invasion, including metalloprotease inhibitors such as marimastat and inhibitors of urokinase-type plasminogen activator receptor function;

[0141] (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;

[0142] (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;

[0143] (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; (vii) antisense therapy, e.g., directed against the targets mentioned above, e.g., ISIS 2503, an anti-Ras antisense;

[0144] (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

[0145] (ix) Immunotherapeutic approaches, including ex-vivo and in-vivo approaches to increase the immunogenicity of tumor cells in a patient, 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.

[0146] (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.

[0147] Medicaments from Table 1 may preferably, but not exclusively, be combined with compounds of the present invention. [Table 1-1]

[0148] [Table 1-2]

[0149] [Table 1-3]

[0150] [Table 1-4]

[0151] [Table 1-5]

[0152] [Table 1-6]

[0153] [Table 1-7]

[0154] [Table 1-8]

[0155] 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.

[0156] 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 to a value between 2 and 10 if necessary, 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. 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)

[0157] 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

[0158] 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.

[0159] 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.

[0160] 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. Chemical shifts (δ) are reported in ppm relative to tetramethylsilane (TMS) referenced to the internal deuterated solvent. 1H 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).

[0161] 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.

[0162] Details of the conditions applied for HPLC / MS spectra recorded on a Shimadzu LCMS-2020 system or an Agilent 1100 HPLC system: (A): Column: HALO C18, 3.0*30mm, 2.0μm; Mobile phase A: water with 0.05% TFA, Mobile phase B: ACN with 0.05% TFA; Gradient: 5%B~100%B until min 0.70, hold until min 1.10, 100%B~5%B until min 1.12, stop after 1.20; Flow: 1.5mL / min.

[0163] (B): Column: Titank C18 2.1*30mm, 1.8μm; Mobile phase A: water with 0.04%NH4OH, Mobile phase B: ACN; Gradient: 10%B~95%B in 1.4min, hold until min 1.90, 95%B~10%B until min 1.92, stop after 2.00; Flow rate: 0.8mL / min. (C): Column: HALO C18, 3.0*30mm, 2.0μm; Mobile phase A: water with 0.05% TFA, Mobile phase B: ACN with 0.05% TFA; Gradient: 5%B~100%B until min 1.20, hold until min 1.80, 100%B~5%B until min 1.82, stop after 2.00; Flow: 1.5mL / min.

[0164] (D): Column: HALO C18, 3.0*30mm, 2.0μm; Mobile phase A: water with 0.05% TFA, Mobile phase B: ACN with 0.05% TFA; Gradient: 5%B~50%B until min 1.80, 50%B~95%B until min 2.50, hold until min 2.80, 95%B~5%B until min 2.81, stop after 3.00; Flow: 1.5mL / min. (E): Column: HALO C18, 3.0*30mm, 2.0μm; Mobile phase A: water with 0.1%FA, Mobile phase B: ACN with 0.1%FA; Gradient: 10%B~95%B until min 1.20, hold until min 1.80, 95%B~10%B until min 1.82, stop after 2.00; Flow: 1.5mL / min.

[0165] (F): 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. (G): Column: Kinetex EVO C18, 3.0x50mm, 2.6µm; Mobile phase A: water with 5mM NH4HCO3, Mobile phase B: ACN; Gradient: 10%B to 95%B in 2.0min, hold to min 2.7, 95%B to 10%B to min 2.75, stop after 3.0, Flow: 1.2mL / min; Wavelength: 254nm.

[0166] (H): Column: Chromolith HR C18, 4.6x50mm, 5.0µm; 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. (I): Column: Shim-pack velox, 3.0*30mm, 2.7μm; Mobile phase A: water with 0.1%FA, Mobile phase B: ACN with 0.1%FA; Gradient: 5%B~100%B until min 1.50, hold until min 1.80, 100%B~5%B until min 1.81, stop after 2.00; Flow: 1.5mL / min.

[0167] (J): Column: HALO C18, 3.0*30mm, 2.0μm; Mobile phase A: water with 0.05%TFA, Mobile phase B: ACN with 0.05%TFA; Gradient: 5%B~95%B until min 2.50, hold until min 2.80, 95%B~5%B until min 2.81, stop after 3.00; Flow: 1.5mL / min. (K): Column: HALO C18, 3.0*30mm, 2.0μm; Mobile phase A: water with 0.1%FA, Mobile phase B: ACN with 0.1%FA; Gradient: 5%B~95%B until min 2.50, hold until min 2.80, 95%B~5%B until min 2.81, stop after 3.00; Flow: 1.5mL / min.

[0168] (L): Column: HALO C18, 3.0*30mm, 2.0μm; Mobile phase A: water with 0.1%FA, Mobile phase B: ACN with 0.1%FA; Gradient: 5%B~100%B until min 1.50, hold until min 1.80, 100%B~5%B until min 1.81, stop after 2.00; Flow: 1.5mL / min. (M): Column: Chromolith HR C18 RP-18e, 4.6x50mm; Mobile phase A: water with 0.05% FA, Mobile phase B: ACN with 0.04% FA; 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.

[0169] (N): Column: Titank C18 2.1*30mm, 1.8μm; Mobile phase A: water with 0.04%NH4OH, Mobile phase B: ACN; Gradient: 10%B~95%B in 2.0min, hold until min 2.80, 95%B~10%B until min 2.81, stop after 3.00; Flow: 0.8mL / min. (O): Column: HALO C18, 3.0*30mm, 2.0μm; Mobile phase A: water with 0.1%FA, Mobile phase B: ACN with 0.1%FA; Gradient: 5%B~95%B until min 2.10, hold until min 2.75, 95%B~5%B until min 2.81, stop after 3.00; 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.

[0170] (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 4 min gradient elution at a flow rate of 0.75 mL / min with 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 reversed to 5:95 (A / B) over 0.1 min, and finally 5:95 (A / B) for 0.4 min.

[0171] 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 equipped with a multimode ESI / APCI source.

[0172] (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 min 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 back to 10:90 (A / B) over 0.15 min, and finally 10:90 (A / B) for 0.1 min.

[0173] (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 min 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.

[0174] (T): Analytical separation was performed on an Agilent Poroshell C18 column (30x2.1mm, 2.6u, 100A) at 30°C using a 2 min 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.

[0175] (U): Analytical separation was performed on an Agilent Poroshell C18 column (30x2.1mm, 2.6u, 100A) at 30°C using a 4 min 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.

[0176] 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.

[0177] (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 2min 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.

[0178] (X): Analytical separation was performed on an Agilent Poroshell C18 column (30x2.1mm, 2.6u, 100A) at 40°C using a 4 min 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.

[0179] (Y): Analytical separation was performed on a Phenomenex Kinetex C18 column (30x2.1 mm, 2.6 u, 100 A) at 40°C using a 2 min gradient elution at a flow rate of 0.6 mL / min with 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.

[0180] (Z): Analytical separation was performed on a Phenomenex Kinetex C18 column (30x2.1 mm, 2.6 u, 100 A) at 40°C using a 4 min 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.

[0181] Example 1: Ethyl 4-methyl-2-(3-(3-methylbenzamido)propanamido)thiazole-5-carboxylate [ka]

[0182] Example 1.1.: To a stirred solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (2 g, 10.57 mmol) and HOBt (3.24 g, 21.14 mmol) in dry DMF at rt under a nitrogen atmosphere were added successively EDC (4.05 g, 21.14 mmol) and ethyl 2-amino-4-methylthiazole-5-carboxylate (2.165 g, 11.63 mmol). The mixture was stirred at 50° C. overnight. The mixture was concentrated in vacuo. The crude product was dissolved in EtOAc and washed with water, 1N HCl, aqueous saturated bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give ethyl 2-[3-(tert-butoxycarbonylamino)propanoylamino]-4-methyl-thiazole-5-carboxylate (3.428 g, 91%, 9.59 mmol) as a yellow solid. HPLC / MS m / z: 358.1 [M+H] + , Rt (R): 1.32 min.

[0183] Example 1.2.: 4M HCl in dioxane (26.86 mL, 107.43 mmol) was added dropwise to a solution of ethyl 2-[3-(tert-butoxycarbonylamino)propanoylamino]-4-methyl-thiazole-5-carboxylate (1.28 g, 3.5811 mmol) in EtOH (35.81 mL). The reaction mixture was stirred at rt for 2 h before being concentrated in vacuo. Purification by ion-exchange SCX-II column chromatography, eluting with 2M NH3 followed by washing with MeOH, gave ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate (867.4 mg, 94%, 3.371 mmol) as a very pale yellow solid. HPLC / MS m / z: 258.1 [M+H] + , Rt (S): 1.52 min.

[0184] Example 1.3.: To 3-methylbenzoic acid (38.1 mg, 0.280 mmol), ethyl 2-(3-aminopropanoylamino)-4-methylthiazole-5-carboxylate (80 mg, 0.311 mmol), and DIPEA (163 μl, 0.933 mmol) in DMF (3109 μl) was added HATU (110 mg, 0.466 mmol), and the reaction mixture was stirred at rt overnight. The mixture was concentrated in vacuo. The crude was dissolved in EtOAc and washed with 1N HCl, aqueous saturated bicarbonate, and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo, and purified by reverse-phase column chromatography (eluent: 0-80% methanol / water, each with 0.1% formic acid) to afford 83 mg (71%, 0.221 mmol) of ethyl 4-methyl-2-(3-(3-methylbenzamido)propanamido)thiazole-5-carboxylate as a colorless solid. HPLC / MS m / z: 376.2 [M+H] + , Rt (P): 1.50 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.55 (t, J = 5.6 Hz, 1H), 7.64 (h, J = 0.9 Hz, 1H), 7.60 (ddd, J = 5.8, 3.4, 1.8 Hz, 1H), 7.34-7.31 (m, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.60-3.51 (m, 2H), 2.75 (t, J = 6.9 Hz, 2H), 2.53 (s, 3H), 2.34 (s, 3H), 1.27 (t, J = 7.1Hz, 3H).

[0185] The following examples were prepared similarly: Example 2: Ethyl 4-methyl-2-(3-(3-(pyrrolidin-1-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 14 mg (26%, 0.0325 mmol) yellow solid. HPLC / MS m / z: 431.2 [M+H] + , Rt (S): 3.05 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.45 (t, J = 5.6 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.95-6.91 (m, 1H), 6.64 (dd, J = 8.2, 1.9 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.54 (q, J = 6.7 Hz, 2H), 3.26-3.18 (m, 4H), 2.74 (t, J = 6.9 Hz, 2H), 2.53 (s, 3H), 2.00-1.90 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H).

[0186] Example 3: Ethyl 2-(3-(3-(1H-pyrazol-1-yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate [ka] 27 mg (51%, 0.0632 mmol) colorless solid. HPLC / MS m / z: 428.1 [M+H] + , Rt (S): 2.70 min. 1H NMR (500 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.78 (t, J = 5.5 Hz, 1H), 8.56-8.52 (m, 1H), 8.26 (t, J = 1.8 Hz, 1H), 7.98 (ddd, J = 8.1, 2.2, 0.9 Hz, 1H), 7.78 (d, J = 1.4 Hz, 1H), 7.74 (dt, J = 7.7, 1.1 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 6.57 (dd, J = 2.5, 1.8 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.60 (q, J = 6.7 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0187] Example 4: Ethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 47 mg (68%, 0.1060 mmol) off-white solid. HPLC / MS m / z: 444.1 [M+H] + , Rt (S): 2.77 min. 1H NMR (500 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.78 (t, J = 5.5 Hz, 1H), 8.56-8.52 (m, 1H), 8.26 (t, J = 1.8 Hz, 1H), 7.98 (ddd, J = 8.1, 2.2, 0.9 Hz, 1H), 7.78 (d, J = 1.4 Hz, 1H), 7.74 (dt, J = 7.7, 1.1 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 6.57 (dd, J = 2.5, 1.8 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.60 (q, J = 6.7 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0188] Example 5:エチル4-メチル-2-(3-(5,6,7,8-テトラヒドロナフタレン-2-カルボキサミド)プロパンアミド)チアゾール-5-カルボキシラート

change

[0189] Example 6: Ethyl 4-methyl-2-(3-(3-(oxazol-5-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 40mg (60%, 0.0934mmol) yellow solid. HPLC / MS m / z: 429.1 [M+H] + , Rt (S): 2.67 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.77 (t, J = 5.5 Hz, 1H), 8.50 (s, 1H), 8.16 (t, J = 1.6 Hz, 1H), 7.93-7.85 (m, 1H), 7.83-7.81 (m, 1H), 7.81-7.80 (m, 1H), 7.75 (s, 1H), 7.57 (t, J = 7.7 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.59 (q, J = 6.7 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0190] Example 7: Ethyl 4-methyl-2-(3-(3-morpholinobenzamido)propanamido)thiazole-5-carboxylate [ka] 22 mg (32%, 0.0493 mmol) off-white solid. HPLC / MS m / z: 447.2 [M+H] + , Rt (S): 2.67 min. 1H NMR (500 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.54 (t, J = 5.6 Hz, 1H), 7.35-7.32 (m, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.08 (ddd, J = 8.1, 2.5, 1.1 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.80-3.69 (m, 4H), 3.55 (q, J = 6.7 Hz, 2H), 3.17-3.07 (m, 4H), 2.75 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0191] Example 8: Ethyl (S)-2-(2-hydroxy-3-(3-methylbenzamido)propanamido)-4-methylthiazole-5-carboxylate [ka] Using (S)-3-((tert-butoxycarbonyl)amino)-2-hydroxypropanoic acid provided 16 mg (12%, 0.041 mmol) of ethyl (S)-2-(2-hydroxy-3-(3-methylbenzamido)propanamido)-4-methylthiazole-5-carboxylate as a colorless solid. HPLC / MS m / z: 392.1 [M+H] + , Rt (S): 2.69 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.46 (t, J = 5.8 Hz, 1H), 7.62 (quint, J = 1.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.33 (dd, J = 5.0, 0.9 Hz, 2H), 5.96 (s, 1H), 4.40 (s, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 2.55 (s, 3H), 2.34 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0192] Example 9: Ethyl 2-[3-[(3-methoxycarbonylbenzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 3-Methoxycarbonylbenzoic acid (35 mg, 0.19 mmol), ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate (50 mg, 0.19 mmol), and DIPEA (103 μL, 0.58 mmol) were dissolved in DMF (1.94 mL). HATU (215.17 mg, 0.9100 mmol) was added, and the reaction mixture was stirred at rt over the weekend. The reaction mixture was then diluted with EtOAc (40 mL) and washed with water (40 mL). The aqueous layer was re-extracted with EtOAc (40 mL). The combined organic layers were washed with aqueous saturated sodium bicarbonate solution (50 mL) and brine (50 mL). The organic layers were dried (MgSO), filtered, and concentrated in vacuo. The crude material was purified using reverse-phase column chromatography with a 12 g C18 Biotage ULTRA column. Elution of the column with 30-100% MeOH in water (both + 0.1% formic acid modifier) ​​gave 16 mg (20%, 0.04 mmol) of ethyl 2-[3-[(3-methoxycarbonylbenzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate as a colorless fluffy solid. HPLC / MS m / z: 420.07 [M+H] + , Rt (R): 1.29 min. 1H NMR (500 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.85 (t, J = 5.5 Hz, 1H), 8.42 (t, J = 1.8 Hz, 1H), 8.09 (dd, J = 7.8, 1.8 Hz, 2H), 7.62 (t, J = 7.8 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.59 (q, J = 6.6 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0193] The following examples were prepared in a similar manner: Example 10: Ethyl 2-[3-[(3-fluoro-5-methoxycarbonyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 43mg(51%) Colorless fluffy solid. HPLC / MS m / z: 438.11 [M+H] + , Rt (R): 1.35 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.93 (t, J = 5.5 Hz, 1H), 8.28 (t, J = 1.5 Hz, 1H), 7.92 (ddd, J = 9.4, 2.6, 1.5 Hz, 1H), 7.85 (ddd, J = 8.8, 2.6, 1.4 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.66-3.47 (m, 2H), 2.77 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0194] Example 11: Ethyl 2-[3-[(2-fluoro-3-methoxycarbonyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 26mg(31%) Colorless fluffy solid. HPLC / MS m / z: 438.11 [M+H] + , Rt (R): 1.23 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.62 (t, J = 5.4 Hz, 1H), 7.95 (ddd, J = 7.7, 6.8, 1.9 Hz, 1H), 7.78 (ddd, J = 8.0, 6.3, 1.9 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.57 (q, J = 6.5 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.54 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0195] Example 12: Ethyl 2-[3-[(2-chloro-5-methoxycarbonyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 41 mg (46%) fine colorless powder. HPLC / MS m / z: 454.08 [M+H] + , Rt (R): 1.27 min. 1H NMR (500 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.72 (t, J = 5.6 Hz, 1H), 7.96 (dd, J = 8.4, 2.2 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.56 (q, J = 6.4 Hz, 2H), 2.77 (t, J = 6.7 Hz, 2H), 2.54 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0196] Example 13: Ethyl 2-[3-[(3-chloro-5-methoxycarbonyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 37mg(42%) Colorless granular solid. HPLC / MS m / z: 454.08 [M+H] + , Rt (R): 1.41 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.95 (t, J = 5.5 Hz, 1H), 8.35 (t, J = 1.5 Hz, 1H), 8.14 (dd, J = 2.1, 1.6 Hz, 1H), 8.06 (dd, J = 2.1, 1.5 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 3.59 (q, J = 6.5 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0197] Example 14: Ethyl 2-[3-[(3-methoxycarbonyl-4-methyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 56mg(66%) Colorless solid. HPLC / MS m / z: 434.14 [M+H] + , Rt (R): 1.33 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.73 (t, J = 5.5 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 7.9, 2.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 3.57 (q, J = 6.7 Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.55 (s, 3H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0198] Example 15: Ethyl 2-[3-[(3-methoxycarbonyl-5-methyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 56mg(67%) Colorless solid. HPLC / MS m / z: 434.14 [M+H] + , Rt (R): 1.35 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.78 (t, J = 5.5 Hz, 1H), 8.30-8.10 (m, 1H), 7.91 (dd, J = 1.6, 0.8 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.57 (q, J = 6.5 Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.54 (s, 3H), 2.41 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0199] Example 16: Ethyl 2-[3-[(3-methoxy-5-methoxycarbonyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 35mg(40%) Colorless solid. HPLC / MS m / z: 450.13 [M+H] + , Rt (R): 1.33 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.81 (t, J = 5.5 Hz, 1H), 8.02 (t, J = 1.4 Hz, 1H), 7.64 (dd, J = 2.6, 1.5 Hz, 1H), 7.57 (dd, J = 2.6, 1.4 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.58 (q, J = 6.6 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0200] Example 17: Ethyl 2-[3-[(3-cyano-5-methoxycarbonyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 32 mg (37%) colorless amorphous solid. HPLC / MS m / z: 445.12 [M+H] + , Rt (R): 1.30 min. 1H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.02 (t, J = 5.5 Hz, 1H), 8.64 (t, J = 1.7 Hz, 1H), 8.50 (t, J = 1.6 Hz, 1H), 8.47 (t, J = 1.6 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.60 (q, J = 6.4 Hz, 2H), 3.32 (s, 4H), 2.78 (t, J = 6.7 Hz, 2H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0201] Example 18: Ethyl 2-[3-[(3-bromo-5-methoxycarbonyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 163mg (47%) amorphous colorless solid. HPLC / MS m / z: 498.03 [M+H] + , Rt (R): 1.43 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.96 (t, J = 5.5 Hz, 1H), 8.39 (s, 1H), 8.27 (t, J = 1.8 Hz, 1H), 8.18 (t, J = 1.7 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.58 (q, J = 6.4 Hz, 2H), 2.76 (q, J = 5.7, 4.7 Hz, 2H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0202] Example 19: Ethyl 2-[3-[(3-ethyl-5-methoxycarbonyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 3mg (7%) colorless amorphous solid. HPLC / MS m / z: 448.15 [M+H] + , Rt (R): 1.40 min. 1 H NMR (500 MHz, MeOD-d4) δ 8.28 (t, J = 1.7 Hz, 1H), 8.03-7.99 (m, 1H), 7.90 (dt, J = 2.3, 1.1 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.76 (t, J = 6.7 Hz, 2H), 2.85 (t, J = 6.7 Hz, 2H), 2.77 (q, J = 7.6 Hz, 2H), 2.58 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.6 Hz, 3H).

[0203] Example 20: Ethyl 2-[3-[(3-hydroxy-5-methoxycarbonyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 20 mg (12%) colorless amorphous solid. HPLC / MS m / z: 436.12 [M+H] + , Rt (R): 1.26 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.52 (s, 1H), 10.12 (s, 1H), 8.73 (t, J = 5.6 Hz, 1H), 7.86 (t, J = 1.6 Hz, 1H), 7.53-7.34 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 3.55 (q, J = 6.5 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.54 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0204] Example 21: Ethyl 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propylamino]thiazole-5-carboxylate [ka] 50mg (51%) colorless amorphous solid. HPLC / MS m / z: 430.15 [M+H] + , Rt (R): 1.31 min. 1 H NMR (500 MHz, DMSO-d6) δ 8.74 (t, J = 5.6 Hz, 1H), 8.47 (dt, J = 1.8, 1.0 Hz, 1H), 8.36 (t, J = 5.5 Hz, 1H), 8.16-8.10 (m, 1H), 8.04 (ddd, J = 7.8, 1.8, 1.2 Hz, 1H), 7.70-7.61 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.33 (m, 4H, plus H2O peak), 2.69 (s, 3H), 2.39 (s, 3H), 1.83 (quint, J = 6.9 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H).

[0205] Example 22: Ethyl 2-[3-[[3-methoxycarbonyl-5-[(E)-styryl]benzoyl]amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 15 mg (24%) colorless amorphous solid. HPLC / MS m / z: 522.17 [M+H] + , Rt (R): 1.56 min. 1H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.90 (t, J = 5.5 Hz, 1H), 8.34 (t, J = 1.7 Hz, 1H), 8.29 (t, J = 1.6 Hz, 1H), 8.27 (t, J = 1.7 Hz, 1H), 7.72-7.59 (m, 2H), 7.48-7.37 (m, 4H), 7.31 (t, J = 7.4 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.62 (q, J = 6.4 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0206] Example 23: Ethyl 2-(3-(3-(1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate [ka] 51 mg (75%). HPLC / MS m / z: 430.1 [M+H] + , Rt (U): 2.77 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.53 (s, 1H), 9.76 (s, 1H), 8.87 (t, J = 5.5 Hz, 1H), 8.50 (t, J = 1.7 Hz, 1H), 8.18 (dt, J = 7.7, 1.4 Hz, 1H), 8.07-8.02 (m, 1H), 7.68 (t, J = 7.8 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.60 (q, J = 6.6 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0207] Example 24: Ethyl 2-(3-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate [ka]

[0208] Example 24.1.: Methyl 3-chloro-5-cyanobenzoate (250.00 mg, 1.2781 mmol) was dissolved in MeOH (12.78 mL). Hydroxylamine (50% in water) (0.20 mL, 6.3906 mmol) was added and the solution was stirred at rt overnight. Removal of the solvent afforded 264 mg (90%, 1.1547 mmol) of methyl 3-chloro-5-[(Z)-N'-hydroxycarbamimidoyl]benzoate as a brown oil, which was used without further purification. HPLC / MS m / z: 229.04, [M+H] + , Rt (P): 0.59 min.

[0209] Example 24.2: Acetic acid (0.06 mL, 1.0852 mmol), methyl 3-chloro-5-[(Z)-N'-hydroxycarbamimidoyl]benzoate (175.00 mg, 0.7654 mmol), and EDC.HCl (207.37 mg, 1.0818 mmol) were dissolved in THF (4.53 mL) and MeCN (4.53 mL) in a microwave vial under N2. The reaction mixture was stirred at rt overnight. DIPEA (0.38 mL, 2.1652 mmol) was added, and the solution was heated at 150 °C for 30 min under microwave irradiation. The solvent was evaporated, and EtOAc was added. The residue was washed twice with HCl 0.1 N, once with a saturated solution of NaHCO3, brine, and dried over MgSO4. Purification by silica gel column chromatography (eluent: 0-4% EtOAc in cyclohexane) provided 50 mg (26%, 0.1979 mmol) of methyl 3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate as a beige oil. HPLC / MS m / z: 253.04, [M+H] +, Rt (R): 1.54 min.

[0210] Example 24.3: To methyl 3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate (50.00 mg, 0.1979 mmol) in THF (0.99 mL) was added water (0.99 mL), followed by LiOH hydrate (24.91 mg, 0.5937 mmol). After stirring at rt, the volatiles were removed in vacuo and the crude material was partitioned between EtOAc (15 mL) and 1 M HCl (15 mL). The organic was retained and the aqueous was extracted with additional EtOAc (10 mL). The organics were combined, dried over MgSO4, and evaporated to dryness to give 46 mg (97%, 0.1928 mmol) of 3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid as a colorless powder, which was used in the next step without further purification. HPLC / MS m / z: 239.02, [M+H] + , Rt (R): 1.44 min.

[0211] Example 24.4.: A procedure similar to the preparation using 3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid and ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate provided 26 mg (52%, 0.0544 mmol) of ethyl 2-(3-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate as a colorless solid. HPLC / MS m / z: 478.09, [M+H] + , Rt (S): 3.06 min. 1H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.98 (t, J = 5.5 Hz, 1H), 8.40 (t, J = 1.6 Hz, 1H), 8.08 (dt, J = 9.4, 1.9 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.60 (q, J = 6.4 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0212] The following example was prepared in an analogous manner using propyl 2-amino-4-methyl-thiazole-5-carboxylate. Example 25: Propyl 2-(3-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate [ka] 31 mg (60%) colorless solid. HPLC / MS m / z: 492.11, [M+H] + , Rt (S): 3.20 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.98 (t, J = 5.6 Hz, 1H), 8.40 (t, J = 1.5 Hz, 1H), 8.08 (dt, J = 7.6, 1.9 Hz, 2H), 4.15 (t, J = 6.5 Hz, 2H), 3.60 (q, J = 6.5 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.53 (s, 3H), 1.67 (sext, J = 7.1 Hz, 2H), 0.93 (t, J = 7.4Hz, 3H).

[0213] Example 26: Propyl 4-methyl-2-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] A similar procedure was used to prepare methyl 3-cyano-5-methyl-benzoate to provide 58 mg (73%) of propyl 4-methyl-2-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate as a colorless solid. HPLC / MS m / z: 472.16, [M+H] + , Rt (S): 3.04 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.80 (t, J = 5.5 Hz, 1H), 8.25 (t, J = 1.6 Hz, 1H), 7.95 (td, J = 1.6, 0.8 Hz, 1H), 7.85 (td, J = 1.7, 0.8 Hz, 1H), 4.15 (t, J = 6.5 Hz, 2H), 3.59 (q, J = 6.5 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.67 (s, 3H), 2.53 (s, 3H), 2.44-2.41 (m, 3H), 1.67 (dtd, J = 13.8, 7.4, 6.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0214] Example 27: Propyl 1-methyl-3-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-1H-pyrazole-5-carboxylate [ka] Propyl 1-methyl-3-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-1H-pyrazole-5-carboxylate (20 mg, 21%, 0.0440 mmol) was prepared in a similar manner from methyl 3-cyano-5-methylbenzoate and propyl 5-amino-2-methylpyrazole-3-carboxylate as a colorless solid. HPLC / MS m / z: 455.20, [M+H] + , Rt (S): 2.86 min. 1 H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.75 (t, J = 5.5 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 7.95 (td, J = 1.7, 0.8 Hz, 1H), 7.86 (td, J = 1.7, 0.8 Hz, 1H), 7.05 (s, 1H), 4.20 (t, J = 6.5 Hz, 2H), 3.98 (s, 3H), 3.54 (td, J = 7.0, 5.4 Hz, 2H), 2.67 (s, 3H), 2.62 (t, J = 7.1 Hz, 2H), 2.43 (s, 3H), 1.76-1.65 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0215] Example 28: Propyl 2-(3-(3-cyano-5-(trifluoromethyl)benzamido)propanamido)-4-methylthiazole-5-carboxylate [ka] 40.5 mg (53%) yellow solid. HPLC / MS m / z: 469.12, [M+H] + , Rt (S): 3.09 min. 1H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 9.04 (t, J = 5.5 Hz, 1H), 8.54 (d, J = 1.8 Hz, 2H), 8.43 (s, 1H), 4.15 (t, J = 6.5 Hz, 2H), 3.61 (q, J = 6.4 Hz, 2H), 2.78 (t, J = 6.7 Hz, 2H), 2.54 (s, 3H), 1.67 (h, J = 7.0 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0216] Example 29: Propyl 2-(3-(3-(tert-butyl)-5-(methoxycarbonyl)benzamido)-propanamido)-4-methylthiazole-5-carboxylate [ka] 23mg(36%) Colorless solid. HPLC / MS m / z: 490.20, [M+H] + , Rt (R): 3.31 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.86 (t, J = 5.6 Hz, 1H), 8.25 (t, J = 1.6 Hz, 1H), 8.11 (t, J = 1.8 Hz, 1H), 8.07 (t, J = 1.7 Hz, 1H), 4.15 (t, J = 6.5 Hz, 2H), 3.88 (s, 3H), 3.59 (q, J = 6.5 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.67 (dtd, J = 13.7, 7.4, 6.5 Hz, 2H), 1.32 (s, 9H), 0.94 (t, J = 7.4 Hz, 3H).

[0217] Example 30: Propyl 2-(3-(3-cyano-5-(methoxycarbonyl)benzamido)propanamido)-4-methylthiazole-5-carboxylate [ka] 15mg(10%) Colorless solid. HPLC / MS m / z: 459.13, [M+H] + , Rt (S): 2.94 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.02 (t, J = 5.5 Hz, 1H), 8.64 (t, J = 1.7 Hz, 1H), 8.50 (t, J = 1.7 Hz, 1H), 8.47 (t, J = 1.6 Hz, 1H), 4.15 (t, J = 6.5 Hz, 2H), 3.92 (s, 3H), 3.60 (q, J = 6.4 Hz, 2H), 2.78 (t, J = 6.6 Hz, 2H), 2.53 (s, 3H), 1.67 (sext, J = 7.0 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0218] Example 31: N-[3-[(5-tert-butyl-4-methyl-thiazol-2-yl)amino]-3-oxo-propyl]-3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide [ka]

[0219] Example 31.1.: 3-Chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid [0] was used in a procedure similar to 0 to provide 3-[[3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid. HPLC / MS m / z: 310.06, [M+H] + , Rt (T): 1.21 min.

[0220] Example 31.2.: To a vial was added 3-[[3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid (20.00 mg, 0.0646 mmol), 5-tert-butyl-4-methyl-thiazol-2-ylamine (32.99 mg, 0.1937 mmol), PyBrop (72.25 mg, 0.1550 mmol), followed by dry DMF (0.32 mL) and DIPEA (40.49 μL, 0.2325 mmol). The resulting solution was stirred at rt overnight. The crude material was partitioned between water (14 mL) and EtOAc (35 mL). After separation, the organic layer was then washed with brine (40 mL), dried (MgSO), filtered, and concentrated to dryness under reduced pressure. Purification was performed by silica gel column chromatography (eluent: 0-10% MeOH in DCM). Further purification by reverse-phase column chromatography (eluent: 30-100% MeOH in water (both + 0.1% formic acid)) provided 3.97 mg (13%, 0.0086 mmol) of N-[3-[(5-tert-butyl-4-methyl-thiazol-2-yl)amino]-3-oxopropyl]-3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide as a colorless solid. HPLC / MS m / z: 462.14 [M+H] + , Rt (T): 1.58 min. 1 H NMR (600 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.95 (t, J = 5.5 Hz, 1H), 8.41 (t, J = 1.6 Hz, 1H), 8.10 (t, J = 1.8 Hz, 1H), 8.08 (t, J = 1.8 Hz, 1H), 3.56 (q, J = 6.7 Hz, 2H), 2.69 (s, 3H), 2.68 (d, J = 7.0 Hz, 2H), 2.30 (s, 3H), 1.35 (s, 9H).

[0221] Example 32: Propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzamido)propanamido)thiazole-5-carboxylate [ka]

[0222] Example 32.1.: Propyl 2-[3-[[3-cyano-5-(trifluoromethyl)benzoyl]amino]propanoylamino]-4-methyl-thiazole-5-carboxylate[0] (105.00 mg, 0.2241 mmol) and TEA (0.03 mL, 0.2241 mmol) were heated in [bmim]OAc (0.22 mL) at 80 °C and hydroxylamine hydrochloride (31.15 mg, 0.4483 mmol) was added. The solution was stirred for 30 min. The solution was diluted with EtOAc (30 mL), washed with water (3 x 20 mL), brine (30 mL) before drying over MgSO and concentrating in vacuo to provide 115 mg (102%, 0.2293 mmol) of propyl 2-[3-[[3-(N-hydroxycarbamimidoyl)-5-(trifluoromethyl)benzoyl]amino]propanoylamino]-4-methyl-thiazole-5-carboxylate as a colorless solid, which was used in the next step without further purification. HPLC / MS m / z: 502.14, [M+H] + , Rt (R): 1.46 min.

[0223] Example 32.2.: To a solution of propyl 2-[3-[[3-(N-hydroxycarbamimidoyl)-5-(trifluoromethyl)benzoyl]amino]propanoylamino]-4-methyl-thiazole-5-carboxylate (20.00 mg, 0.0368 mmol) in DMSO (0.40 mL) was added potassium hydroxide (2.06 mg, 0.0368 mmol). The solution was stirred at rt for 1 h. Water (15 mL) was added and the residue was extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with brine (15 mL), dried over MgSO4, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: 0-55% EtOAc in cyclohexane), followed by further purification by reverse-phase column chromatography (eluent: 25-100% MeOH in water, both with 0.1% formic acid as buffer) provided propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzamido)propanamido)thiazole-5-carboxylate (6 mg, 31%, 0.0114 mmol) as a colorless solid. HPLC / MS m / z: 527.14, [M+H] + , Rt (S): 3.27 min. 1 H NMR (500 MHz, Methanol-d4) δ 8.74-8.71 (m, 1H), 8.44-8.42 (m, 1H), 8.29-8.27 (m, 1H), 4.20 (t, J = 6.6 Hz, 2H), 3.79 (t, J = 6.7 Hz, 2H), 2.87 (t, J = 6.7 Hz, 2H), 2.68 (s, 3H), 2.56 (d, J = 1.2 Hz, 3H), 1.75 (dtd, J = 14.0, 7.4, 6.5 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0224] Example 33: Propyl 2-[3-[(3-methoxycarbonyl-5-nitro-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate [ka] 134mg (58%) pale yellow powder (134mg, 58%, 0.28mmol). HPLC / MS m / z: 479.12 [M+H] + , Rt (R): 1.42 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.56 (s, 1H), 9.23 (t, J = 5.5 Hz, 1H), 8.90 (dd, J = 2.2, 1.6 Hz, 1H), 8.79 (t, J = 1.6 Hz, 1H), 8.72 (dd, J = 2.2, 1.4 Hz, 1H), 4.15 (t, J = 6.5 Hz, 2H), 3.95 (s, 3H), 3.63 (q, J = 6.4 Hz, 2H), 2.80 (t, J = 6.7 Hz, 2H), 2.53 (s, 3H), 1.67 (dtd, J = 13.8, 7.4, 6.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0225] Example 34: Ethyl 4-methyl-2-(3-(3-(3-methyl-1,2,4-oxadiazol-5-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 3-(3-Methyl-1,2,4-oxadiazol-5-yl)benzoic acid (31.74 mg, 0.1555 mmol), ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate (40.00 mg, 0.1555 mmol), and DIPEA (81.45 μL, 0.4664 mmol) were dissolved in DMF (1.55 mL). HATU (54.86 mg, 0.2332 mmol) was added and stirred at rt for 18 h. The mixture was diluted with EtOAc and washed with water, aqueous saturated bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: 0-3% MeOH in DCM). This material was further purified by recrystallization in warm DMSO to provide 4-methyl-2-(3-(3-(3-methyl-1,2,4-oxadiazol-5-yl)benzamido)propanamido)thiazole-5-carboxylate (8 mg, 12%, 0.0180 mmol) as colorless needles. HPLC / MS m / z: 444.1 [M+H] + , Rt (P): 1.49 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.93 (t, J = 5.5 Hz, 1H), 8.54 (dt, J = 1.8, 1.0 Hz, 1H), 8.22 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 8.13 (ddd, J = 7.9, 1.9, 1.2 Hz, 1H), 7.76-7.69 (m, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.61 (q, J = 6.5 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 2.54 (s, 3H), 2.44 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0226] The following examples were also prepared by similar procedures: Example 35: Cyclopropylmethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 30mg(57%) Colorless powder. HPLC / MS m / z: 470.15, [M+H] + , Rt (S): 2.93 min. 1 H NMR (500 MHz, Methanol-d4) δ 8.49 (t, J = 1.8 Hz, 1H), 8.18 (dt, J = 7.7, 1.4 Hz, 1H), 7.96 (dt, J = 7.8, 1.5 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 4.09 (d, J = 7.2 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H), 2.86 (t, J = 6.7 Hz, 2H), 2.66 (s, 3H), 2.57 (s, 3H), 1.27-1.19 (m, 1H), 0.65-0.57 (m, 2H), 0.40-0.30 (m, 2H).

[0227] Example 36: Ethyl 2-(3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate [ka] To ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate (40.00 mg, 0.1555 mmol), 3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzoic acid (33.92 mg, 0.1555 mmol) in DMF (1.55 mL) was added DIPEA (81.45 μL, 0.4664 mmol), followed by HATU (54.86 mg, 0.2332 mmol). The reaction was stirred at rt for 18 h. The mixture was diluted with EtOAc and washed with water, aqueous saturated bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: 2-8% EtOH in DCM). Further purification by reverse-phase column chromatography (eluent: 20-100% MeOH in water (both + 0.1% formic acid modifier)) provided ethyl 2-(3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4-methyl-thiazole-5-carboxylate (15 mg, 21%, 0.0328 mmol) as a fine, colorless powder. HPLC / MS m / z: 458.1 [M+H] + , Rt (S): 3.00 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.45 (t, J = 1.7 Hz, 1H), 8.14 (dt, J = 7.7, 1.3 Hz, 1H), 8.02 (dt, J = 7.9, 1.3 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.60 (q, J = 6.5 Hz, 2H), 3.03 (q, J = 7.6 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.35 (t, J = 7.6 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0228] Example 37: Ethyl 4-methyl-2-(3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] To ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate (40.00 mg, 0.1555 mmol), 3-(5-methyl-1,3,4-oxadiazol-2-yl)benzoic acid (31.74 mg, 0.1555 mmol) in DMF (1.55 mL) was added DIPEA (81.45 uL, 0.4664 mmol), followed by HATU (54.86 mg, 0.2332 mmol). The reaction was stirred at rt overnight and allowed to stand at rt over the weekend. The mixture was diluted with EtOAc (25 mL) and washed with water (25 mL), saturated aqueous bicarbonate (10 mL), and the organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by reverse-phase column chromatography (eluent: 30-90% MeOH in water (both + 0.1% formic acid modifier)) provided ethyl-4-methyl-2-(3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)benzamido)propanamido)-thiazole-5-carboxylate (10 mg, 15%, 0.0225 mmol) as a colorless powder. HPLC / MS m / z: 444.1 [M+H] + , Rt (S): 2.73 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.90 (t, J = 5.5 Hz, 1H), 8.42 (t, J = 1.8 Hz, 1H), 8.14-8.09 (m, 1H), 8.05 (dt, J = 7.9, 1.3 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.60 (td, J = 6.6 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.60 (s, 3H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0229] Example 38: Ethyl 4-methyl-2-(3-(3-(2-methyl-2H-tetrazol-5-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] To ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate (40.00 mg, 0.1555 mmol), 3-(2-methyltetrazol-5-yl)benzoic acid (31.74 mg, 0.1555 mmol) in DMF (1.55 mL) was added DIPEA (108.60 uL, 0.6218 mmol), followed by HATU (54.86 mg, 0.2332 mmol). The reaction was stirred at rt overnight. The mixture was diluted with EtOAc and washed with water, aqueous saturated bicarbonate, and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. This was purified by reverse-phase column chromatography (eluent: 30-100% MeOH in water (both + 0.1% formic acid modifier)) to provide ethyl 4-methyl-2-(3-(3-(2-methyl-2H-tetrazol-5-yl)benzamido)propanamido)thiazole-5-carboxylate (21 mg, 30%, 0.0474 mmol) as a colorless powder. HPLC / MS m / z: 444.1 [M+H] + , Rt (R): 1.59 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.52 (t, J = 1.7 Hz, 1H), 8.19 (dt, J = 7.7, 1.3 Hz, 1H), 7.98 (dt, J = 7.9, 1.3 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 4.45 (s, 3H), 4.23 (q, J = 7.1 Hz, 2H), 3.60 (q, J = 6.5 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.32-1.24 (m, 3H).

[0230] Example 39: tert-Butyl 4-methyl-2-[3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate [ka] Example 39.1.: 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 at rt overnight. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (120 mL). The water was extracted with fresh EtOAc (100 mL). The organics were combined and washed with saturated aqueous bicarbonate (150 mL) and brine (200 mL) before drying 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 in the next step without further purification. HPLC / MS m / z: 290.13, [M+H] + , Rt (P): 1.15 min.

[0231] Example 39.2.: 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 LiOH monohydrate (98.63 mg, 2.3506 mmol). After stirring for 45 min, LCMS indicated complete conversion (product peak m / z = 276, rt = 1.03 min), so 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 combined organics were washed with brine (60 mL) and dried over MgSO4. This gave 3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propanoic acid (137 mg, 85%, 0.4977 mmol) as a colorless solid. HPLC / MS m / z: 276.11, [M+H] + , Rt (P): 1.03 min.

[0232] Example 39.3.: To a solution of HOBt (29.45 mg, 0.2180 mmol), 3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propanoic acid (30.00 mg, 0.1090 mmol) in DMF (0.54 mL) was added EDC (33.84 mg, 0.2180 mmol) and tert-butyl 2-amino-4-methyl-thiazole-5-carboxylate (27.79 mg, 0.1297 mmol). The mixture was stirred at 70° C. for 18 h. Purification by reverse-phase column chromatography (eluent: 10–100% MeOH in water (both + 0.1% formic acid modifier)) provided (tert-butyl 4-methyl-2-[3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate (41 mg, 80%, 0.0870 mmol) as a colorless solid. HPLC / MS m / z: 472.12 [M+H] + , Rt (R): 1.41 min. 1H NMR (600 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.53 (t, J = 1.8 Hz, 1H), 8.19 (dt, J = 7.7, 1.4 Hz, 1H), 7.99 (dt, J = 7.8, 1.5 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 4.45 (s, 3H), 3.61 (q, J = 6.5 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 1.51 (s, 9H).

[0233] The following examples were prepared similarly: Example 40: Isopropyl 4-methyl-2-[3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]-propanoylamino]thiazole-5-carboxylate [ka] 27 mg (54%) colorless amorphous solid. HPLC / MS m / z: 458.16 [M+H] + , Rt (R): 1.36 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.52 (t, J = 1.8 Hz, 1H), 8.19 (dt, J = 7.7, 1.4 Hz, 1H), 7.98 (dt, J = 7.9, 1.4 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 4.45 (s, 3H), 3.60 (q, J = 6.5 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.28 (d, J = 6.2 Hz, 6H).

[0234] Example 41: N-[3-[(5-tert-butyl-4-methyl-thiazol-2-yl)amino]-3-oxo-propyl]-3-(2-methyltetrazol-5-yl)benzamide [ka] 7mg(24%) Colorless solid. HPLC / MS m / z: 428.19 [M+H] + , Rt (T): 1.40 min. 1 H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.83 (t, J = 5.5 Hz, 1H), 8.62-8.47 (m, 1H), 8.27-8.14 (m, 1H), 7.98 (ddd, J = 7.9, 1.9, 1.2 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.45 (s, 3H), 3.57 (q, J = 6.6 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H), 2.29 (s, 3H), 1.35 (s, 9H).

[0235] Example 42: Ethyl 2-(3-(3-(ethoxycarbonyl)benzamido)propanamido)-4-methylthiazole-5-carboxylate [ka] To 3-ethoxycarbonylbenzoic acid (37.73 mg, 0.1943 mmol), ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate (50.00 mg, 0.1943 mmol) in DMF (0.97 mL) was added DIPEA (135.75 uL, 0.7773 mmol), followed by HATU (68.57 mg, 0.2915 mmol). The reaction was stirred at rt overnight. The mixture was diluted with EtOAc and washed with water, aqueous saturated bicarbonate, and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by reverse-phase column chromatography (eluent: 30-100% MeOH in water (both + 0.1% formic acid modifier)), followed by silica gel column chromatography (eluent: 20-50% MeOH in DCM) furnished ethyl 2-(3-(3-(ethoxycarbonyl)benzamido)propanamido)-4-methylthiazole-5-carboxylate (5.6 mg, 7%, 0.0129 mmol) as a clear glass. HPLC / MS m / z: 434.1 [M+H] + , Rt (S): 2.90 min. 1 H NMR (500 MHz, Acetone-d6) δ 11.34 (s, 1H), 8.50 (td, J = 1.9, 0.6 Hz, 1H), 8.22 (s, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.61 (td, J = 7.8, 0.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.82 (q, J = 6.3 Hz, 2H), 2.97 (t, J = 6.5 Hz, 2H), 2.53 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0236] Example 43: Ethyl 4-methyl-2-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka]

[0237] Example 43.1.: Methyl 3-cyano-5-methylbenzoate (268.00 mg, 1.5299 mmol) was dissolved in MeOH (15.30 mL). Hydroxylamine (50% in water) (0.47 mL, 3.8246 mmol) was added and the solution was stirred at rt overnight. The solvent was removed in vacuo to afford methyl 3-[(Z)-N'-hydroxycarbamimidoyl]-5-methyl-benzoate (159 mg, 50%, 0.7637 mmol) as a brown oil, which was used without further purification. HPLC / MS m / z: 194.1 [M+H] + , Rt (P): 1.10 min.

[0238] Example 43.2: Acetic acid (0.06 mL, 1.0827 mmol), methyl 3-[(Z)-N'-hydroxycarbamimidoyl]-5-methyl-benzoate (159.00 mg, 0.7637 mmol), and EDC.HCl (206.89 mg, 1.0793 mmol) were dissolved in THF (3.00 mL) and MeCN (3.00 mL) in a microwave vial under a nitrogen atmosphere. The reaction mixture was stirred at rt overnight. DIPEA (0.38 mL, 2.1601 mmol) was added, and the solution was heated at 150 °C under microwave irradiation for 1 hr. The solvent was removed in vacuo, and DCM (25 mL) and water (25 mL) were added. After shaking, the DCM was separated using a Telos phase extractor, and the volatiles were removed in vacuo. Purification by reverse-phase column chromatography (eluent: 30–100% MeOH in water (both + 0.1% formic acid modifier)) provided methyl 3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate (25 mg, 13%, 0.0980 mmol). 1H NMR (500 MHz, Chloroform-d) δ 8.53 (d, J = 1.9 Hz, 1H), 8.07 (td, J = 1.7, 0.9 Hz, 1H), 8.00 (td, J = 1.7, 0.9 Hz, 1H), 3.94 (s, 3H), 2.67 (s, 3H), 2.47 (d, J = 0.8 Hz, 3H).

[0239] Example 43.3.: To methyl 3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate (23.00 mg, 0.0990 mmol) in THF (0.50 mL) was added water (0.50 mL), followed by lithium hydroxide hydrate (8.31 mg, 0.1981 mmol). After stirring overnight, the volatiles were removed in vacuo and the crude material was partitioned between EtOAc (15 mL) and 1 M HCl (15 mL). The organic was retained and the aqueous was extracted with additional EtOAc (10 mL). The organics were combined, dried over MgSO4, and concentrated to give 3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (17 mg, 59% yield, 75% purity, 0.0584 mmol) as a colorless powder. This was used in the next step without further purification. HPLC / MS m / z: 219.1 [M+H] + , Rt (R): 1.18 min.

[0240] Example 43.4.: To 3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (17.00 mg, 0.0779 mmol), ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate (20.05 mg, 0.0779 mmol) in DMF (0.73 mL) was added HATU (29.62 mg, 0.0779 mmol) and DIPEA (54.43 uL, 0.3116 mmol). After stirring at rt for 1.5 h, the volatiles were removed in vacuo. Purification was carried out by silica gel column chromatography (eluent: EtOH gradient in DCM) followed by reverse-phase column chromatography (eluent: MeCN gradient in DCM). Final purification by semi-preparative HPLC (65%-80% MeOH in water) provided ethyl 4-methyl-2-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate (4 mg, 11%, 0.0087 mmol) as a clear glass. HPLC / MS m / z: 458.1 [M+H] + , Rt (S): 2.90 min. 1 H NMR (500 MHz, Acetone-d6) δ 11.35 (s, 1H), 8.32 (d, J = 1.8 Hz, 1H), 8.23 ​​(s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.84 (q, J = 6.4 Hz, 2H), 2.98 (t, J = 6.6 Hz, 2H), 2.67 (s, 3H), 2.52 (s, 3H), 2.46 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0241] Example 44: Propyl 2-(3-(3-(methoxycarbonyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate [ka]

[0242] Example 44.1.: Propyl 2-[3-[(3-cyano-5-methoxycarbonyl-benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate[0] (61.00 mg, 0.1330 mmol) and TEA (0.02 mL, 0.1330 mmol) in [bmim]OAc (0.13 mL) were heated at 80 °C and hydroxylamine hydrochloride (18.49 mg, 0.2661 mmol) was added. The solution was stirred for 30 min. The solution was cooled to rt and water was added (15 mL). The residue was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, and concentrated under reduced pressure to provide propyl 2-[3-[[3-(N-hydroxycarbamimidoyl)-5-methoxycarbonyl-benzoyl]amino]propanoylamino]-4-methyl-thiazole-5-carboxylate (63.5 mg, 97%, 0.1292 mmol). HPLC / MS m / z: 492.15, [M+H] + , Rt (P): 1.35 min.

[0243] Example 44.2: Acetic acid (0.004 mL, 0.0712 mmol), propyl 2-[3-[[3-(N-hydroxycarbamimidoyl)-5-methoxycarbonyl-benzoyl]amino]propanoylamino]-4-methyl-thiazole-5-carboxylate (35.00 mg, 0.0712 mmol), and EDC.HCl (14.33 mg, 0.0748 mmol) were dissolved in MeCN (0.43 mL) and THF (0.43 mL) in a 0.5-2 mL microwave vial under a nitrogen atmosphere. The solution was stirred at rt overnight. DIPEA (0.03 mL, 0.1709 mmol) was added, and the mixture was heated in a microwave at 150 °C for 30 min. The solvent was removed in vacuo. The residue was dissolved in EtOAc (30 mL), washed with water (30 mL), saturated aqueous bicarbonate (30 mL), and brine (30 mL) before drying over magnesium sulfate and concentrating under reduced pressure. Purification by reverse-phase column chromatography (eluent: 25-100% MeOH in water, both with 0.1% formic acid as buffer) provided propyl 2-(3-(3-(methoxycarbonyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate as a colorless solid. HPLC / MS m / z: 516.15, [M+H] + , Rt (S): 3.09 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.56 (s, 1H), 9.11 (t, J = 5.5 Hz, 1H), 8.70 (t, J = 1.7 Hz, 1H), 8.63 (t, J = 1.7 Hz, 1H), 8.60 (t, J = 1.7 Hz, 1H), 4.15 (t, J = 6.5 Hz, 2H), 3.93 (s, 3H), 3.62 (q, J = 6.4 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 2.71 (s, 3H), 2.53 (s, 3H), 1.71-1.63 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0244] Example 45: Ethyl 4-methyl-2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoylamino]thiazole-5-carboxylate [ka]

[0245] Example 45.1.: 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-adsorbed onto silica, and purified by column chromatography (eluent: MeOH / DCM = 0-10% gradient) to provide 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).

[0246] Example 45.2: 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 provide 0.235 g (92%) of N′,1-dihydroxyisoquinoline-7-carboxamidine. HPLC / MS m / z: 204.07 [M+H] + , Rt (R): 0.36 min.

[0247] Example 45.3.: 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 at 180 °C for 10 min by microwave irradiation. Water (25 mL) was added and the resulting precipitate was filtered, washed with water (25 mL), diethyl ether (2 x 10 mL) and dried to provide 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.

[0248] Example 45.4.: 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 provide 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.

[0249] Example 45.5.: 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole (70 mg, 0.28 mmol) and 3-aminopropanenitrile (0.42 mL, 5.69 mmol) in NMP (1.10 mL) were heated at 160 °C for 1 h. EtOAc (30 mL) was added, the resulting precipitate was filtered, and the filtrate was concentrated. The residue was purified by reverse-phase column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 20 to 100% gradient) to provide 0.020 g (25%) of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanenitrile. HPLC / MS m / z: 280.12 [M+H] + , Rt (R): 0.79 min.

[0250] Example 45.6.: 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanenitrile (19 mg, 0.068 mmol) in concentrated aqueous HCl (2 mL) and acetic acid (4 mL) was heated at 80° C. for 1.5 h. The mixture was concentrated to provide 0.020 g (100%) of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid. HPLC / MS m / z: 299.11 [M+H] + , Rt (R): 0.93 min.

[0251] Example 45.7.: 3-(Ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (26 mg, 0.14 mmol) was added to a solution of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid (20 mg, 0.068 mmol), ethyl 2-amino-4-methyl-thiazole-5-carboxylate (15 mg, 0.082 mmol), and HOBt (18 mg, 0.014 mmol) in DMF (0.68 mL) under nitrogen. The mixture was heated at 60° C. for 17 h. The solution was cooled, injected directly onto a column, and purified by reverse-phase column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 10-100% gradient) to provide 0.012 g (38%) as an off-white solid. HPLC / MS m / z: 467.15 [M+H] + , Rt (P): 1.34 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.87 (s, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.02 (t, J = 5.5 Hz, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 5.9 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.81 (q, J = 6.5 Hz, 2H), 2.89 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 2.53 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0252] The following examples were prepared similarly: Example 46: Methyl 4-methyl-2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoylamino]thiazole-5-carboxylate [ka] 3 mg (6%) colorless amorphous solid [formate]. HPLC / MS m / z: 453.13 [M+H] + , Rt (P): 1.29 min. 1 H NMR (500 MHz, MeOD-d4) δ 8.87 (s, 1H), 8.33-8.15 (m, 2H), 7.91 (d, J = 6.1 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 6.1 Hz, 1H), 3.96 (t, J = 6.6 Hz, 2H), 3.84 (s, 3H), 2.98 (t, J = 6.6 Hz, 2H), 2.69 (s, 3H), 2.57 (s, 3H).

[0253] Example 47: N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[[6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl]amino]propane formate [ka]

[0254] Example 47.1: 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 rt and water was added (50 mL). The precipitate was filtered off, washed with water (50 mL) and dried under reduced pressure to give 536 mg (90%) of N,4-dihydroxyquinazoline-6-carboxamidine. HPLC / MS m / z: 205.1 [M+H] + , Rt (U): 0.46 min.

[0255] Example 47.2: 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 rt 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.

[0256] Example 47.3.: A mixture of 6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-ol (271 mg, 1.19 mmol) and phosphorus oxychloride (5.0 mL, 53.6 mmol) under an argon atmosphere was heated at 100° C. for 4 h. The solution was cooled to rt and the volatiles were removed under reduced pressure. The crude brown solid was used in the next reaction without further purification. HPLC / MS m / z: 243.1 [M+H] + , Rt (T): 1.25 min.

[0257] Example 47.4: 3-(4-chloroquinazolin-6-yl)-5-methyl-1,2,4-oxadiazole (150 mg, 0.61 mmol) and sodium 3-aminopropanoate (270 mg, 2.43 mmol) were mixed in anhydrous NMP (2.0 mL) under argon and stirred at rt for 1 h. The reaction mixture was purified by reverse-phase flash chromatography (10-100% MeOH in water) to afford 52 mg (29%) of 3-[[6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl]amino]propanoic acid as a colorless solid. HPLC / MS m / z: 300.1098 [M+H] + , Rt (U): 1.41 min.

[0258] Example 47.5: 3-[[6-(5-Methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl]amino]propanoic acid (25 mg, 0.084 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.167 mmol), 1-hydroxybenzotriazole hydrate (256 mg, 0.167 mmol), and DIPEA (0.04 mL, 0.251 mmol) were mixed in anhydrous DMF (0.17 mL) at rt under an argon atmosphere and stirred for 1 h. 5-tert-Butyl-4-methyl-thiazol-2-ylamine (28 mg, 0.167 mmol) was added, and the reaction was heated at 60 °C for 1 h. The mixture was cooled to rt, diluted with EtOAc (30 mL), washed with saturated NaHCO3 (2 x 20 mL) and saturated NaCl (20 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (10-100% MeOH in water [0.1% FA]). Yield: 24 mg (64%) off-white solid. HPLC / MS m / z: 452.1861 [M+H] + , Rt (U): 2.70 min. 1 H NMR (600 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.93 (d, J = 1.9 Hz, 1H), 8.87 (t, J = 5.5 Hz, 1H), 8.53 (s, 1H), 8.29 (dd, J = 8.7, 1.8 Hz, 1H), 8.15 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 3.82 (q, J = 6.4 Hz, 2H), 2.81 (t, J = 6.7 Hz, 2H), 2.70 (s, 3H), 2.28 (s, 3H), 1.34 (s, 9H).

[0259] Example 48: tert-Butyl 4-methyl-2-((1s,3s)-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl)amino)cyclobutane-1-carboxamido)thiazole-5-carboxylate [ka]

[0260] Example 48.1: 6-(5-Methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-ol (250 mg, 1.10 mmol), cis-methyl 3-aminocyclobutanecarboxylate hydrochloride (200 mg, 1.21 mmol), and DIPEA (0.57 mL, 3.29 mmol) were dissolved in anhydrous DMF (11 mL) at rt under an argon atmosphere. PyBOP (798 mg, 1.53 mmol) was added, and the reaction mixture was stirred for 5 h. The reaction mixture was mixed with water (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated NaCl (3 x 10 mL), dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (40-100% EtOAc in cyclohexane) to afford 142 mg (38%) of methyl (1s,3s)-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl)amino)cyclobutane-1-carboxylate as an off-white solid. HPLC / MS m / z: 340.1410 [M+H] + , Rt (X): 1.87 min.

[0261] Example 48.2.: Methyl (1s,3s)-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl)amino)cyclobutane-1-carboxylate (135 mg, 0.40 mmol), THF (1.6 mL), MeOH (0.8 mL), and water (1.6 mL) were mixed at ambient temperature. LiOH monohydrate (33 mg, 0.80 mmol) was added, and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (5–50% MeOH in water [0.1% FA]) to afford 54 mg (42%) of (1s,3s)-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl)amino)cyclobutane-1-carboxylic acid as a colorless powder. HPLC / MS m / z: 326.1247 [M+H] +, Rt (X): 1.63 min.

[0262] Example 48.3.: (1s,3s)-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl)amino)cyclobutane-1-carboxylic acid (20 mg, 0.062 mmol) and BTFFH (39 mg, 0.123 mmol) were mixed in anhydrous DCM (0.50 mL) in a microwave vial at rt under an argon atmosphere. DIPEA (0.05 mL, 0.277 mmol) was added and the reaction mixture was stirred for 20 min. tert-Butyl 2-amino-4-methyl-thiazole-5-carboxylate[0] (26 mg, 0.123 mmol) was added and the reaction mixture was heated at 80 °C under microwave irradiation for 1 h. Volatiles were removed under reduced pressure, and the crude reaction mixture was directly purified by reverse-phase flash chromatography (10–40% MeOH in water [0.1% FA]). The product-containing fractions were filtered through a 1 g SCX-2 cartridge. The compound was released with 2 M NH in MeOH and the solvent removed under reduced pressure to yield 27 mg (83%) of tert-butyl 4-methyl-2-((1s,3s)-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl)amino)cyclobutane-1-carboxamide)thiazole-5-carboxylate as an off-white solid. HPLC / MS m / z: 522.1921 [M+H] + , Rt (X): 2.81 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.06 (d, J = 1.8 Hz, 1H), 8.95 (d, J = 6.9 Hz, 1H), 8.53 (s, 1H), 8.30 (dd, J = 8.7, 1.8 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 4.81-4.73 (m, 1H), 3.17-3.10 (m, 1H), 2.71 (s, 3H), 2.64-2.58 (m, 2H), 2.51 (s, 3H), 2.49-2.42 (m, 2H), 1.51 (s, 9H).

[0263] Example 49: tert-Butyl 4-methyl-2-((1s,3s)-N-methyl-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl)amino)cyclobutane-1-carboxamido)thiazole-5-carboxylate formate [ka] tert-Butyl 4-methyl-2-((1s,3s)-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl)amino)cyclobutane-1-carboxamido)thiazole-5-carboxylate (20 mg, 0.038 mmol) was dissolved in anhydrous DMF (0.38 mL) under an argon atmosphere and cooled in an ice bath. Sodium hydride 60% dispersion in mineral oil (1.6 mg, 0.040 mmol) was added and the mixture was stirred at 0°C for 30 min. Iodomethane (2.6 µL, 0.042 mmol) was added. The reaction mixture was allowed to warm to rt and continued stirring for 5 h. The reaction mixture was purified by reverse-phase flash chromatography (40-80% MeOH in water [0.1% FA]) to yield 13 mg (63%) of tert-butyl 4-methyl-2-((1s,3s)-N-methyl-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl)amino)cyclobutane-1-carboxamide)thiazole-5-carboxylate formate as a colorless powder. HPLC / MS m / z: 536.2084 [M+H] + , Rt (X): 2.86 min.

[0264] Example 50: N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[(7-cyano-1-isoquinolyl)amino]propenamide [ka]

[0265] Example 50.1.: Isoquinoline-7-carbonitrile (1.00 g, 6.49 mmol) was suspended in anhydrous chloroform (20 mL) under an argon atmosphere and cooled in an ice bath. 3-Chloroperoxybenzoic acid (1.74 g, 7.78 mmol) was added. The reaction mixture was allowed to warm to rt and stirred overnight. The off-white precipitate was filtered off, washed with chloroform, and dried under reduced pressure to yield 1.10 g (100%) of 2-oxidoisoquinolin-2-ium-7-carbonitrile as an off-white powder. HPLC / MS m / z: 171.0559 [M+H] + , Rt (U): 1.11 min.

[0266] Example 50.2: 2-Oxidoisoquinolin-2-ium-7-carbonitrile (300 mg, 1.76 mmol), beta-alanine tert-butyl ester hydrochloride (400 mg, 2.2037 mmol), and DIPEA (1.46 mL, 8.37 mmol) were mixed in anhydrous THF (7.05 mL). PyBroP (1.07 g, 2.29 mmol) was added to the suspension, and the mixture was stirred at 60 °C overnight. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (10-60% EtOAc in cyclohexane) to afford 271 mg (52%) of tert-butyl 3-[(7-cyano-1-isoquinolyl)amino]propanoate as an off-white solid. HPLC / MS m / z: 298.2 [M+H] + , Rt (P): 1.15 min.

[0267] Example 50.3.: To a solution of tert-butyl 3-[(7-cyano-1-isoquinolyl)amino]propanoate (271 mg, 0.911 mmol) in DCM (1.82 mL) under an argon atmosphere was added TFA (0.70 mL, 9.11 mmol). The resulting solution was stirred at rt overnight. Volatiles were removed under reduced pressure, and the crude material was purified by reverse flash chromatography (5-40% MeOH in water [0.1% FA]) to afford 119 mg (54%) of 3-[(7-cyano-1-isoquinolyl)amino]propanoic acid as an off-white solid. HPLC / MS m / z: 242.1 [M+H] + , Rt (Q): 0.39 min.

[0268] Example 50.4.: Prepared as described for Example 47.5 using 3-[(7-cyano-1-isoquinolyl)amino]propanoic acid (60 mg, 0.249 mmol) and 5-tert-butyl-4-methyl-thiazol-2-ylamine (85 mg, 0.497 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration provided N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[(7-cyano-1-isoquinolyl)amino]propanamide (57 mg, 58%) as an off-white crystalline solid. HPLC / MS m / z: 394.1698 [M+H] + , Rt (U): 2.58 min. 1 H NMR (600 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.82 (s, 1H), 8.05 (d, J = 5.7 Hz, 1H), 7.89 (dd, J = 8.5, 1.5 Hz, 1H), 7.87-7.84 (m, 2H), 6.98 (d, J = 5.8 Hz, 1H), 3.80-3.75 (m, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.29 (s, 3H), 1.35 (s, 9H).

[0269] Example 51: 3-[(7-cyano-1-isoquinolyl)amino]-N-[4-methyl-5-[1-(trifluoromethyl)-cyclopropyl]thiazol-2-yl]propenamide [ka]

[0270] Example 51.1: 2-Amino-4-methylthiazole (97 mg, 0.850 mmol) and sodium 1-(trifluoromethyl)cyclopropanesulfinate (500 mg, 2.55 mmol) were mixed in diethyl carbonate / water (3:2, 8.50 mL) and cooled in an ice bath. tert-Butyl hydroperoxide (70% solution in water, 0.84 mL, 4.25 mmol) was added, and the mixture was stirred at 0 °C for 5 min before heating at 90 °C for 3 h. The reaction mixture was cooled to rt, mixed with saturated NaHCO (30 mL), and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with saturated NaHCO (20 mL) and saturated NaCl (2 x 20 mL), dried over anhydrous MgSO, and concentrated under reduced pressure. The crude reaction mixture was directly purified by reverse-phase flash chromatography (10–80% MeOH in water [0.1% FA]). The product-containing fractions were filtered through a 1 g SCX-2 cartridge. The compound was released with 7 M NH3 in MeOH and the solvent removed under reduced pressure to yield 65 mg (34%) of 4-methyl-5-[1-(trifluoromethyl)cyclopropyl]thiazol-2-amine as an amorphous yellow solid. HPLC / MS m / z: 223.0518 [M+H] + , Rt (U): 1.65 min.

[0271] Example 51.2.: Prepared as described for 0 using 3-[(7-cyano-1-isoquinolyl)amino]propanoic acid (20 mg, 0.083 mmol) and 4-methyl-5-[1-(trifluoromethyl)cyclopropyl]thiazol-2-amine (20 mg, 0.091 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration provided 3-[(7-cyano-1-isoquinolyl)amino]-N-[4-methyl-5-[1-(trifluoromethyl)cyclopropyl]thiazol-2-yl]propanamide (11.3 mg, 30%) as an off-white solid. HPLC / MS m / z: 446.1252 [M+H] + , Rt (U): 2.56 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.82 (s, 1H), 8.04 (d, J = 5.7 Hz, 1H), 7.91-7.84 (m, 3H), 6.98 (d, J = 5.7 Hz, 1H), 3.81-3.76 (m, 2H), 2.82 (t, J = 6.8 Hz, 2H), 2.26 (s, 3H), 1.47-1.44 (m, 2H), 1.18-1.15 (m, 2H).

[0272] Example 52: 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-N-[4-methyl-5-[1-(trifluoromethyl)cyclopropyl]thiazol-2-yl]propenamide [ka] Prepared as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid [Example 45.6] (25 mg, 0.083 mmol) and 4-methyl-5-[1-(trifluoromethyl)cyclopropyl]thiazol-2-amine [Example 51.1] (20 mg, 0.091 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration provided 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-N-[4-methyl-5-[1-(trifluoromethyl)cyclopropyl]thiazol-2-yl]propanamide (13.3 mg, 31%) as an off-white solid. HPLC / MS m / z: 503.1474 [M+H] + , Rt (U): 2.70 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.87 (s, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 8.00 (t, J = 5.5 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 5.7 Hz, 1H), 3.79 (q, J = 6.5 Hz, 2H), 2.84 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 2.25 (s, 3H), 1.47-1.43 (m, 2H), 1.18-1.15 (m, 2H).

[0273] Example 53: N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[(7-cyano-5-fluoro-1-isoquinolyl)amino]propenamide [ka]

[0274] Example 53.1.: A mixture of N-Boc-hydroxylamine (9.0 g, 67.6 mmol) and trimethylacetic anhydride (15.1 mL, 74.4 mmol) in anhydrous MeCN (135 mL) under an argon atmosphere was stirred at reflux overnight. Volatiles were removed under reduced pressure, and the remaining colorless oil was mixed with EtOAc (100 mL), washed with saturated NaHCO (3 x 50 mL), dried over anhydrous MgSO, and concentrated under reduced pressure to give (tert-butoxycarbonylamino) 2,2-dimethylpropanoate in quantitative yield (14.7 g, 100%) as a colorless amorphous solid, which was used in the next step without further purification. HPLC / MS m / z: 240.1208 [M+Na] + , Rt (U): 2.64 min.

[0275] Example 53.2: Trifluoromethanesulfonic acid (5.9 mL, 65.8 mmol) was added to a solution of (tert-butoxycarbonylamino)-2,2-dimethylpropanoate (14.3 g, 65.8 mmol) in diethyl ether (132 mL) at rt under an argon atmosphere and stirred for 3 h. The white crystalline precipitate was filtered off, washed with diethyl ether, and dried under reduced pressure to yield 7.0 g (40%) of 2,2-dimethylpropanoyloxyammonium trifluoromethanesulfonate. 1 H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 3H), 1.22 (s, 9H).

[0276] Example 53.3.: 3-Cyano-5-fluorobenzoic acid (1.00 g, 6.06 mmol) and 4-methylmorpholine (2.00 mL, 18.17 mmol) were mixed in anhydrous THF (12.0 mL) under an argon atmosphere and cooled in an ice bath. Isobutyl chloroformate (0.86 mL, 6.66 mmol) was added, and the reaction mixture was stirred at 0 °C for 20 min. 2,2-Dimethylpropanoyloxyammonium trifluoromethanesulfonate (1.94 g, 7.27 mmol) was then added, and the reaction mixture was allowed to warm to rt and stirred overnight. The precipitate was filtered off and washed with EtOAc. The filtrate was concentrated under reduced pressure and purified by flash chromatography (0–40% EtOAc in cyclohexane) to afford 1.17 g (73%) of [(3-cyano-5-fluorobenzoyl)amino]2,2-dimethylpropanoate as a colorless oil. HPLC / MS m / z: 287.0810 [M+Na] + , Rt (U): 2.55 min.

[0277] Example 53.4.: [(3-cyano-5-fluorobenzoyl)amino]2,2-dimethylpropanoate (1.00 g, 3.784 mmol), [Cp*RhCl2]2 (58 mg, 0.095 mmol), and cesium acetate (219 mg, 1.135 mmol) were mixed in MeOH (9.5 mL) at rt under an argon atmosphere. Vinyl acetate (1.05 mL, 11.353 mmol) was added, and the reaction mixture was heated at 45 °C for 18 h. The precipitate was filtered off, washed with water and MeOH, and dried under reduced pressure to yield 428 mg (60%) of 5-fluoro-1-oxo-2H-isoquinoline-7-carbonitrile as an off-white powder. HPLC / MS m / z: 189.1 [M+H] + , Rt (T): 0.97 min.

[0278] Example 53.5.: A mixture of 5-fluoro-1-hydroxy-isoquinoline-7-carbonitrile (207 mg, 1.10 mmol) and phosphorus oxychloride (4.6 mL, 49.7 mmol) was heated at 110 °C for 4 h under an argon atmosphere. The reaction mixture was cooled to rt and the volatiles were removed under reduced pressure to provide crude 1-chloro-5-fluoro-isoquinoline-7-carbonitrile as an off-white solid in quantitative yield, which was used in the next reaction without further purification. HPLC / MS m / z: 207.0 [M+H] + , Rt (U): 1.19 min.

[0279] Example 53.6: 1-Chloro-5-fluoro-isoquinoline-7-carbonitrile (227 mg, 1.10 mmol) and sodium 3-aminopropanoate (488 mg, 4.40 mmol) were mixed in anhydrous NMP (3.7 mL) under an argon atmosphere and stirred at 60° C. overnight. The reaction mixture was purified by reverse-phase flash chromatography (5-30% MeOH in water [0.1% FA]) to afford 107 mg (38%) of 3-[(7-cyano-5-fluoro-1-isoquinolyl)amino]propanoic acid as an off-white solid. HPLC / MS m / z: 260.0840 [M+H] + , Rt (U): 1.33 min.

[0280] Example 53.7.: Prepared as described for Example 47.5 using 3-[(7-cyano-5-fluoro-1-isoquinolyl)amino]propanoic acid (50 mg, 0.193 mmol) and 5-tert-butyl-4-methyl-thiazol-2-ylamine (39 mg, 0.231 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration provided N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[(7-cyano-5-fluoro-1-isoquinolyl)amino]propanamide (61 mg, 77%) as an off-white crystalline solid. HPLC / MS m / z: 412.1602 [M+H] + , Rt (Q): 2.93 min. 1H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.70 (d, J = 1.2 Hz, 1H), 8.15 (d, J = 5.8 Hz, 1H), 8.02 (t, J = 5.4 Hz, 1H), 7.93 (dd, J = 10.1, 1.3 Hz, 1H), 7.00 (dd, J = 5.8, 0.9 Hz, 1H), 3.81-3.75 (m, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.29 (s, 3H), 1.35 (s, 9H).

[0281] Example 54: Propyl 4-methyl-2-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamido)thiazole-5-carboxylate [ka]

[0282] Example 54.1.: To sodium 3-aminopropanoate (213.42 mg, 1.9214 mmol) was added NMP (1.60 mL). The vial was heated to 100° C. and stirred for 30 min before adding 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole [Example 45] (118.00 mg, 0.4803 mmol) under a nitrogen atmosphere. Stirring was continued at 100° C. overnight. The reaction mixture was cooled and water (3 mL) was added. Purification by reverse-phase column chromatography (eluent: 20-70% MeOH in water (both + 0.1% formic acid modifier)) provided 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid (123 mg, 86%, 0.4123 mmol) as a colorless powder. HPLC / MS m / z: 299.1, [M+H] + , Rt (P): 0.98 min.

[0283] Example 54.2.: To a mixture of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid (30.00 mg, 0.1006 mmol), EDC.HCl (38.56 mg, 0.2011 mmol), HOBt (27.18 mg, 0.2011 mmol), and propyl 2-amino-4-methyl-thiazole-5-carboxylate [Example 63.1] (30.21 mg, 0.1509 mmol) was added DMF (0.40 mL) under a nitrogen atmosphere. The resulting solution was stirred at 70 °C overnight. LCMS showed total conversion. Purification by reverse-phase column chromatography (eluent: 10-100% MeOH in water (+0.1% formic acid)), followed by ion-exchange SCX-II column chromatography washing with MeOH before eluting with 2M NH in MeOH, provided propyl 4-methyl-2-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamido)thiazole-5-carboxylate (32 mg, 66%, 0.0666 mmol) as a colorless solid. HPLC / MS m / z: 481.2, [M+H] + , Rt (Q): 2.65 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.88 (d, J = 1.5 Hz, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.02 (t, J = 5.4 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 5.7 Hz, 1H), 4.16 (t, J = 6.5 Hz, 2H), 3.82 (q, J = 6.4 Hz, 2H), 2.90 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 2.54 (s, 3H), 1.68 (sext, J = 7.1 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H).

[0284] The following examples were also prepared by similar procedures: Example 55: N-(5-cyanothiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propenamide [ka] 38mg(54%) Colorless solid. HPLC / MS m / z: 406.11, [M+H] + , Rt (U): 2.11 min. 1 H NMR (600 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.87 (s, 1H), 8.35 (s, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.05 (t, J = 5.5 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 5.7 Hz, 1H), 3.83 (q, J = 6.3 Hz, 2H), 2.94 (t, J = 6.7 Hz, 2H), 2.70 (s, 3H).

[0285] Example 56: 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)propenamide [ka] 14mg(47%) Colorless solid. HPLC / MS m / z: 446.16, [M+H] + , Rt (U): 2.39 min. 1H NMR (600 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.88 (s, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.96 (t, J = 6.5 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.00 (s, 1H), 6.96 (d, J = 5.7 Hz, 1H), 3.85 (s, 3H), 3.77 (q, J = 6.8 Hz, 2H), 2.75 (t, J = 7.0 Hz, 2H), 2.70 (s, 3H).

[0286] Example 57: 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(1-methyl-5-pentyl-1H-pyrazol-3-yl)propanamide [ka]

[0287] Example 57.1.: To a solution of diisopropylamine (0.33 mL, 2.3603 mmol) in THF (1.9 mL) at −78 °C was added 1.6 M nBuLi (1.48 mL, 2.3603 mmol). The solution was stirred at 0 °C for 15 min. The solution was then re-cooled at −78 °C, and a solution of 1-methyl-3-nitro-1H-pyrazole (250.00 mg, 1.967 mmol) in THF (1.9 mL) was added. After stirring at this temperature for 1 h, a solution of iodine (599.07 mg, 2.3603 mmol) in THF (0.8 mL) was added, and the reaction mixture was allowed to warm to rt and stirred for 2 h. The reaction was quenched with a saturated solution of NaSO (10 mL) and NHCl (25 mL). The residue was extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo, and purified by silica gel column chromatography (eluent: 0-40% EtOAc in cyclohexane) to provide 5-iodo-1-methyl-3-nitro-pyrazole (240 mg, 48%, 0.9486 mmol) as a light brown solid. 1 H NMR (600 MHz, Chloroform-d) δ 7.09 (s, 1H), 4.06 (s, 3H).

[0288] Example 57.2: To a mixture of 5-iodo-1-methyl-3-nitro-pyrazole (240.00 mg, 0.9486 mmol), copper(I) iodide (10.84 mg, 0.0569 mmol), bis(triphenylphosphine)palladium(II) chloride (39.95 mg, 0.0569 mmol), and 1-pentyne (0.14 mL, 1.4229 mmol) was added a degassed solution of DMF (1.50 mL) in TEA (3.00 mL). The resulting solution was heated at 90 °C for 30 min under microwave irradiation. Volatiles were removed under reduced pressure. Purification by silica gel column chromatography (eluent: 0-8% EtOAc in cyclohexane) provided 1-methyl-3-nitro-5-pent-1-ynyl-pyrazole (120 mg, 65%, 0.6211 mmol) as a brown oil. HPLC / MS m / z: 194.09, [M+H] +, Rt (P): 1.43 min.

[0289] Example 57.3.: To a solution of 1-methyl-3-nitro-5-pent-1-ynyl-pyrazole (60.00 mg, 0.3106 mmol) in EtOH (1.55 mL) was added 10% Pd / C (33.05 mg, 0.0311 mmol). The flask was placed under an H atmosphere and the solution was stirred at rt for 7.5 h. The Pd / C was filtered through a pad of Celite and washed with MeOH (5 mL). Purification by ion-exchange SCX-II column chromatography eluting with 2M NH in MeOH followed by washing with MeOH gave 1-methyl-5-pentyl-pyrazol-3-amine (41 mg, 79%, 0.2451 mmol) as a yellow oil, which was used in the next step without further purification. HPLC / MS m / z: 168.15, [M+H] + , Rt (T): 0.95 min.

[0290] Example 57.4.: A procedure similar to Example 54.2 using 1-methyl-5-pentyl-pyrazol-3-amine and 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolin-1-yl]amino]propanoic acid provided 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(1-methyl-5-pentyl-1H-pyrazol-3-yl)propanamide (10.2 mg, 34%, 0.0228 mmol) as a colorless solid. HPLC / MS m / z: 448.25, [M+H] + , Rt (U): 2.62 min. 1H NMR (600 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.88 (s, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.93 (t, J = 5.4 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 5.7 Hz, 1H), 6.30 (s, 1H), 3.74 (td, J = 7.1, 5.2 Hz, 2H), 3.59 (s, 3H), 2.69 (d, J = 8.1 Hz, 5H), 2.54 (t, J = 7.6 Hz, 2H), 1.55 (quint, J = 7.3 Hz, 2H), 1.37-1.26 (m, 4H), 0.91-0.83 (m, 3H).

[0291] Example 58: N-(5-(tert-butyl)-4-methylthiazol-2-yl)-3-((7-(5-methyl-2H-tetrazol-2-yl)isoquinolin-1-yl)amino)propenamide [ka]

[0292] Example 58.1.: 7-Aminoisoquinoline (720.85 mg, 5 mmol) was dissolved in a mixture of 50% aqueous hydrofluoroboric acid (1.25 mL, 19.929 mmol) and EtOH (1.50 mL). The reaction mixture was cooled to 0 °C and tert-butyl nitrite (1.35 mL, 10 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 off, washed with diethyl ether (3 x 5 mL), and dried to provide isoquinoline-7-diazonium tetrafluoroborate (1.02 g, 84%, 4.1857 mmol) as a dark red powder. 1H NMR (500 MHz, DMSO-d6) δ 9.77 (d, J = 0.9 Hz, 1H), 9.75 (d, J = 2.1 Hz, 1H), 8.97 (d, J = 5.7 Hz, 1H), 8.65 (dd, J = 9.0, 2.1 Hz, 1H), 8.50 (d, J = 9.1 Hz, 1H), 8.22-8.17 (m, 1H).

[0293] Example 58.2.: To a solution of acetamidine hydrochloride (155.64 mg, 1.6463 mmol) and potassium carbonate (1.14 g, 8.2315 mmol) in DMSO (8.00 mL) was added isoquinoline-7-diazonium tetrafluoroborate (400.00 mg, 1.6463 mmol) in portions. After stirring at rt for 1.5 h, potassium iodide (409.93 mg, 2.4694 mmol) and iodine (501.41 mg, 1.9756 mmol) were added. The mixture was stirred at rt for 1.5 h before a solution of brine and sodium thiosulfate was added. The product was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (eluent: 30-60% EtOAc in cyclohexane) provided 7-(5-methyltetrazol-2-yl)isoquinoline (62 mg, 18%, 0.2935 mmol) as a yellow powder. HPLC / MS m / z: 212.1, [M+H] + , Rt (T): 0.96 min.

[0294] Example 58.3: 7-(5-Methyltetrazol-2-yl)isoquinoline (120.00 mg, 0.5681 mmol) was dissolved in CHCl3 (1.54 mL) and cooled in an ice bath. 3-Chloroperoxybenzoic acid (0.15 g, 0.6818 mmol) was added. The reaction was stirred at rt for 2 h. K2CO3 (0.31 g, 2.2725 mmol) was added and stirred for 0.5 h before filtering. The filtrate was concentrated in vacuo. The residue was dissolved 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 (122 mg, 95%, 0.5369 mmol) as a yellow powder. HPLC / MS m / z: 228.1, [M+H] + , Rt (P): 1.04 min.

[0295] Example 58.4: 7-(5-Methyltetrazol-2-yl)-2-oxide-isoquinolin-2-ium (120.00 mg, 0.5281 mmol) and beta-alanine tert-butyl ester hydrochloride (124.72 mg, 0.6866 mmol) were dissolved in dry DCM (2.80 mL). DIPEA (0.43 mL, 2.4822 mmol) was added, followed by PyBroP (369.30 mg, 0.7922 mmol), and the flask was stirred at rt overnight. One equivalent of PyBroP, the amine, and DIPEA were added, and the mixture was stirred at 30 °C for 20 h. The solvent was removed in vacuo. Purification by silica gel column chromatography (eluent: 5-40% EtOAc in cyclohexane) provided tert-butyl 3-[[7-(5-methyltetrazol-2-yl)-1-isoquinolyl]amino]propanoate (95 mg, 51%, 0.2681 mmol) as an orange powder. HPLC / MS m / z: 355.2, [M+H] + , Rt (T): 1.13 min.

[0296] Example 58.5: tert-Butyl 3-[[7-(5-methyltetrazol-2-yl)-1-isoquinolyl]amino]propanoate (85.00 mg, 0.2398 mmol) and potassium hydroxide (134.57 mg, 2.3984 mmol) were dissolved in THF (1.20 mL). A few drops of water and MeOH were added. The reaction was stirred at 50 °C for 2 h. Additional potassium hydroxide (134.57 mg, 2.3984 mmol) and more water were added and stirred at 50 °C for 3 h. Purification by reverse-phase column chromatography (eluent: 20–80% MeOH / HO + 0.1% formic acid) provided 3-[[7-(5-methyltetrazol-2-yl)-1-isoquinolyl]amino]propanoic acid (60 mg, 84%, 0.2011 mmol) as a colorless powder. HPLC / MS m / z: 299.1, [M+H] + , Rt (P): 0.98 min.

[0297] Example 58.6: 3-[[7-(5-Methyltetrazol-2-yl)-1-isoquinolyl]amino]propanoic acid (60.00 mg, 0.2011 mmol), EDC (116.84 mg, 0.6034 mmol), HOBt (92.41 mg, 0.6034 mmol), and 5-tert-butyl-4-methyl-thiazol-2-ylamine (102.75 mg, 0.6034 mmol) were dissolved in dry DMF (2.01 mL). DIPEA (176.05 μL, 1.0057 mmol) was added and the reaction mixture was stirred at 50° C. for 21 h. Purification was achieved by reverse-phase column chromatography (eluent: 30-100% MeOH / HO + 0.1% formic acid), followed by ion-exchange SCX-II column chromatography, washing with MeOH before eluting with 2M NH in MeOH. Trituration with MeOH provided N-(5-(tert-butyl)-4-methylthiazol-2-yl)-3-((7-(5-methyl-2H-tetrazol-2-yl)isoquinolin-1-yl)amino)propanamide (8 mg, 9%, 0.0172 mmol) as a colorless powder. HPLC / MS m / z: 451.2, [M+H] + , Rt (Q): 2.69 min. 1H NMR (600 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.96 (d, J = 2.1 Hz, 1H), 8.28 (dd, J = 8.8, 2.1 Hz, 1H), 8.06-7.90 (m, 3H), 7.02 (d, J = 5.8 Hz, 1H), 3.81-3.74 (m, 2H), 2.80 (t, J = 6.8 Hz, 2H), 2.62 (s, 3H), 2.28 (s, 3H), 1.35 (s, 9H).

[0298] Example 59: N-(3-((5-(tert-butyl)-4-methylthiazol-2-yl)amino)-3-oxopropyl)-3-(5-methyl-2H-tetrazol-2-yl)benzamide [ka]

[0299] Example 59.1.: 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) dissolved in water (1.00 mL) was added dropwise. The reaction was stirred at 0 °C for 30 min. The reaction was filtered and the solid was washed with EtO and dried to provide 3-(ethoxycarbonyl)benzenediazonium tetrafluoroborate (1.19 g, 90%, 4.489 mmol). 1 H NMR (600 MHz, DMSO-d6) δ 9.26 (t, J = 1.9 Hz, 1H), 8.88 (ddd, J = 8.3, 2.1, 1.1 Hz, 1H), 8.70 (dt, J = 8.0, 1.4 Hz, 1H), 8.12 (t, J = 8.1 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).

[0300] Example 59.2.: To a solution of acetamidine hydrochloride (0.42 g, 4.47 mmol) and potassium carbonate (3.09 g, 22.35 mmol) in DMSO (21.72 mL) was added 3-(ethoxycarbonyl)benzenediazonium tetrafluoroborate (1.18 g, 4.47 mmol) in portions. After stirring at rt for 1.5 h, potassium iodide (1113.04 mg, 6.7051 mmol) and iodine (1361.45 mg, 5.364 mmol) were added. The mixture was stirred at rt for 1.5 h before a solution of brine and sodium thiosulfate was added. The product was extracted with EtOAc, and the organic layer was dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (eluent: 0-30% EtOAc in cyclohexane) gave ethyl 3-(5-methyltetrazol-2-yl)benzoate (250 mg, 24%, 1.0765 mmol) as an orange powder. HPLC / MS m / z: 233.1, [M+H] + , Rt (P): 1.46 min.

[0301] Example 59.3.: Ethyl 3-(5-methyltetrazol-2-yl)benzoate (240.00 mg, 1.0334 mmol) was dissolved in THF (5.17 mL). LiOH (247.50 mg, 10.334 mmol) was added, and the mixture was stirred at 50 °C for 1 h. Water (1 mL) and methanol (1 mL) were added, and the mixture was stirred at 50 °C for 2 h. After cooling to rt, the mixture was diluted with EtOAc and water, and the pH was adjusted to pH 2-3. The product was extracted with EtOAc, dried over MgSO4, and concentrated in vacuo to give 3-(5-methyltetrazol-2-yl)benzoic acid (222 mg, 105%, 1.0872 mmol) as a yellow powder. HPLC / MS m / z: 205.1, [M+H] + , Rt (P): 1.23 min.

[0302] Example 59.4: 3-[[3-(5-Methyltetrazol-2-yl)benzoyl]amino]propanoic acid (185.00 mg, 0.6721 mmol), EDC (260.28 mg, 1.3442 mmol), HOBt (205.85 mg, 1.3442 mmol), and 5-tert-butyl-4-methyl-thiazol-2-ylamine (114.44 mg, 0.6721 mmol) were dissolved in dry DMF (3.36 mL). DIPEA (235.30 μL, 1.3442 mmol) was added, and the reaction mixture was stirred at 50° C. for 2 h. The mixture was cooled to rt and diluted with a mixture of water and EtOAc. The product was extracted with EtOAc, washed with water, dried over MgSO4, and concentrated in vacuo. Purification by reverse-phase column chromatography (eluent: 30-100% MeOH / HO + 0.1% formic acid) provided N-(3-((5-(tert-butyl)-4-methylthiazol-2-yl)amino)-3-oxopropyl)-3-(5-methyl-2H-tetrazol-2-yl)benzamide (60 mg, 20%, 0.1361 mmol) as a colorless powder. HPLC / MS m / z: 428.2, [M+H] + , Rt (Q): 2.98 min. 1 H NMR (500 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.92 (t, J = 5.6 Hz, 1H), 8.52 (t, J = 1.9 Hz, 1H), 8.21 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 8.03 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 3.58 (q, J = 6.7 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H), 2.61 (s, 3H), 2.29 (s, 3H), 1.35 (s, 9H).

[0303] Example 60: (S)—N-(1-((5-(tert-butyl)-4-methylthiazol-2-yl)amino)-6-(methylamino)-1-oxohexan-3-yl)-3-(5-methyl-2H-tetrazol-2-yl)benzamide [ka]

[0304] Example 60.1.: 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) dissolved in water (1.00 mL) was added dropwise. The reaction was stirred at 0°C for 30 min. 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. HPLC / MS m / z: 177.07, [M+H] + , Rt (T): 0.31 min.

[0305] Example 60.2.: To a solution of acetamidine hydrochloride (0.39 g, 4.167 mmol) and potassium carbonate (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, potassium iodide (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 sodium thiosulfate was added to the mixture. The product was extracted with EtOAc, and the organic layer was dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (eluent: 5-30% EtOAc in cyclohexane) provided ethyl 3-(5-methyltetrazol-2-yl)benzoate (582 mg, 60%, 2.506 mmol) as a yellow powder. HPLC / MS m / z: 233.10, [M+H] + , Rt (T): 1.36 min.

[0306] Example 60.3.: Ethyl 3-(5-methyltetrazol-2-yl)benzoate (300.00 mg, 1.2918 mmol) was dissolved in THF (6.46 mL). LiOH (309.38 mg, 12.918 mmol) was added, and the mixture was stirred at 50 °C for 1 h. 1 mL of water and methanol was added to help dissolve the LiOH, and the mixture was stirred for 1 h 15 min. The mixture was cooled to rt, diluted with EtOAc and water, and the pH was adjusted to pH 2-3. The product was extracted with EtOAc, dried over MgSO4, and concentrated in vacuo to give 3-(5-methyltetrazol-2-yl)benzoic acid (260 mg, 99%, 1.2733 mmol) as a yellow powder. HPLC / MS m / z: 205.07, [M+H] + , Rt (T): 1.13 min.

[0307] Example 60.4: 3-(5-Methyltetrazol-2-yl)benzoic acid (264.00 mg, 1.2929 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (688.25 mg, 1.8101 mmol), and tert-butyl (3S)-3-amino-6-[tert-butoxycarbonyl(methyl)amino]hexanoate (572.78 mg, 1.8101 mmol) were dissolved in dry DMF (6.46 mL). N,N-Diisopropylethylamine (0.68 mL, 3.8787 mmol) was added, and the reaction mixture was stirred at rt for 3 d. A solution of EtOAc and NaHCO was added. The product was extracted with EtOAc, washed with water, and dried over MgSO. Purification by silica gel column chromatography (eluent: 10-50% EtOAc in cyclohexane) provided tert-butyl (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[3-(5-methyltetrazol-2-yl)benzoyl]amino]hexanoate (570 mg, 88%, 1.1341 mmol) as a pale yellow powder. HPLC / MS m / z: 525.28, [M+Na] + , Rt (T): 1.50 min.

[0308] Example 60.5: tert-Butyl (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[3-(5-methyltetrazol-2-yl)benzoyl]amino]hexanoate was used in a procedure similar to that described in Examples 152.6 to 152.8 to provide (S)—N-(1-((5-(tert-butyl)-4-methylthiazol-2-yl)amino)-6-(methylamino)-1-oxohexan-3-yl)-3-(5-methyl-2H-tetrazol-2-yl)benzamide (36 mg, 56%, 0.0722 mmol) as a colorless powder. HPLC / MS m / z: 499.3, [M+H] + , Rt (U): 2.66 min. 1 H NMR (600 MHz, DMSO-d6) δ 8.66 (d, J = 8.5 Hz, 1H), 8.51 (t, J = 1.9 Hz, 1H), 8.25-8.19 (m, 1H), 8.05-8.00 (m, 1H), 7.76 (t, J = 7.9 Hz, 1H), 4.48-4.40 (m, 1H), 2.70-2.64 (m, 2H), 2.62 (s, 3H), 2.60-2.53 (m, 2H), 2.32 (s, 3H), 2.30 (s, 3H), 1.62-1.56 (m, 2H), 1.56-1.43 (m, 2H), 1.34 (s, 9H). (Note: 2 x NH was not observed).

[0309] Example 61: Ethyl 2-(3-(3-(5-methyl-1,2,4-oxazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] To a solution of ethyl 2-aminothiazole-5-carboxylate (37.11 mg, 0.2155 mmol), 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid [Example 63.3] (50.00 mg, 0.1816 mmol) in DMF (0.91 mL) was added HOBt (49.09 mg, 0.3633 mmol) and EDC (56.40 mg, 0.3633 mmol). The mixture was stirred at 60 °C for 18 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (40 mL). The organics were washed with water (40 mL), 1 N HCl (20 mL), saturated aqueous bicarbonate (20 mL), and brine (20 mL). The organic layer was dried over sodium sulfate and concentrated. The crude material was purified by reverse-phase chromatography (eluent: 30-100% MeOH in water (both + 0.1% formic acid modifier)) to provide ethyl 2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate (10 mg, 13%, 0.0233 mmol) as a colorless fluffy powder. HPLC / MS m / z: 430.1 [M+H] + , Rt (Q): 2.75 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.89 (t, J = 5.5 Hz, 1H), 8.47 (t, J = 1.7 Hz, 1H), 8.17-8.11 (m, 2H), 8.07-8.01 (m, 1H), 7.66 (t, J = 7.8 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.62 (q, J = 6.5 Hz, 2H), 2.82 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0310] Example 62: Methyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] To 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid [Example 63.3] (99.00 mg, 0.3597 mmol), methyl 2-amino-4-methyl-thiazole-5-carboxylate (73.49 mg, 0.4267 mmol), and HOBt (97.19 mg, 0.7193 mmol) in DMF (1.80 mL) under a nitrogen atmosphere was added 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine hydrochloride (137.89 mg, 0.7193 mmol). The solution was stirred at 60 °C for 18 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (40 mL). The organic layer was retained, and the aqueous layer was re-extracted with fresh EtOAc. The organics were combined, washed with saturated aqueous bicarbonate (30 mL) and brine (30 mL), and dried over MgSO. Concentration in vacuo gave a yellow crude product (~150 mg), which was purified by reverse-phase column chromatography (eluent: 30-100% MeOH in water (both + 0.1% formic acid modifier)) to provide methyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate (40 mg, 26%, 0.0931 mmol) as a colorless powder. HPLC / MS m / z: 430.1 [M+H] + , Rt (Q): 3.08 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.89 (t, J = 5.5 Hz, 1H), 8.47 (t, J = 1.7 Hz, 1H), 8.17-8.11 (m, 2H), 8.07-8.01 (m, 1H), 7.66 (t, J = 7.8 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.62 (q, J = 6.5 Hz, 2H), 2.82 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0311] Example 63: Propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka]

[0312] Example 63.1.: 2-Amino-4-methyl-thiazole-5-carboxylic acid (200.00 mg, 1.2644 mmol) and N,N-dimethylpyridin-4-amine (15.45 mg, 0.1264 mmol) were suspended in DMF (3.16 mL). EDC.HCl (290.86 mg, 1.5173 mmol) and propan-1-ol (1.90 mL, 25.288 mmol) were added sequentially, and the solution was stirred at 60 °C for 1 h. Partitioned between EtOAc and water. The organics were washed with aqueous saturated bicarbonate and brine before drying over MgSO. Purification by silica gel column chromatography (eluent: 25-60% EtOAc in cyclohexane) gave propyl 2-amino-4-methyl-thiazole-5-carboxylate (115 mg, 45%, 0.5743 mmol) as an off-white powder. HPLC / MS m / z: 201.1 [M+H] + , Rt (R): 1.00 min.

[0313] Example 63.2.: To methyl 3-aminopropanoate hydrochloride (546.89 mg, 3.9181 mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (800.00 mg, 3.9181 mmol) in DMF (19.59 mL) was added DIPEA (2.74 mL, 15.672 mmol), followed by HATU (1382.69 mg, 5.8772 mmol). Stirred at rt for 20 h. Diluted with EtOAc (200 mL) and washed with water (250 mL). The aqueous phase was extracted with fresh EtOAc (100 ml). The organics were combined and washed with saturated aqueous bicarbonate (150 mL) and brine (200 mL) before drying over MgSO4. After filtration and concentration in vacuo, methyl 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoate (1.12 g, 99%, 3.8715 mmol) was isolated as an off-white powder. HPLC / MS m / z: 312.1 [M+Na] + , Rt (R): 1.02 min.

[0314] Example 63.3.: To methyl 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoate (1.12 g, 3.8715 mmol) in THF (19.26 mL) was added water (19.26 mL), followed by lithium hydroxide hydrate (0.65 g, 15.486 mmol). After stirring for 1 h 20 min, 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 100 mL). The combined organics were washed with brine (150 mL) and dried over MgSO4. This gave 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid (917.3 mg, 86%, 3.3325 mmol) as a colorless solid. HPLC / MS m / z: 276.1 [M+H] + , Rt (R): 0.93 min.

[0315] Example 63.4: Propyl 2-amino-4-methyl-thiazole-5-carboxylate (24.00 mg, 0.1198 mmol), 1-hydroxybenzotriazole (32.39 mg, 0.2397 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine, HCl (37.21 mg, 0.2397 mmol), and 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid (42.88 mg, 0.1558 mmol) were dissolved in dry DMF (0.60 mL) at rt for 60 h. The reaction mixture was diluted with EtOAc, washed with NaHCO (2 × 8 mL) and water (8 mL), dried over MgSO, and concentrated under reduced pressure. Purification by reverse-phase column chromatography (eluent: 30-100% MeOH / HO + 0.1% formic acid) provided propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate (30 mg, 55%, 0.0656 mmol) as an off-white solid. HPLC / MS m / z: 458.1 [M+H] + , Rt (S): 2.93 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.12 (dt, J = 7.7, 1.4 Hz, 1H), 8.05-8.01 (m, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.15 (t, J = 6.5 Hz, 2H), 3.60 (q, J = 6.6 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.53 (s, 3H), 1.72-1.62 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).

[0316] The following examples were prepared in a similar manner: Example 64: N-(3-((5-butyl-4-methylthiazol-2-yl)amino)-3-oxopropyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide [ka] 31 mg (27%). HPLC / MS m / z: 428.18 [M+H] + , Rt (R): 1.44 min. 1 H NMR (500 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.85 (t, J = 5.5 Hz, 1H), 8.47 (t, J = 1.7 Hz, 1H), 8.12 (dt, J = 7.7, 1.4 Hz, 1H), 8.03 (dt, J = 7.9, 1.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 3.57 (q, J = 6.7 Hz, 2H), 2.69 (d, J = 9.5 Hz, 5H), 2.63 (t, J = 7.4 Hz, 2H), 2.14 (s, 3H), 1.57-1.42 (m, 2H), 1.39-1.24 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H).

[0317] Example 65: Ethyl 4-methyl-2-(3-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)butanamido)thiazole-5-carboxylate [ka] Using ethyl 3-amino-3-methylbutanoate hydrochloride, ethyl 4-methyl-2-(3-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)butanamido)thiazole-5-carboxylate (40 mg, 33%, 0.0848 mmol) was prepared as a colorless solid. HPLC / MS m / z: 472.17, [M+H] + , Rt (S): 2.98 min. 1H NMR (500 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.38 (t, J = 1.7 Hz, 1H), 8.22 (s, 1H), 8.11 (dt, J = 7.8, 1.4 Hz, 1H), 7.97 (dt, J = 7.9, 1.4 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.07 (s, 2H), 2.68 (s, 3H), 2.52 (s, 3H), 1.48 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H).

[0318] Example 66: Isopropyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka]

[0319] Example 66.1.: Prepared in a similar procedure to Example 63 using 2-amino-4-methyl-thiazole-5-carboxylic acid to provide 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylic acid (84 mg, 62%, 0.2022 mmol) as a brown powder. HPLC / MS m / z: 416.1 [M+H] + , Rt (R): 1.13 min.

[0320] Example 66.2: 4-Methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylic acid (40.00 mg, 0.0963 mmol) was dissolved in dry DCM (1.50 mL). After stirring at rt for 6 h, the solvent was removed under reduced pressure. The residue was dissolved in dry i-PrOH and stirred at 50 °C overnight. The reaction mixture was concentrated, and the residue was purified by reverse-phase column chromatography (eluent: 30-100% MeOH / HO + 0.1% formic acid) to provide isopropyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate (22 mg, 50%, 0.0481 mmol) as a colorless powder. HPLC / MS m / z: 458.2 [M+H] + , Rt (S): 2.90 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.47-8.44 (m, 1H), 8.13 (ddd, J = 7.7, 1.7, 1.2 Hz, 1H), 8.02 (ddd, J = 7.8, 1.9, 1.2 Hz, 1H), 7.65 (td, J = 7.7, 0.5 Hz, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 3.63-3.57 (m, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.53 (s, 3H), 1.28 (d, J = 6.2 Hz, 6H).

[0321] The following examples were prepared similarly: Example 67: 2-Methoxyethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 23 mg (50%) colorless amorphous solid. HPLC / MS m / z: 474.1 [M+H] + , Rt (S): 2.59 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.46 (td, J = 1.8, 0.5 Hz, 1H), 8.13 (ddd, J = 7.7, 1.8, 1.2 Hz, 1H), 8.02 (ddd, J = 7.9, 1.9, 1.2 Hz, 1H), 7.65 (td, J = 7.7, 0.6 Hz, 1H), 4.34-4.28 (m, 2H), 3.63-3.55 (m, 4H), 3.29 (s, 3H), 2.79 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.54 (s, 3H).

[0322] Example 68: Isobutyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 18mg(40%) Colorless powder. HPLC / MS m / z: 472.2 [M+H] + , Rt (S): 3.06 min. 1H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.87 (t, J = 5.5 Hz, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.13 (dt, J = 7.7, 1.4 Hz, 1H), 8.03 (dt, J = 7.9, 1.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.00 (d, J = 6.4 Hz, 2H), 3.66-3.55 (m, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.54 (s, 3H), 2.02-1.91 (m, 1H), 0.94 (d, J = 6.7 Hz, 6H).

[0323] Example 69: 4-Methoxybutyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 30mg(62%) Colorless powder. HPLC / MS m / z: 502.2 [M+H] + , Rt (S): 2.83 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.47-8.43 (m, 1H), 8.15-8.10 (m, 1H), 8.05-8.00 (m, 1H), 7.69-7.62 (m, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.63-3.56 (m, 2H), 3.35 (t, J = 6.3 Hz, 2H), 3.22 (s, 3H), 2.78 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.53 (s, 3H), 1.73-1.65 (m, 2H), 1.62-1.55 (m, 2H).

[0324] Example 70: Propyl 4-methyl-2-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)thiazole-5-carboxylate [ka]

[0325] Example 70.1.: A solution of 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole (60.00 mg, 0.2442 mmol) and ethylenediamine (0.33 mL, 4.8848 mmol) in NMP (0.98 mL) in a 0.5-2 mL microwave vial was heated at 160 °C under microwave irradiation for 1 h. The volatiles were removed under reduced pressure. The residue was added to saturated bicarbonate solution (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate, and concentrated in vacuo. Purification by Biotage KP-NH silica gel column chromatography (eluent: 0-15% (EtOAc / MeOH - 3 / 1) in DCM) provided N'-[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]ethane-1,2-diamine (48.8 mg, 74%, 0.1812 mmol) as a colorless solid. HPLC / MS m / z: 270.13, [M+H] + , Rt (P): 0.23 min.

[0326] Example 70.2.: To a mixture of N'-[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]ethane-1,2-diamine (50.75 mg, 0.1884 mmol), 4-methyl-5-propoxycarbonyl-thiazole-2-carboxylic acid [Example 74] (36.00 mg, 0.1570 mmol), EDC.HCl (60.21 mg, 0.3141 mmol), and 1-hydroxybenzotriazole (42.44 mg, 0.3141 mmol) was added DMF (0.79 mL) under a nitrogen atmosphere. The solution was stirred at rt for 3 h. LCMS showed 50% conversion. The solution was stirred at rt over the weekend. LCMS showed complete conversion. The solution was added to water (20 mL) and extracted with EtOAc (3 x 10 mL). The organic layers were combined, washed with saturated bicarbonate solution (15 mL), brine (15 mL), dried over magnesium sulfate, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (eluent: 20-50% EtOAc in cyclohexane), followed by reverse-phase column chromatography (eluent: 10-100% MeOH in water (both + 0.1% formic acid)). Purification by ion-exchange SCX-II column chromatography, eluting with 2M NH3 in MeOH before washing with MeOH, provided propyl 4-methyl-2-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)thiazole-5-carboxylate (29 mg, 38%, 0.0603 mmol) as a colorless solid. HPLC / MS m / z: 481.16, [M+H] + , Rt (S): 2.61 min. 1H NMR (600 MHz, DMSO-d6) δ 9.37 (t, J = 5.5 Hz, 1H), 8.89-8.87 (m, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.03 (t, J = 5.5 Hz, 1H), 7.99 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.00-6.96 (m, 1H), 4.22 (t, J = 6.5 Hz, 2H), 3.72 (q, J = 5.6 Hz, 2H), 3.59 (q, J = 5.7 Hz, 2H), 2.71-2.68 (m, 6H), 1.73-1.65 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0327] Example 71: Ethyl 1-methyl-3-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)-1H-pyrazole-5-carboxylate [ka] To a stirred solution containing 1-methyl-1H-pyrazole-3,5-dicarboxylic acid 5-ethyl ester (65.00 mg, 0.3280 mmol), HATU (187.06 mg, 0.4920 mmol), and DIPEA (0.11 mL, 0.6560 mmol) in DMF (0.82 mL) in an LCMS vial, N'-[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]ethane-1,2-diamine [Example 70] (97.16 mg, 0.3608 mmol) was added. The resulting solution was stirred at RT overnight. Purification by reverse-phase column chromatography (eluent: 20-70% MeOH in water (both + 0.1% formic acid)) followed by ion-exchange SCX-II column chromatography, washing with MeOH before eluting with a 7M mixture of DCM / NH3 in MeOH (1 / 1), provided ethyl 1-methyl-3-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)-1H-pyrazole-5-carboxylate (94 mg, 64%, 0.2091 mmol) as a colorless solid. HPLC / MS m / z: 450.19, [M+H] + , Rt (S): 2.12 min. 1 H NMR (600 MHz, DMSO-d6) δ 8.90-8.86 (m, 1H), 8.78 (t, J = 5.7 Hz, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.00 (t, J = 5.5 Hz, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.37 (s, 1H), 6.99-6.96 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.13 (s, 3H), 3.68 (q, J = 6.1 Hz, 2H), 3.54 (q, J = 6.1 Hz, 2H), 2.70 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0328] Example 72: Propyl 1-methyl-3-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)-1H-pyrazole-5-carboxylate [ka] Example 72.1.: Ethyl 1-methyl-3-(4-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)butanoyl)-1H-pyrazole-5-carboxylate (65.00 mg, 0.1446 mmol) was dissolved in THF (0.75 mL) and water (0.75 mL) at rt, and hydroxylithium hydrate (24.27 mg, 0.5785 mmol) was added. The resulting solution was heated at 70° C. for 4 h. The solution was cooled to rt and the volatiles were removed under reduced pressure. Water (2 mL) was added, and then the solution was acidified by adding a few drops of HCl 37% until a pH of approximately 1 was reached. A solid crashed out of solution, was filtered off, washed with water (5 mL), and dried under high vacuum to provide 2-methyl-5-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]ethylcarbamoyl]pyrazole-3-carboxylic acid (45 mg, 74%, 0.1068 mmol) as a colorless solid. HPLC / MS m / z: 422.15, [M+H] + , Rt (P): 1.11 min.

[0329] Example 72.2: 2-Methyl-5-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]ethylcarbamoyl]pyrazole-3-carboxylic acid (20.00 mg, 0.0475 mmol) and DMAP (1.16 mg, 0.0095 mmol) were dissolved in dry DCM (0.16 mL) at rt. 1 M DCC (0.06 mL, 0.0570 mmol) and propan-1-ol (0.04 mL, 0.4746 mmol) were added successively, and the reaction mixture was stirred at rt overnight. The DCM was removed under reduced pressure and the residue was purified by reverse-phase column chromatography (eluent: 20-70% MeOH in water (both + 0.1% formic acid)), followed by ion-exchange SCX-II column chromatography, washing with MeOH before eluting with 2M NH in MeOH to provide (10 mg, 45%, 0.0216 mmol) propyl 1-methyl-3-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)-1H-pyrazole-5-carboxylate as a colorless solid. HPLC / MS m / z: 464.20, [M+H] + , Rt (U): 2.29 min. 1 H NMR (600 MHz, DMSO-d6) δ 8.91-8.87 (m, 1H), 8.79 (t, J = 5.7 Hz, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.01 (t, J = 5.6 Hz, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.37 (s, 1H), 6.99-6.94 (m, 1H), 4.18 (t, J = 6.6 Hz, 2H), 4.13 (s, 3H), 3.69 (q, J = 6.1 Hz, 2H), 3.54 (q, J = 6.1 Hz, 2H), 2.70 (s, 3H), 1.68 (sext, J = 7.1 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H).

[0330] Example 73: 1-methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamido)-N-propyl-1H-pyrazole-5-carboxamide [ka] A solution of 2-methyl-5-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]ethylcarbamoyl]pyrazole-3-carboxylic acid formate [Example 72.1] (30.00 mg, 0.0642 mmol), HOBt (19.64 mg, 0.1284 mmol), and propylamine (0.03 mL, 0.3209 mmol) in DMF (0.64 mL) was stirred at rt for 16 h. 2 eq EDC.HCl, 2 eq HOBt, and 5 eq propylamine were added, and the resulting solution was stirred at 40 °C for 4 h. Cooling to rt and purification by reverse-phase column chromatography (eluent: 20-80% MeOH in water (+0.1% formic acid)), followed by ion-exchange SCX-II column chromatography washing with MeOH before eluting with 2M NH in MeOH, provided 1-methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamido)-N-propyl-1H-pyrazole-5-carboxamide (10.4 mg, 35%, 0.0225 mmol) as a colorless solid. HPLC / MS m / z: 463.22, [M+H] + , Rt (U): 2.11 min. 1H NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.90-8.87 (m, 1H), 8.52 (t, J = 5.7 Hz, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 7.99 (d, J = 5.7 Hz, 1H), 7.94 (t, J = 5.4 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.16 (s, 1H), 6.97 (d, J = 5.7 Hz, 1H), 3.95 (s, 3H), 3.78 (td, J = 7.1, 5.3 Hz, 2H), 3.15 (dt, J = 7.3, 6.0 Hz, 2H), 2.74 (t, J = 7.1 Hz, 2H), 2.71 (s, 3H), 1.51 (sext, J = 7.3 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H).

[0331] Example 74: Propyl 4-methyl-2-(methyl(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)thiazole-5-carboxylate [ka]

[0332] Example 74.1.: A solution of 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole [Example 45] (50.00 mg, 0.2035 mmol) and N-(2-aminoethyl)-N-methylcarbamic acid tert-butyl ester (0.73 mL, 4.0707 mmol) in NMP (0.81 mL) in a 0.5-2 mL microwave vial was heated at 160 °C under microwave irradiation for 1 h. The residue was added to water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, and concentrated in vacuo. Purification by reverse-phase column chromatography (eluent: 20-70% MeOH in water (both + 0.1% formic acid)) provided tert-butyl N-methyl-N-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]ethyl]carbamate (60 mg, 77%, 0.1565 mmol) as a pale yellow oil. HPLC / MS m / z: 384.20, [M+H] + , Rt (P): 1.25 min.

[0333] Example 74.2: tert-Butyl N-methyl-N-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]ethyl]carbamate (55.00 mg, 0.1434 mmol) was dissolved in dioxane (0.48 mL) and 4 M HCl in dioxane (0.72 mL, 2.8688 mmol) was added dropwise with stirring at rt. The mixture was stirred at rt for 5.5 h. Purification by ion-exchange SCX-II column chromatography eluting with 2 M NH in MeOH followed by washing with MeOH provided N-methyl-N'-[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]ethane-1,2-diamine (30 mg, 74%, 0.1059 mmol) as a colorless powder. HPLC / MS m / z: 284.15, [M+H] + , Rt (P): 0.31 min.

[0334] Example 74.3: 2-Bromo-4-methyl-thiazole-5-carboxylic acid (530.00 mg, 2.3867 mmol) and N,N-dimethylpyridin-4-amine (29.16 mg, 0.2387 mmol) were suspended in DMF (11.93 mL). EDC.HCl (549.05 mg, 2.8641 mmol) and propan-1-ol (3.59 mL, 47.735 mmol) were added sequentially, and the solution was stirred at 60 °C for 1 h. The solution was then cooled to rt, added to water (75 mL), and extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with water (70 mL), saturated bicarbonate solution (70 mL), 1 M HCl solution (70 mL), brine (70 mL), dried over magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: 0-40% in cyclohexane (cyclohexane / EtOAc - 9 / 1)) provided propyl 2-bromo-4-methyl-thiazole-5-carboxylate (410 mg, 65%, 1.5522 mmol) as a colorless solid. HPLC / MS m / z: 265.97, [M+H] + , Rt (P): 1.55 min.

[0335] Example 74.4: A solution of isopropyl magnesium chloride-lithium chloride complex (1.53 mL, 1.9933 mmol) was added to a solution of propyl 2-bromo-4-methyl-thiazole-5-carboxylate (405.00 mg, 1.5333 mmol) in dry THF (10.00 mL) at −78° C. The resulting solution was stirred at −78° C. for 10 min, and then 4-formylmorpholine (0.39 mL, 3.8332 mmol) was added. After stirring for 15 min, the solution was quenched with saturated NH4Cl solution (20 mL) and extracted with EtOAc (2 × 15 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: 0-40% of a mixture (cyclohexane / EtOAc - 9 / 1) in cyclohexane) afforded propyl 2-formyl-4-methyl-thiazole-5-carboxylate (186 mg, 57%, 0.8722 mmol) as a colorless oil. HPLC / MS m / z: 214.05, [M+H] + , Rt (T): 1.35 min.

[0336] Example 74.5.: t-BuOH (2.85 mL) was added to a solution of propyl 2-formyl-4-methyl-thiazole-5-carboxylate (80.00 mg, 0.3751 mmol) and 2-methyl-2-butene (1.19 mL, 11.254 mmol) in THF (3.01 mL). The resulting solution was stirred at rt for 10 min. A freshly prepared solution of sodium chlorite (111.96 mg, 1.238 mmol) and sodium dihydrogen phosphate hydrate (155.30 mg, 1.1254 mmol) in water (0.56 mL) was added, and the solution was stirred at rt for 15 min. The solution was quenched with saturated NaSO solution (20 mL) and extracted with EtOAc (3 x 15 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to provide 4-methyl-5-propoxycarbonyl-thiazole-2-carboxylic acid (44 mg, 51%, 0.1919 mmol) as a colorless oil, which was used immediately in the next step without further purification. HPLC / MS m / z: 230.05, [M+H]+ , Rt (T): 1.14 min.

[0337] Example 74.6.: To a stirred solution containing 4-methyl-5-propoxycarbonyl-thiazole-2-carboxylic acid (24.27 mg, 0.1059 mmol), N-methyl-N'-[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]ethane-1,2-diamine (30.00 mg, 0.1059 mmol), and HATU (60.39 mg, 0.1588 mmol) in DMF (0.53 mL) was added DIPEA (0.04 mL, 0.2118 mmol). The resulting solution was stirred at rt for 4.5 h. The solution was added to water (15 mL), and the residue was extracted with EtOAc (3 x 10 mL). Purification by silica gel column chromatography (eluent: 20-50% EtOAc in cyclohexane) followed by reverse-phase column chromatography (eluent: 20-70% MeOH in water (both + 0.1% formic acid)). Purification by ion-exchange SCX-II column chromatography, washing with MeOH before eluting with DCM / NH3 7M (1 / 1) in MeOH, provided propyl 4-methyl-2-(methyl(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)thiazole-5-carboxylate (24.2 mg, 46%, 0.0489 mmol) as a colorless solid. HPLC / MS m / z: 495.18, [M+H] + , Rt (P): 2.55 min. 1H NMR (600 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.05 (dd, J = 8.4, 1.5 Hz, 1H), 7.89 (t, J = 5.7 Hz, 1H), 7.84 (d, J = 5.7 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 6.82 (d, J = 5.7 Hz, 1H), 4.36-4.31 (m, 2H), 3.94 (t, J = 6.6 Hz, 2H), 3.61 (q, J = 5.2 Hz, 2H), 3.13 (s, 3H), 2.71 (s, 3H), 2.25 (s, 3H), 1.50 (hept, J = 6.8 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H).

[0338] Example 75: N-(5-(tert-butyl)-4-methylthiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propenamide [ka]

[0339] Example 75.1.: To sodium 3-aminopropanoate (795.82 mg, 7.1644 mmol) in a 50 mL RBF equipped with an air condenser was added NMP (5.97 mL). The mixture was heated to 100° C. and stirred until all solids dissolved. 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole[0] (440.00 mg, 1.7911 mmol) was then added and the solution was stirred overnight at 100° C. under a nitrogen atmosphere. After cooling to rt, water (6 mL) was added. The resulting solution was directly purified by reverse-phase column chromatography (eluent: 20-70% MeOH in water (both + 0.1% formic acid modifier)) to provide 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid (503 mg, 94%, 1.6862 mmol) as a beige powder. HPLC / MS m / z: 299.11, [M+H]+ , Rt (R): 0.78 min.

[0340] Example 75.2.: To 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid (20.00 mg, 0.0670 mmol) was added 5-tert-butyl-4-methyl-thiazol-2-ylamine (34.25 mg, 0.2011 mmol), PyBrop (75.01 mg, 0.1609 mmol), followed by dry DMF (0.34 mL) and DIPEA (42.04 uL, 0.2414 mmol). The resulting solution was stirred at rt overnight. Water was added (2 mL), and the residue was extracted with DCM (3 x 1 mL) using a small separator phase column. The combined organic layers were concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: 20-60% EtOAc in cyclohexane) followed by reverse-phase column chromatography (eluent: 30-80% MeOH in water (both + 0.1% formic acid)) was performed. Ion-exchange SCX-II column chromatography, eluting with 2M NH in MeOH before washing with MeOH, provided N-(5-(tert-butyl)-4-methylthiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide (15.7 mg, 52%, 0.0348 mmol) as a colorless solid. HPLC / MS m / z: 452.19, [M+H] + , Rt (Q): 2.69 min. 1H NMR (500 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.93-8.85 (m, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.03-7.95 (m, 2H), 7.86 (d, J = 8.4 Hz, 1H), 6.98 (dd, J = 5.9, 0.9 Hz, 1H), 3.83-3.75 (m, 2H), 2.81 (t, J = 6.9 Hz, 2H), 2.71 (s, 3H), 2.30 (s, 3H), 1.36 (s, 9H).

[0341] The following examples were also synthesized by similar procedures: Example 76: N-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propenamide [ka] 7mg (30%) pale yellow solid. HPLC / MS m / z: 406.20, [M+H] + , Rt (S): 2.04 min. 1 H NMR (600 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.90-8.87 (m, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.93 (t, J = 5.4 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 5.7 Hz, 1H), 6.32 (s, 1H), 3.74 (td, J = 7.1, 5.3 Hz, 2H), 3.59 (s, 3H), 2.69 (d, J = 8.3 Hz, 5H), 2.56 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H).

[0342] Example 77: N-(5-(tert-butyl)isoxazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propenamide [ka] 10mg(41%) Colorless solid. HPLC / MS m / z: 421.20, [M+H] + , Rt (S): 2.41 min. 1 H NMR (600 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.92-8.83 (m, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.95 (t, J = 5.4 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.00-6.92 (m, 1H), 6.61 (s, 1H), 3.80-3.74 (m, 2H), 2.77 (t, J = 6.9 Hz, 2H), 2.70 (s, 3H), 1.28 (s, 9H).

[0343] Example 78: N-(5-cyclopropylisoxazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propenamide [ka] 9mg(41%) Colorless solid. HPLC / MS m / z: 405.17, [M+H] + , Rt (P): 1.21 min. 1H NMR (600 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.90-8.84 (m, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 7.97 (d, J = 5.8 Hz, 1H), 7.95 (d, J = 5.4 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 5.7 Hz, 1H), 6.58 (s, 1H), 3.76 (td, J = 6.9, 5.2 Hz, 2H), 2.77 (t, J = 6.9 Hz, 2H), 2.70 (s, 3H), 2.10 (tt, J = 8.5, 5.0 Hz, 1H), 1.07-0.99 (m, 2H), 0.90-0.82 (m, 2H).

[0344] Example 79: N-(5-ethylisoxazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide [ka] 1mg (4%) colorless oil. HPLC / MS m / z: 393.17, [M+H] + , Rt (S): 2.10 min. 1 H NMR (600 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.90-8.86 (m, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 7.99 (d, J = 5.4 Hz, 1H), 7.97 (d, J = 5.8 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 5.7 Hz, 1H), 6.17 (s, 1H), 3.78 (q, J = 6.6 Hz, 2H), 2.80 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 2.56 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H).

[0345] Example 80: N-(5-(tert-butyl)thiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide [ka] 8mg (27%). HPLC / MS m / z: 437.17, [M+H] + , Rt (Q): 2.62 min. 1 H NMR (600 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.91-8.84 (m, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 7.99 (t, J = 5.4 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.12 (s, 1H), 6.97 (dd, J = 5.9, 0.8 Hz, 1H), 3.79 (td, J = 6.8, 5.2 Hz, 2H), 2.83 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 1.32 (s, 9H).

[0346] Example 81: N-(5-(tert-butyl)-4-ethylthiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide [ka] 9.5mg(30%) Colorless solid. HPLC / MS m / z: 465.21, [M+H] + , Rt (U): 2.92 min. 1H NMR (600 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.91-8.85 (m, 1H), 8.14 (dd, J = 8.4, 1.5 Hz, 1H), 8.02-7.93 (m, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.00-6.93 (m, 1H), 3.78 (td, J = 6.9, 5.4 Hz, 2H), 2.80 (t, J = 6.9 Hz, 2H), 2.70 (s, 3H), 2.64 (q, J = 7.4 Hz, 2H), 1.36 (s, 9H), 1.15 (t, J = 7.4 Hz, 3H).

[0347] Example 82: N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide [ka] 13mg(45%) Colorless solid. HPLC / MS m / z: 434.23, [M+H] + , Rt (U): 2.41 min. 1 H NMR (600 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.89 (s, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.94 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 5.8 Hz, 1H), 6.33 (s, 1H), 3.79-3.71 (m, 5H), 2.69 (d, J = 11.8 Hz, 5H), 1.31 (s, 9H).

[0348] Example 83: N-[5-(3-methoxyoxetan-3-yl)-4-methyl-thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide [ka]

[0349] Example 83.1: To a microwave vial was added 2-amino-4-methylthiazole (500.00 mg, 4.3794 mmol), p-toluenesulfonic acid (83.31 mg, 0.4379 mmol), 2,5-hexanedione (0.52 mL, 4.3794 mmol), and toluene (15.87 mL). The vial was capped and irradiated at 150 °C for 1 h. The mixture was diluted with MeOH and evaporated to dryness. Purification by silica gel column chromatography (eluent: 0-30% EtOAc in cyclohexane) provided 2-(2,5-dimethylpyrrol-1-yl)-4-methyl-thiazole (565.7 mg, 67%, 2.9421 mmol) as a pale yellow oil. HPLC / MS m / z: 193.08, [M+H] + , Rt (T): 1.35 min.

[0350] Example 83.2.: 1.6 M n-BuLi (0.98 mL, 1.5612 mmol) in hexane was added dropwise to a solution of 2-(2,5-dimethylpyrrol-1-yl)-4-methyl-thiazole (300.00 mg, 1.5602 mmol) in THF (11 mL) at −48° C., and the reaction was stirred for 45 min (the temperature warmed slightly to −20° C.). The temperature was then lowered to −48° C., and a solution of 3-oxetanone (75.00 mg, 1.0408 mmol) in THF (4 mL) was added, and the reaction mixture was stirred for 30 min. The temperature was allowed to gradually warm to rt (overnight). 1.65 mL of a saturated aqueous solution of NH4Cl was added dropwise, and the volatiles were evaporated almost completely. The crude was partitioned between EtOAc (40 mL) and water (40 mL). After phase separation, the organic layer was washed with brine (40 mL), dried over MgSO, filtered, and evaporated to dryness. Purification by silica gel column chromatography (eluent: 20-80% EtOAc in cyclohexane) provided 3-[2-(2,5-dimethylpyrrol-1-yl)-4-methyl-thiazol-5-yl]oxetan-3-ol (220 mg, 80%, 0.8323 mmol) as a pale yellow film. HPLC / MS m / z: 265.10, [M+H] + , Rt (T): 1.22 min.

[0351] Example 83.3.: NaH (83.23 mg, 2.0807 mmol) was added to a solution of 3-[2-(2,5-dimethylpyrrol-1-yl)-4-methyl-thiazol-5-yl]oxetan-3-ol (220.00 mg, 0.8323 mmol) in DMF (3.53 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, followed by the addition of iodomethane (0.13 mL, 2.0807 mmol). The reaction was allowed to warm to rt and left stirring overnight. The reaction mixture was then partitioned between water (50 mL) and EtOAc (40 mL). After phase separation, the organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and evaporated to dryness to give 2-(2,5-dimethylpyrrol-1-yl)-5-(3-methoxyoxetan-3-yl)-4-methyl-thiazole (230.5 mg, 99%, 0.8280 mmol) as a light beige solid. This compound was carried forward without further purification. HPLC / MS m / z: 279.12, [M+H] + , Rt (T): 1.35 min.

[0352] Example 83.4.: Concentrated HCl (0.07 mL, 2.1285 mmol) was added dropwise to a mixture of 2-(2,5-dimethylpyrrol-1-yl)-5-(3-methoxyoxetan-3-yl)-4-methylthiazole (79.00 mg, 0.2838 mmol) and MeOH (0.69 mL) in a vial. The vial was capped and irradiated in a microwave at 90 °C for 15 min. The volatiles were carefully evaporated to dryness. The crude product obtained was purified by SCX-II cartridge (2 g, 15 mL). The basic fractions were evaporated to dryness. Purification by silica gel column chromatography (eluent: 5% MeOH in DCM) provided 5-(3-methoxyoxetan-3-yl)-4-methyl-thiazol-2-amine (11.2 mg, 20%, 0.056 mmol). HPLC / MS m / z: 171.06, [M+H] + , Rt (T): 0.44 min.

[0353] Example 83.5.: Using 5-(3-methoxyoxetan-3-yl)-4-methyl-thiazol-2-amine and the procedure according to Example 45.7, N-[5-(3-methoxyoxetan-3-yl)-4-methyl-thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide (1.2 mg, 3%) was obtained as a colorless amorphous solid. HPLC / MS m / z: 481.16 [M+H] + , Rt (T): 1.04 min. 1 H NMR (500 MHz, DMSO-d6) δ 11.90 (brs, 1H), 8.91-8.86 (m, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.02 (d, J = 5.3 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 6.2 Hz, 1H), 4.78 (s, 4H), 3.80 (q, J = 6.5 Hz, 2H), 3.05 (s, 3H), 2.85 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 2.13 (s, 3H).

[0354] Example 84: 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-N-[4-methyl-5-(3-propoxyoxetan-3-yl)thiazol-2-yl]propenamide [ka]

[0355] Example 84.1: 2-(2,5-dimethylpyrrol-1-yl)-4-methyl-5-(3-propoxyoxetan-3-yl)thiazole was prepared using iodopropane in the procedure from Example 83. 2-(2,5-dimethylpyrrol-1-yl)-4-methyl-5-(3-propoxyoxetan-3-yl)thiazole (162.5 mg, 99%, 0.5303 mmol) as a light brown gum. HPLC / MS m / z: 307.15, [M+H] + , Rt (T): 1.52 min.

[0356] Example 84.2.: TFA (0.21 mL, 2.7413 mmol) was added dropwise to a solution of 2-(2,5-dimethylpyrrol-1-yl)-4-methyl-5-(3-propoxyoxetan-3-yl)thiazole (84.00 mg, 0.2741 mmol), 1-propanol (1.75 mL), and water (0.18 mL) in a microwave vial. The vial was capped and irradiated in a microwave at 110 °C for 2 h 5 min. The reaction mixture was evaporated to dryness and purified on an SCX-II cartridge (2 g, 15 mL) using MeOH and a 2 M solution of NH in MeOH. Purification by silica gel column chromatography (eluent: 0-15% MeOH in DCM) provided 4-methyl-5-(3-propoxyoxetan-3-yl)thiazol-2-amine (11.7 mg, 19%, 0.0512 mmol) as a brown amorphous solid. HPLC / MS m / z: 229.10, [M+H] + , Rt (T): 0.73 min. Example 84.3.: Using 4-methyl-5-(3-propoxyoxetan-3-yl)thiazol-2-amine and the procedure according to Example 45.7, 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-N-[4-methyl-5-(3-propoxyoxetan-3-yl)thiazol-2-yl]propanamide (17 mg, 71%) was obtained as a light beige solid. HPLC / MS m / z: 509.20 [M+H] + , Rt (P): 1.34 min. 1H NMR (600 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.95-8.81 (m, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.00 (t, J = 5.5 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.01-6.92 (m, 1H), 4.78 (s, 4H), 3.80 (q, J = 6.7 Hz, 2H), 3.12 (t, J = 6.5 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 2.14 (s, 3H), 1.48 (sext, J = 7.1 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H).

[0357] Example 85: N,4-Dimethyl-2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoylamino]-N-propyl-thiazole-5-carboxamide [ka]

[0358] Example 85.1: 2-Amino-4-methyl-thiazole-5-carboxylic acid (100.00 mg, 0.6322 mmol), DIPEA (0.44 mL, 2.5288 mmol), HATU (223.09 mg, 0.9483 mmol) were suspended in dry DMF (3.61 mL) under nitrogen before adding N-methylpropan-1-amine (0.10 mL, 0.9483 mmol). The mixture was stirred at rt for 22 h. The reaction mixture was partitioned between EtOAc (50 mL) and water (40 mL). The organic layer was retained, washed with saturated aqueous bicarbonate (50 mL) and brine (50 mL), dried over MgSO4, and concentrated to dryness in vacuo to provide 2-amino-N,4-dimethyl-N-propyl-thiazole-5-carboxamide (44 mg, 33%, 0.2063 mmol) as a yellow solid. HPLC / MS m / z: 214.10, [M+H]+ , Rt (T): 0.63 min.

[0359] Example 85.2. Using 2-amino-N,4-dimethyl-N-propyl-thiazole-5-carboxamide and the procedure according to Example 45.7, N,4-dimethyl-2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoylamino]-N-propyl-thiazole-5-carboxamide (24.6 mg, 50%, 0.0498 mmol) was obtained as a transparent film. HPLC / MS m / z: 494.20 [M+H] + , Rt (T): 1.07 min. 1 H NMR (600 MHz, MeOD-d4) δ 8.87-8.77 (m, 1H), 8.20 (dd, J = 8.5, 1.6 Hz, 1H), 7.95 (dd, J = 6.0, 1.7 Hz, 1H), 7.86-7.76 (m, 1H), 6.99 (dt, J = 5.9, 1.4 Hz, 1H), 3.96 (t, J = 6.7 Hz, 2H), 3.50-3.41 (m, 2H), 3.06 (s, 3H), 2.96 (t, J = 6.7 Hz, 2H), 2.69 (s, 3H), 2.28 (s, 3H), 1.66 (brd, J = 8.5 Hz, 2H), 0.90 (brs, 3H).

[0360] Example 86: N-[5-(cyclohexen-1-yl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propenamide [ka] To 1-(2-amino-1,3-thiazol-5-yl)cyclohexan-1-ol (15.39 mg, 0.0738 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (25.71 mg, 0.1341 mmol), and HOBt (18.12 mg, 0.1341 mmol) under a nitrogen atmosphere was added 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid (20.00 mg, 0.0670 mmol) in DMF (0.34 mL), and the reaction mixture was heated at 70° C. for 20 h. Purification by reverse-phase column chromatography (eluent: 10-100% MeOH in water (both + 0.1% formic acid modifier)) provided N-[5-(cyclohexen-1-yl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide (8.2 mg, 27%, 0.0178 mmol) as a colorless solid. HPLC / MS m / z: 461.18 [M+H] + , Rt (T): 1.36 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.88 (d, J = 1.6 Hz, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 8.01 (t, J = 5.4 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.30 (s, 1H), 6.97 (d, J = 5.7 Hz, 1H), 5.97 (tt, J = 4.0, 1.6 Hz, 1H), 3.79 (q, J = 6.4 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 2.33 (ddt, J = 6.4, 4.4, 2.0 Hz, 2H), 2.21-2.11 (m, 2H), 1.72-1.65 (m, 2H), 1.62-1.54 (m, 2H).

[0361] Example 87: N-[5-(1-methoxycyclohexyl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propenamide [ka] To 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid (20.00 mg, 0.0670 mmol) was added 1-(2-amino-1,3-thiazol-5-yl)cyclohexan-1-ol (27.99 mg, 0.1341 mmol) and PyBrop (75.01 mg, 0.1609 mmol), followed by dry DMF (0.34 mL) and DIPEA (42.04 µL, 0.2414 mmol). The resulting solution was stirred at rt for 19 h. Purification was performed by reverse-phase column chromatography (eluent: 10–100% MeOH in water (both + 0.1% formic acid)). Further purification by ion-exchange SCX-II column chromatography eluting with 2M NH in MeOH followed by washing with MeOH provided a mixture of N-[5-(1-hydroxycyclohexyl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide and N-[5-(1-methoxycyclohexyl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide. Preparative TLC (500 microns) using 5% MeOH in DCM as the eluent provided N-[5-(1-methoxycyclohexyl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide (3 mg, 8%) as a colorless amorphous solid. HPLC / MS m / z: 493.21 [M+H] + , Rt (P): 1.34 min. 1H NMR (600 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.89 (d, J = 1.6 Hz, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.01 (t, J = 5.4 Hz, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 6.97 (d, J = 5.7 Hz, 1H), 3.80 (q, J = 6.4 Hz, 2H), 2.93 (s, 3H), 2.85 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 1.96 (d, J = 13.4 Hz, 2H), 1.82-1.68 (m, 2H), 1.61-1.42 (m, 3H), 1.30-1.21 (m, 3H).

[0362] Example 88: Ethyl 4-isopropyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate [ka] To a stirred solution of 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid [Example 63.3] (35 mg, 0.13 mmol), ethyl 2-amino-4-isopropyl-thiazole-5-carboxylate (25 mg, 0.12 mmol), and DIPEA (0.030 mL, 0.17 mmol) in DMF (0.98 mL) was added HATU (57 mg, 0.15 mmol) at rt, and the resulting mixture was stirred for 17 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 20-100% gradient) to provide 0.031 g (57%) as an off-white solid. HPLC / MS m / z: 472.16 [M+H] + , Rt (R): 1.42 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.85 (t, J = 5.5 Hz, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.13 (dt, J = 7.8, 1.3 Hz, 1H), 8.02 (dt, J = 7.9, 1.3 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.89 (quint, J = 6.9 Hz, 1H), 3.60 (q, J = 6.6 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.18 (d, J = 6.8 Hz, 6H).

[0363] The following examples were also prepared in a similar manner: Example 89: tert-Butyl-4-methyl-2-(3-(3-(1-methyl-1H-pyrazol-4-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] Using 3-(1-methylpyrazol-4-yl)benzoic acid and the procedure from Example 63.3 provided 3-[[3-(1-methylpyrazol-4-yl)benzoyl]amino]propanoic acid, which was used in the above procedure to provide tert-butyl 4-methyl-2-(3-(3-(1-methyl-1H-pyrazol-4-yl)benzamido)propanamido)thiazole-5-carboxylate (25 mg, 26%, 0.0532 mmol) as a pale yellow powder. HPLC / MS m / z: 470.2, [M+H] + , Rt (Z): 2.72 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.62 (t, J = 5.6 Hz, 1H), 8.16 (d, J = 0.8 Hz, 1H), 7.99 (t, J = 1.8 Hz, 1H), 7.88 (d, J = 0.9 Hz, 1H), 7.69 (ddd, J = 7.7, 1.8, 1.1 Hz, 1H), 7.62 (dt, J = 7.8, 1.3 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 3.87 (s, 3H), 3.63-3.55 (m, 2H), 2.77 (t, J = 6.8 Hz, 2H), 2.50 (s, 3H), 1.50 (s, 9H).

[0364] Example 90: Methyl 4-ethyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate [ka] To a stirred solution of 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid [Example 63.3] (35 mg, 0.13 mmol), methyl 2-amino-4-ethyl-thiazole-5-carboxylate (23 mg, 0.12 mmol), and DIPEA (0.030 mL, 0.17 mmol) in DMF (0.98 mL) was added HATU (57 mg, 0.15 mmol) at rt, and the resulting mixture was stirred for 17 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 20-100% gradient) to provide 0.035 g (64%) as an off-white solid. HPLC / MS m / z: 444.13 [M+H] + , Rt (R): 1.30 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.58 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.13 (dd, J = 7.8, 1.7 Hz, 1H), 8.02 (dd, J = 7.8, 1.7 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 3.77 (s, 3H), 3.64-3.56 (m, 2H), 2.98 (q, J = 7.5 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 1.17 (t, J = 7.5 Hz, 3H).

[0365] Example 91: Ethyl 2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]-4-(trifluoromethyl)thiazole-5-carboxylate [ka] To a stirred solution of 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid [Example 63.3] (35 mg, 0.13 mmol), ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate (28 mg, 0.12 mmol), and DIPEA (0.030 mL, 0.17 mmol) in DMF (0.98 mL) was added HATU (57 mg, 0.15 mmol) at rt, and the resulting mixture was stirred for 17 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 20-100% gradient) to afford 0.014 g (24%) as an off-white solid. HPLC / MS m / z: 498.11 [M+H] + , Rt (R): 1.37 min. 1 H NMR (500 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.86 (t, J = 5.6 Hz, 1H), 8.45 (t, J = 1.7 Hz, 1H), 8.13 (dt, J = 7.7, 1.4 Hz, 1H), 8.02 (dt, J = 7.9, 1.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.62 (q, J = 6.5 Hz, 2H), 2.82 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0366] Example 92: Ethyl 4-ethyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate [ka] To a stirred solution of 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid [0] (35 mg, 0.13 mmol), ethyl 2-amino-4-ethyl-thiazole-5-carboxylate (23 mg, 0.12 mmol), and DIPEA (0.030 mL, 0.17 mmol) in DMF (0.98 mL) was added HATU (57 mg, 0.15 mmol) at rt, and the resulting mixture was stirred for 23 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 40-100% gradient) to provide 0.023 g (43%) as an off-white solid. HPLC / MS m / z: 458.15 [M+H] + , Rt (R): 1.36 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.13 (dt, J = 7.7, 1.4 Hz, 1H), 8.02 (dt, J = 7.9, 1.3 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.60 (q, J = 6.5 Hz, 2H), 2.98 (q, J = 7.5 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.5 Hz, 3H).

[0367] Example 93: N-[3-[[5-[(E)-2-cyclopentylvinyl]-4-methyl-thiazol-2-yl]amino]-3-oxopropyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide [ka]

[0368] Example 93.1.: To a stirred solution of 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid [Example 63.3] (600 mg, 2.18 mmol), 5-bromo-4-methyl-thiazol-2-amine (421 mg, 2.18 mmol), and DIPEA (0.570 mL, 3.27 mmol) in DMF (16.8 mL) was added HATU (1078 mg, 2.83 mmol) at rt, and the resulting mixture was stirred for 20 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (150 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / cyclohexane = 50-100% gradient) to provide 0.506 g (52%) of N-[3-[(5-bromo-4-methyl-thiazol-2-yl)amino]-3-oxa-propyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide. HPLC / MS m / z: 450 / 452 Br split [M+H] + , Rt (R): 1.35 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.87 (t, J = 5.5 Hz, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.12 (dt, J = 7.7, 1.4 Hz, 1H), 8.02 (dt, J = 8.0, 1.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 3.58 (q, J = 6.5 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.21 (s, 3H).

[0369] Example 93.2.: Nitrogen gas was bubbled through a mixture of N-[3-[(5-bromo-4-methyl-thiazol-2-yl)amino]-3-oxo-propyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide (50 mg, 0.11 mmol) and [(E)-2-cyclopentylvinyl]boronic acid (23 mg, 0.17 mmol) in 1,4-dioxane (1.11 mL) and 2 M aqueous sodium carbonate (0.22 mL, 0.44 mmol) for 5 min. Palladium tetrakis(triphenylphosphine) (13 mg, 0.011 mmol) was added, and the mixture was heated at 110 °C in a sealed vial for 30 min. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / cyclohexane = 50-100% gradient) and reverse-phase column chromatography (eluent: methanol / water with 0.1% formic acid modifier = 20-100% gradient) to provide 0.023 g (44%) as an off-white solid. HPLC / MS m / z: 466.19 [M+H] + , Rt (P): 1.67 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.85 (t, J = 5.5 Hz, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.13 (dt, J = 7.7, 1.4 Hz, 1H), 8.03 (dt, J = 7.9, 1.3 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 6.48 (dd, J = 15.6, 1.1 Hz, 1H), 5.75 (dd, J = 15.6, 7.9 Hz, 1H), 3.58 (q, J = 6.6 Hz, 2H), 2.73 (t, J = 6.9 Hz, 2H), 2.68 (s, 3H), 2.61-2.51 (m, 1H), 2.21 (s, 3H), 1.84-1.73 (m, 2H), 1.71-1.47 (m, 4H), 1.39-1.28 (m, 2H).

[0370] Example 94: N-[3-[[5-[(E)-3-methoxyprop-1-enyl]-4-methyl-thiazol-2-yl]amino]-3-oxo-propyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide [ka] Nitrogen gas was passed through a mixture of N-[3-[(5-bromo-4-methylthiazol-2-yl)amino]-3-oxopropyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide (50 mg, 0.11 mmol) [Example 93.1] and 2-[(E)-3-methoxyprop-1-enyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (33 mg, 0.17 mmol) in 1,4-dioxane (1.11 mL) and 2 M aqueous sodium carbonate (0.22 mL, 0.44 mmol) for 5 min. Palladium tetrakis(triphenylphosphine) (13 mg, 0.011 mmol) was added, and the mixture was heated at 110 °C in a sealed vial for 30 min. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / cyclohexane = 50-100% gradient), reverse-phase column chromatography (eluent: methanol / water with 0.1% formic acid modifier = 20-100% gradient), and column chromatography (eluent: methanol / dichloromethane = 0-8% gradient) to provide 0.011 g (22%) as a pale yellow gum. HPLC / MS m / z: 442.15 [M+H] + , Rt (R): 1.29 min. 1H NMR (500 MHz, MeOD-d4) δ 8.49 (td, J = 1.7, 0.5 Hz, 1H), 8.18 (ddd, J = 7.7, 1.7, 1.2 Hz, 1H), 7.96 (ddd, J = 7.8, 1.8, 1.2 Hz, 1H), 7.61 (td, J = 7.8, 0.6 Hz, 1H), 6.74 (dt, J = 15.7, 1.4 Hz, 1H), 5.89 (dt, J = 15.7, 6.1 Hz, 1H), 4.05 (dd, J = 6.1, 1.4 Hz, 2H), 3.76 (t, J = 6.7Hz, 2H), 3.36 (s, 3H), 2.83 (t, J = 6.7 Hz, 2H), 2.66 (s, 3H), 2.27 (s, 3H).

[0371] Example 95: 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-[3-[[4-methyl-5-(1-phenylvinyl)thiazol-2-yl]amino]-3-oxo-propyl]benzamide [ka] Nitrogen gas was bubbled through a mixture of N-[3-[(5-bromo-4-methylthiazol-2-yl)amino]-3-oxopropyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide (50 mg, 0.11 mmol) [Example 93.1], 4,4,5,5-tetramethyl-2-(1-phenylvinyl)-1,3,2-dioxaborolane (38 mg, 0.17 mmol) in 1,4-dioxane (1.11 mL) and 2 M aqueous sodium carbonate (0.22 mL, 0.44 mmol) for 5 min. Palladium tetrakis(triphenylphosphine) (13 mg, 0.011 mmol) was added, and the mixture was heated at 110 °C in a sealed vial for 30 min. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / cyclohexane = 50-100% gradient) and reverse-phase column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 20-100% gradient) to provide 0.018 g (34%) as a pale yellow gum. HPLC / MS m / z: 474.16 [M+H] + , Rt (R): 1.48 min. 1 H NMR (500 MHz, MeOD-d4) δ 8.49 (td, J = 1.8, 0.6 Hz, 1H), 8.18 (ddd, J = 7.7, 1.7, 1.1 Hz, 1H), 7.96 (ddd, J = 7.8, 1.9, 1.2 Hz, 1H), 7.60 (td, J = 7.8, 0.6 Hz, 1H), 7.37-7.29 (m, 5H), 5.64 (d, J = 1.1 Hz, 1H), 5.37 (d, J = 1.2 Hz, 1H), 3.76 (t, J = 6.7 Hz, 2H), 2.84 (t, J = 6.7 Hz, 2H), 2.65 (s, 3H), 2.02 (s, 3H).

[0372] Example 96: 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-N-[5-(1,1,2,2,2-pentafluoroethyl)thiazol-2-yl]cyclobutanecarboxamide [ka]

[0373] Example 96.1.: Isoquinoline-7-carbonitrile (4.00 g, 25.9 mmol), triethylamine (7.23 mL, 51.9 mmol), and [bmim]OAc (26 mL) were combined 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 rt 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 MgSO, 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.

[0374] Example 96.2.: 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.

[0375] Example 96.3.: 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 rt for 4 h before being filtered through a pad of anhydrous MgSO4. The filtrate was concentrated under reduced pressure to afford 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.

[0376] Example 96.4: 5-Methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] (900.00 mg, 3.9609 mmol) and methyl cis-3-aminocyclobutanecarboxylate hydrochloride (820.01 mg, 4.9511 mmol) were mixed in DCM (7.92 mL) under an argon atmosphere at rt. DIPEA (3.28 mL, 18.814 mmol) and PyBrop (2400.46 mg, 5.1492 mmol) were added, and the reaction mixture was stirred at rt for 3 d. The volatiles were removed in vacuo, and the crude material was purified by silica gel column chromatography (eluent: 20-60% EtOAc in cyclohexane) to give methyl 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylate (1090.6 mg, 81%, 3.2232 mmol) as an off-white solid. HPLC / MS m / z: 339.15, [M+H] + , Rt (T): 1.05 min.

[0377] Example 96.5.: Methyl 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylate (1000.00 mg, 2.9554 mmol), THF (11.82 mL), MeOH (5.91 mL), and water (11.82 mL) were mixed at ambient temperature. LiOH monohydrate (248.02 mg, 5.9109 mmol) was added, and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo. Purification was carried out by reverse-phase column chromatography (eluent: 5-30% MeOH in water). Fractions were combined and concentrated in vacuo to give 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid (776.9 mg, 81%, 2.3954 mmol) as a fine, colorless solid. HPLC / MS m / z: 325.13, [M+H] + , Rt (T): 0.97 min.

[0378] Example 96.6: 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid formate (40.00 mg, 0.1080 mmol) and bis(tetramethylene)fluoroformamidinium (68.30 mg, 0.2160 mmol) were mixed in DCM (0.43 mL) under a nitrogen atmosphere at rt for 10 min. DIPEA (0.09 mL, 0.4860 mmol) was added, and the reaction mixture was stirred for 30 min. 5-(pentafluoroethyl)-1,3-thiazol-2-amine (47.12 mg, 0.2160 mmol) was added. The vial was capped, and the reaction was heated to 80 °C in a microwave for 1 h. Volatiles were removed in vacuo, and the crude reaction mixture was directly purified by flash chromatography (5–70% MeOH in water [0.1% FA]). The product-containing fractions were filtered through a 2 g SCX-2 column. The compound was released with 2N NH3 in MeOH and the solvent removed in vacuo to provide the desired product, 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-N-[5-(1,1,2,2,2-pentafluoroethyl)thiazol-2-yl]cyclobutanecarboxamide (12.3 mg, 21%, 0.0231 mmol) as a fine yellow solid. HPLC / MS m / z 525.1133 [M+H] + , Rt (U): 3.05 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.74-9.27 (m, 1H), 8.15 (dd, J = 1.6, 8.5 Hz, 1H), 8.07-8.12 (m, 2H), 7.96 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 6.94-7.00 (m, 1H), 4.72 (ddt, J = 7.4, 9.3, 16.7 Hz, 1H), 3.17 (d, J = 5.3 Hz, 2H), 2.71 (s, 3H), 2.63 (qd, J = 2.6, 7.8 Hz, 2H), 2.45 (qd, J = 2.6, 9.3 Hz, 2H).

[0379] Example 97: N-(5-Bromo-4-methyl-thiazol-2-yl)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxamide [ka] 3-[[7-(5-Methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [Example 96] (265.00 mg, 0.8171 mmol) and bis(tetramethylene)fluoroformamidinium (335.86 mg, 1.0622 mmol) were mixed in DCM (3.27 mL) under a nitrogen atmosphere at rt for 10 min. DIPEA (0.64 mL, 3.6768 mmol) was added, and the reaction mixture was stirred for 30 min. 5-Bromo-4-methyl-thiazol-2-amine (205.07 mg, 1.0622 mmol) was added. The vial was capped, and the reaction was heated to 80 °C in a microwave for 2 h. Volatiles were removed in vacuo, and the crude reaction mixture was directly purified by flash chromatography (5–70% MeOH in water [0.1% FA]). The product-containing fractions were filtered through a 2 g SCX-2 column. The compound was released with 2N NH3 in MeOH, and the solvent was removed in vacuo to provide the desired product, N-(5-bromo-4-methyl-thiazol-2-yl)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxamide (227.2 mg, 55%, 0.4486 mmol) as a light brown solid. HPLC / MS m / z 531.1241 [M+H] + , Rt (U): 2.37 min. 1H NMR (600 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.92-9.11 (m, 1H), 8.14 (dd, J = 1.6, 8.5 Hz, 1H), 8.08 (d, J = 7.1 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 6.92-6.99 (m, 1H), 4.70 (tq, J = 7.4, 9.3 Hz, 1H), 3.07 (tt, J = 7.8, 9.8 Hz, 1H), 2.54-2.62 (m, 2H), 2.71 (s, 3H), 2.41 (qd, J = 2.6, 9.3 Hz, 2H), 2.23 (s, 3H).

[0380] Example 98: (1s,3s)-N-(5-(tert-butyl)-4-methylthiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutane-1-carboxamide [ka]

[0381] Example 98.1: 5-Methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] (900 mg, 3.96 mmol) and methyl cis-3-amino-cyclobutanecarboxylate hydrochloride (820 mg, 4.95 mmol) were mixed in anhydrous DCM (7.9 mL) under an argon atmosphere at rt. DIPEA (3.3 mL, 18.81 mmol) and PyBroP (2.40 g, 5.15 mmol) were added, and the reaction mixture was stirred at rt overnight. The volatiles were removed under reduced pressure and the crude material was purified by flash chromatography (20-60% EtOAc in cyclohexane) to yield 1.09 g (81%) of methyl (1s,3s)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutane-1-carboxylate as an off-white solid. HPLC / MS m / z: 339.1 [M+H] + , Rt (T): 1.05 min.

[0382] Example 98.2.: Methyl 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarboxylate (1.00 g, 2.96 mmol), THF (12 mL), MeOH (6 mL), and water (12 mL) were mixed at ambient temperature. Lithium hydroxide (248 mg, 5.91 mmol) was added, and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (5-30% MeOH in water [0.1% FA]) to afford 777 mg (81%) of (1s,3s)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutane-1-carboxylic acid as an off-white crystalline solid. HPLC / MS m / z: 325.1 [M+H] + , Rt (T): 0.97 min.

[0383] Example 98.3. Prepared as described for Example 47.5 using (1s,3s)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutane-1-carboxylic acid (30 mg, 0.093 mmol) and 5-tert-butyl-4-methyl-thiazol-2-ylamine (32 mg, 0.185 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration. Yield: 24 mg (52%) off-white solid. HPLC / MS m / z: 477.2068 [M+H] + , Rt (U): 2.84 min. 1 H NMR (600 MHz, DMSO-d6) δ 11.76 (s, 1H), 9.01 (s, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 5.7 Hz, 1H), 4.69-4.60 (m, 1H), 3.06-2.98 (m, 1H), 2.71 (s, 3H), 2.59-2.53 (m, 2H), 2.42-2.34 (m, 2H), 2.31 (s, 3H), 1.36 (s, 9H).

[0384] The following examples were also synthesized analogously: Example 99: Propyl 4-methyl-2-((1s,3s)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutane-1-carboxamido)thiazole-5-carboxylate [ka] Preparation as described for Example 47.5 provided propyl 4-methyl-2-((1s,3s)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutane-1-carboxamido)thiazole-5-carboxylate (17 mg, 45%, 0.0336 mmol). HPLC / MS m / z: 507.18, [M+H] + , Rt (U): 2.84 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.01 (s, 1H), 8.15 (dd, J = 8.4, 1.5 Hz, 1H), 8.12-8.08 (m, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 5.7 Hz, 1H), 4.69 (ddt, J = 16.8, 9.2, 7.3 Hz, 1H), 4.16 (t, J = 6.5 Hz, 2H), 3.11 (ddd, J = 17.5, 9.8, 7.8 Hz, 1H), 2.71 (s, 3H), 2.64-2.57 (m, 2H), 2.55 (s, 3H), 2.42 (qd, J = 9.4, 2.5 Hz, 2H), 1.68 (sext, J = 7.1 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H).

[0385] Example 100: (1s,3s)-N-(5-(tert-butyl)isoxazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutane-1-carboxamide [ka] Prepared as described for Example 48 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [Example 96] (30 mg, 0.093 mmol) and 3-amino-5-tert-butylisoxazole (26 mg, 0.185 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration. Yield: 22 mg (53%) colorless amorphous solid. HPLC / MS m / z: 447.2133 [M+H] + , Rt (U): 2.62 min. 1 H NMR (600 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.02 (d, J = 1.6 Hz, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 5.7 Hz, 1H), 6.63 (s, 1H), 4.68-4.58 (m, 1H), 3.04-2.96 (m, 1H), 2.71 (s, 3H), 2.58-2.52 (m, 2H), 2.40-2.34 (m, 2H), 1.29 (s, 9H).

[0386] Example 101: (1s,3s)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(1-methyl-5-pentyl-1H-pyrazol-3-yl)cyclobutane-1-carboxamide [ka] Prepared as described for Example 48 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [Example 96] (30 mg, 0.093 mmol) and 1-methyl-5-pentyl-pyrazol-3-amine [Example 57] (23 mg, 0.139 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration. Yield: 23 mg (51%) off-white amorphous solid. HPLC / MS m / z: 474.2615 [M+H] + , Rt (Q): 2.72 min. 1 H NMR (600 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.03 (s, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 5.7 Hz, 1H), 6.32 (s, 1H), 4.66-4.56 (m, 1H), 3.61 (s, 3H), 2.96-2.89 (m, 1H), 2.71 (s, 3H), 2.55 (t, J = 7.7 Hz, 2H), 2.52-2.47 (m, 2H), 2.39-2.32 (m, 2H), 1.59-1.51 (m, 2H), 1.36-1.27 (m, 4H), 0.90-0.85 (m, 3H).

[0387] Example 102: (1s,3s)-N-(5-isobutyl-4-methylthiophen-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutane-1-carboxamide formate hydrochloride [ka] Prepared as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [Example 96] and 5-isobutyl-4-methyl-thiophen-2-amine. Purification by reverse-phase flash chromatography. Yield: 41 mg (35%). HPLC / MS m / z: 476.21, [M+H] + , Rt (U): 2.99 min. 1 H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.03 (d, J = 1.5 Hz, 1H), 8.16 (s, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 8.10 (d, J = 7.1 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 6.96 (dd, J = 5.9, 0.9 Hz, 1H), 6.36 (s, 1H), 4.68 (sext, J = 8.2 Hz, 1H), 2.95-2.83 (m, 1H), 2.71 (s, 3H), 2.58-2.50 (m, 2H), 2.46 (d, J = 7.1 Hz, 2H), 2.43-2.32 (m, 2H), 2.01 (s, 3H), 1.74 (hept, J = 6.7 Hz, 1H), 0.89 (d, J = 6.6 Hz, 6H).

[0388] Example 103: (1s,3s)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(4-methyl-5-(trifluoromethyl)thiazol-2-yl)cyclobutane-1-carboxamide [ka] Prepared as described for Example 48 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [Example 96] and 4-methyl-5-(trifluoromethyl)thiazol-2-amine. Purified by reverse-phase flash chromatography. Yield: 7 mg (12%). HPLC / MS m / z: 489.13, [M+H] + , Rt (U): 2.90 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.61 (s, 1H), 9.02-8.99 (m, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 8.09 (d, J = 7.1 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 5.9, 0.8 Hz, 1H), 4.71 (ddt, J = 16.7, 9.2, 7.3 Hz, 1H), 3.12 (tt, J = 9.8, 7.8 Hz, 1H), 2.71 (s, 3H), 2.64-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.40 (q, J = 1.8 Hz, 3H).

[0389] Example 104: tert-Butyl 4-methyl-2-((1s,3s)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)cyclobutane-1-carboxamido)thiazole-5-carboxylate [ka]

[0390] Example 104.1: 3-(tert-Butoxycarbonylamino)cyclobutanecarboxylic acid (200.00 mg, 0.9292 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (356.24 mg, 1.8583 mmol), HOBt (251.09 mg, 1.8583 mmol), and tert-butyl 2-amino-4-methyl-thiazole-5-carboxylate [Example 110.1] (258.83 mg, 1.2079 mmol) were dissolved in dry DMF (4.65 mL). The reaction mixture was stirred at 70 °C overnight. Purification was performed by silica gel column chromatography (eluent: 10-70% EtOAc in cyclohexane). The material was dissolved in EtOAc and washed with HCl (1 M). Concentration in vacuo provided tert-butyl 2-[[3-(tert-butoxycarbonylamino)cyclobutanecarbonyl]amino]-4-methyl-thiazole-5-carboxylate (152 mg, 37%, 0.340 mmol). HPLC / MS m / z: 412.19, [M+H] + , Rt (P): 1.64 min.

[0391] Example 104.2.: tert-Butyl 2-[[3-(tert-butoxycarbonylamino)cyclobutanecarbonyl]amino]-4-methyl-thiazole-5-carboxylate (152.00 mg, 0.3694 mmol) was dissolved in tert-butanol (1.34 mL). HCl in dioxane (2.77 mL, 11.081 mmol) was added and the reaction mixture was stirred at rt for 1 h. Volatiles were removed under vacuum. Purification by ion-exchange SCX-II column chromatography, washing with MeOH before eluting with 2M NH3 in MeOH, provided tert-butyl 2-[(3-aminocyclobutanecarbonyl)amino]-4-methyl-thiazole-5-carboxylate (106 mg, 92%, 0.3404 mmol). HPLC / MS m / z: 312.15, [M+H] + , Rt (P): 1.20 min.

[0392] Example 104.3: 3-(5-Methyl-1,2,4-oxadiazol-3-yl)benzoic acid (15.00 mg, 0.0735 mmol) and BTFFH (30.20 mg, 0.0955 mmol) were mixed in DCM (0.15 mL) at rt under an argon atmosphere. DIPEA (0.06 mL, 0.3306 mmol) was added and the reaction mixture was stirred for 30 min. tert-Butyl 2-[(3-aminocyclobutanecarbonyl)amino]-4-methylthiazole-5-carboxylate (22.88 mg, 0.0735 mmol) was added. The vial was capped and the reaction was heated to 80 °C for 45 min. Purification by reverse-phase column chromatography (eluent: 20-80% MeOH in water) provided tert-butyl 4-methyl-2-((1s,3s)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)cyclobutane-1-carboxamido)thiazole-5-carboxylate (22 mg, 60%, 0.0442 mmol) as a colorless amorphous solid. HPLC / MS m / z: 498.18, [M+H] + , Rt (U): 1.57 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.36 (br s, 1H), 9.00 (d, J = 7.5 Hz, 1H), 8.52-8.49 (m, 1H), 8.16-8.12 (m, 1H), 8.09-8.06 (m, 1H), 7.66 (t, J = 7.8 Hz, 1H), 4.50-4.41 (m, 1H), 3.12-3.04 (m, 1H), 2.70 (s, 3H), 2.56-2.51 (m, 5H), 2.40-2.33 (m, 2H), 1.52 (s, 9H).

[0393] The following examples were prepared similarly: Example 105: tert-Butyl 2-((1s,3s)-3-(3-(1,2,4-oxadiazol-3-yl)benzamido)-cyclobutane-1-carboxamido)-4-methylthiazole-5-carboxylate [ka] 14mg (39%). HPLC / MS m / z: 484.16, [M+H] + , Rt (U): 3.22 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.78 (d, J = 2.3 Hz, 1H), 9.02 (dd, J = 7.4, 2.2 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.24-8.16 (m, 1H), 8.12-8.06 (m, 1H), 7.69 (td, J = 7.8, 2.2 Hz, 1H), 4.46 (dt, J = 9.4, 7.4 Hz, 1H), 3.13-3.04 (m, 1H), 2.57-2.49 (m, 5H), 2.40-2.28 (m, 2H), 1.52 (d, J = 2.4 Hz, 9H).

[0394] Example 106: tert-Butyl 4-methyl-2-((1s,3s)-3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)benzamido)cyclobutane-1-carboxamido)thiazole-5-carboxylate [ka] 20 mg (55%) colorless amorphous solid. HPLC / MS m / z: 498.18, [M+H] + , Rt (U): 3.13 min. 1H NMR (600 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.02 (d, J = 7.5 Hz, 1H), 8.48 (t, J = 1.8 Hz, 1H), 8.11 (ddt, J = 12.0, 7.8, 1.4 Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H), 4.46 (ddt, J = 17.0, 9.3, 7.6 Hz, 1H), 3.08 (tt, J = 9.8, 7.8 Hz, 1H), 2.62 (s, 3H), 2.56-2.47 (m, 5H), 2.37 (qd, J = 9.4, 2.6 Hz, 2H), 1.52 (s, 9H).

[0395] Example 107: tert-Butyl-4-methyl-2-((1s,3s)-3-(3-(2-methyl-2H-tetrazol-5-yl)benzamido)cyclobutane-1-carboxamido)thiazole-5-carboxylate [ka] 20mg (50%). HPLC / MS m / z: 498.19, [M+H] + , Rt (U): 3.20 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.00 (d, J = 7.5 Hz, 1H), 8.58 (t, J = 1.8 Hz, 1H), 8.20 (dt, J = 7.7, 1.4 Hz, 1H), 8.04 (dt, J = 7.9, 1.5 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 4.46 (s, 4H), 3.08 (tt, J = 9.8, 7.8 Hz, 1H), 2.57-2.45 (m, 5H), 2.37 (qd, J = 9.4, 2.6 Hz, 2H), 1.52 (s, 9H).

[0396] Example 108: tert-Butyl 2-((1s,3s)-3-((7-chloroisoquinolin-1-yl)amino)cyclobutane-1-carboxamido)-4-methylthiazole-5-carboxylate [ka]

[0397] Example 108.1: 7-Chloroisoquinoline (0.15 g, 0.9169 mmol) was dissolved in CHCl3 (2.86 mL) and cooled in an ice bath. mCPBA (0.24 g, 1.0885 mmol) was added. The reaction was stirred in the ice bath for 2 h. It was warmed to rt and more CHCl3 (1 mL) was added. K2CO3 (0.51 g, 3.6675 mmol) was added and the mixture was stirred at rt for 3 h before being filtered through a pad of anhydrous MgSO4. The filtrate was concentrated in vacuo to afford 7-chloro-2-oxide-isoquinolin-2-ium (0.15 g, 91%, 0.8352 mmol) as an off-white powder. HPLC / MS m / z: 180.04, [M+H] + , Rt (P): 0.93 min.

[0398] Example 108.2.: 7-Chloro-2-oxide-isoquinolin-2-ium (30 mg, 0.1670 mmol) was dissolved / suspended in DCM (0.70 mL), and tert-butyl 2-[(3-aminocyclobutanecarbonyl)amino]-4-methyl-thiazole-5-carboxylate [Example 104] (57.22 mg, 0.1837 mmol) was added, followed quickly by DIPEA (0.09 mL, 0.5011 mmol). To this solution was added PyBroP (101.23 mg, 0.2171 mmol), and the mixture was stirred at rt overnight. Purification by silica gel column chromatography (eluent: 20-70% EtOAc in cyclohexane) followed by ion-exchange SCX-II column chromatography, washing with MeOH before eluting with 2M NH in MeOH, provided tert-butyl 2-((1s,3s)-3-((7-chloroisoquinolin-1-yl)amino)cyclobutane-1-carboxamido)-4-methylthiazole-5-carboxylate (36 mg, 46%, 0.0761 mmol) as a yellowish powder. HPLC / MS m / z: 473.14, [M+H] + , Rt (U): 3.03 min. 1 H NMR (600 MHz, Chloroform-d) δ 10.74 (s, 1H), 8.35 (d, J = 5.9 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.55 (dd, J = 8.7, 1.9 Hz, 1H), 6.99 (d, J = 5.9 Hz, 1H), 5.64 (d, J = 7.5 Hz, 1H), 4.64 (q, J = 8.2 Hz, 1H), 3.05 (t, J = 8.6 Hz, 1H), 2.82 (ddt, J = 12.1, 6.8, 3.1 Hz, 4H), 2.64 (s, 3H), 1.57 (s, 9H).

[0399] The following examples were prepared similarly: Example 109: tert-butyl 4-methyl-2-((1s,3s)-3-((7-(trifluoromethyl)isoquinolin-1-yl)amino)cyclobutane-1-carboxamido)thiazole-5-carboxylate [ka] 16mg(22%) Yellow powder. HPLC / MS m / z: 507.17, [M+H] + , Rt (U): 3.17 min. 1 H NMR (600 MHz, Chloroform-d) δ 10.57 (s, 1H), 8.46 (d, J = 5.9 Hz, 1H), 8.07-8.01 (m, 1H), 7.83-7.71 (m, 2H), 7.05 (dd, J = 5.9, 0.9 Hz, 1H), 5.87 (d, J = 7.4 Hz, 1H), 4.74-4.59 (m, 1H), 3.07 (quint, J = 8.6 Hz, 1H), 2.85 (ddd, J = 12.0, 6.4, 3.1 Hz, 4H), 2.64 (s, 3H), 1.57 (s, 9H).

[0400] Example 110: tert-Butyl 4-methyl-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate [ka]

[0401] Example 110.1: 2-Amino-4-methyl-thiazole-5-carboxylic acid (3.00 g, 18.97 mmol), DMAP (232 mg, 1.90 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.36 g, 22.76 mmol) were dissolved in anhydrous DMF (38 mL) under an argon atmosphere. Anhydrous tert-butanol (36 mL, 379.31 mmol) was added, and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure, mixed with water (100 mL), and extracted with EtOAc (3 x 75 mL). The combined organic layers were washed with saturated NaCl (3 x 50 mL), dried over MgSO4, and concentrated under reduced pressure. The crude material was purified by flash chromatography (20-60% EtOAc in cyclohexane) to afford 2.10 g (52%) of tert-butyl 2-amino-4-methyl-thiazole-5-carboxylate as an off-white crystalline solid. HPLC / MS m / z: 215.0866 [M+H] + , Rt (X): 2.21 min.

[0402] Example 110.2.: Prepared as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [0] (30 mg, 0.093 mmol) and tert-butyl 2-amino-4-methyl-thiazole-5-carboxylate (50 mg, 0.234 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration. Yield: 33 mg (53%) colorless amorphous solid. HPLC / MS m / z: 521.1965 [M+H] + , Rt (U): 2.92 min. 1H NMR (600 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.01 (s, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 8.09 (d, J = 7.0 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 5.7 Hz, 1H), 4.73-4.64 (m, 1H), 3.13-3.06 (m, 1H), 2.71 (s, 3H), 2.63-2.56 (m, 2H), 2.51 (s, 3H), 2.45-2.38 (m, 2H), 1.51 (s, 9H).

[0403] Example 111: tert-Butyl 4-methyl-2-[methyl-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate [ka]

[0404] Example 111.1: tert-Butyl acetoacetate (0.50 mL, 3.02 mmol) and pyridine (0.24 mL, 3.02 mmol) were dissolved in absolute EtOH (6.0 mL) and heated at 70° C. for 15 min. The mixture was then cooled to rt, followed by the addition of iodine (765 mg, 3.015 mmol) and N-methylthiourea (544 mg, 6.03 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was then heated at 50° C. overnight. The reaction mixture was cooled to rt and diluted with water (20 mL). Solid Na2O3S2 was added and stirred for 5 min. The mixture was mixed with EtOAc (50 mL). The aqueous layer was separated, and the organic layer was washed with saturated NaCl (2 x 20 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography (10-80% EtOAc in cyclohexane) to afford 145 mg (17%) of a 4:1 mixture of tert-butyl 4-methyl-2-(methylamino)thiazole-5-carboxylate and tert-butyl 2-[2-(methylamino)thiazol-4-yl]acetate as an off-white solid, which was used in the next reaction without further purification. tert-Butyl 4-methyl-2-(methylamino)thiazole-5-carboxylate: HPLC / MS m / z: 173.0 [M-C4H8] + , Rt (T): 1.24 min. 1 H NMR (600 MHz, DMSO-d6) δ 8.14 (q, J = 4.9 Hz, 1H), 2.80 (d, J = 4.8 Hz, 3H), 2.37 (s, 3H), 1.46 (s, 9H). tert-Butyl 2-[2-(methylamino)thiazol-4-yl]acetate: 229.1 [M+H] + , Rt (T): 1.08 min. 1 H NMR (600 MHz, DMSO-d6) δ 7.40 (q, J = 4.8 Hz, 1H), 6.32 (s, 1H), 3.38 (d, J = 0.9 Hz, 2H), 2.76 (d, J = 4.8 Hz, 3H), 1.40 (s, 9H).

[0405] Example 111.2: Preparation as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [0] (34 mg, 0.104 mmol) and tert-butyl 4-methyl-2-(methylamino)thiazole-5-carboxylate (30 mg, 0.104 mmol). Purification by reverse-phase flash chromatography. Yield: 7.3 mg (13%) colorless solid. HPLC / MS m / z: 535.2119 [M+H] + , Rt (U): 3.01 min. 1 H NMR (600 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.22-8.14 (m, 1H), 8.08 (br s, 1H), 7.94 (d, J = 5.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 4.80-4.67 (m, 1H), 3.61 (s, 3H), 3.56-3.48 (m, 1H), 2.77-2.70 (m, 2H), 2.71 (s, 3H), 2.54 (s, 3H), 2.51-2.44 (m, 2H), 1.51 (s, 9H).

[0406] Example 112: tert-Butyl 4-chloro-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate [ka]

[0407] Example 112.1: tert-Butyl (5-carboxy-4-chloro-1,3-thiazol-2-yl)carbamate (500 mg, 1.79 mmol) and DMAP (22 mg, 0.179 mmol) were mixed in anhydrous DMF (3.6 mL) at rt under an argon atmosphere. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (413 mg, 2.15 mmol) and anhydrous 2-methyl-2-propanol (3.4 mL, 35.9 mmol) were added successively. The reaction mixture was heated at 60 °C. Due to the formation of two by-products, the reaction was stopped after 3 h. The reaction mixture was cooled to rt, mixed with 0.5 M HCl (50 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with saturated NaCl (3 × 20 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-30% EtOAc in cyclohexane) to afford 100 mg (17%) of tert-butyl 2-(tert-butoxycarbonylamino)-4-chloro-thiazole-5-carboxylate as a colorless powder. HPLC / MS m / z: 357.0648 [M+Na] + , Rt (U): 3.47 min.

[0408] Example 112.2.: tert-Butyl 2-(tert-butoxycarbonylamino)-4-chloro-thiazole-5-carboxylate (100 mg, 0.299 mmol) and anhydrous 2-methyl-2-propanol (1.1 mL, 11.95 mmol) were mixed at rt under an argon atmosphere. 4M HCl in dioxane (2.2 mL, 8.96 mmol) was added, and the reaction mixture was quickly cooled in an ice bath and then allowed to warm slowly to rt. More 4M HCl in dioxane (0.75 mL, 2.99 mmol) was added, and the mixture continued to stir at ambient temperature. The reaction was stopped after 2 d [Note: some starting material was still present, but cleavage of the ester became problematic]. The reaction mixture was concentrated under reduced pressure. The crude material was used in the next reaction without further purification. HPLC / MS m / z: 179.0 [M-C4H8] +, Rt (P): 1.37 min.

[0409] Example 112.3.: Prepared as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [0] (47 mg, 0.144 mmol) and tert-butyl 2-amino-4-chloro-thiazole-5-carboxylate hydrochloride (30 mg, 0.111 mmol). Purification by reverse-phase flash chromatography. Yield: 2.8 mg (5%) off-white solid. HPLC / MS m / z: 541.1420 [M+H] + , Rt (U): 2.96 min. 1 H NMR (600 MHz, Methanol-d4) δ 8.96-8.93 (m, 1H), 8.23 ​​(dd, J = 8.4, 1.6 Hz, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.02 (dd, J = 6.1, 0.9 Hz, 1H), 4.67-4.59 (m, 1H), 3.20-3.13 (m, 1H), 2.86-2.78 (m, 2H), 2.70 (s, 3H), 2.56-2.49 (m, 2H), 1.57 (s, 9H).

[0410] Example 113: N-tert-butyl-4-chloro-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxamide [ka]

[0411] Example 113.1.: tert-Butyl (5-carboxy-4-chloro-1,3-thiazol-2-yl)carbamate (480 mg, 1.72 mmol) and BTFFH (708 mg, 2.24 mmol) were mixed in anhydrous DCM (3.4 mL) in a microwave vial at rt under an argon atmosphere. DIPEA (1.36 mL, 7.75 mmol) was added and the mixture was continued stirring at rt for 30 min. tert-Butylamine (0.36 mL, 3.44 mmol) was added and the reaction mixture was heated at 80 °C under microwave irradiation for 1 h. The mixture was cooled to rt and the volatiles were removed under reduced pressure. The crude material was purified by flash chromatography (0-40% EtOAc in cyclohexane) to afford 201 mg (35%) of tert-butyl N-[5-(tert-butylcarbamoyl)-4-chloro-thiazol-2-yl]carbamate as a colorless amorphous solid. HPLC / MS m / z: 334.1 [M+H] + , Rt (U): 3.12 min.

[0412] Example 113.2.: tert-Butyl N-[5-(tert-butylcarbamoyl)-4-chloro-thiazol-2-yl]carbamate (200 mg, 0.60 mmol) and 4 M HCl in dioxane (4.5 mL, 18.0 mmol) were mixed at 0 °C under an argon atmosphere. The reaction mixture was allowed to warm to ambient temperature and stirred for 6 h [after 4 h, additional 4 M HCl in dioxane (1.5 mL, 6.00 mmol) was added]. The reaction mixture was concentrated under reduced pressure to yield 160 mg (99%) of 2-amino-N-tert-butyl-4-chloro-thiazole-5-carboxamide hydrochloride as an off-white powder. HPLC / MS m / z: 234.0648 [M+H] + , Rt (U): 2.36 min.

[0413] Example 113.3.: Prepared as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [Example 96] (47 mg, 0.144 mmol) and 2-amino-N-tert-butyl-4-chloro-thiazole-5-carboxamide hydrochloride (30 mg, 0.111 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration. Yield: 19 mg (31%) colorless amorphous solid. HPLC / MS m / z: 540.1576 [M+H] + , Rt (U): 2.77 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.59 (s, 1H), 9.02-8.99 (m, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 8.09 (d, J = 7.1 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 6.97 (dd, J = 5.9, 0.9 Hz, 1H), 4.75-4.67 (m, 1H), 3.14-3.07 (m, 1H), 2.71 (s, 3H), 2.63-2.57 (m, 2H), 2.46-2.40 (m, 2H), 1.36 (s, 9H).

[0414] Example 114: [(1R)-2,2,2-trifluoro-1-methyl-ethyl]4-methyl-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate [ka]

[0415] Example 114.1.: (2R)-1,1,1-trifluoropropan-2-ol (250 mg, 2.19 mmol), DMAP (27 mg, 0.22 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (462 mg, 2.41 mmol) were mixed in anhydrous DMF (4.4 mL) at rt under an argon atmosphere. 2-Amino-4-methylthiazole-5-carboxylic acid (381 mg, 2.41 mmol) was added, and the reaction mixture was heated at 60 °C overnight. The reaction mixture was cooled to ambient temperature, mixed with water (100 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated NaHCO (50 mL), saturated NaCl (2 × 50 mL), dried over anhydrous MgSO, and concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (10-70% MeOH in water [0.1% FA]) to yield 61 mg (11%) of [(1R)-2,2,2-trifluoro-1-methyl-ethyl] 2-amino-4-methyl-thiazole-5-carboxylate as an off-white solid. HPLC / MS m / z: 255.0418 [M+H] + , Rt (U): 2.55 min.

[0416] Example 114.2.: Prepared as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [0] (30 mg, 0.093 mmol) and [(1R)-2,2,2-trifluoro-1-methyl-ethyl]2-amino-4-methyl-thiazole-5-carboxylate (26 mg, 0.102 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration. Yield: 37 mg (69%) off-white solid. HPLC / MS m / z: 561.1533 [M+H] + , Rt (U): 2.93 min. 1H NMR (600 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.02-8.99 (m, 1H), 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.09 (d, J = 7.0 Hz, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 6.99-6.95 (m, 1H), 5.63 (hept, 1H), 4.74-4.65 (m, 1H), 3.16-3.09 (m, 1H), 2.71 (s, 3H), 2.64-2.58 (m, 2H), 2.57 (s, 3H), 2.46-2.38 (m, 2H), 1.46 (d, J = 6.6 Hz, 3H).

[0417] Example 115: [(1S)-2,2,2-trifluoro-1-methyl-ethyl]4-methyl-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate [ka]

[0418] Example 115.1.: Preparation as described in 0 using (2S)-1,1,1-trifluoropropan-2-ol (250 mg, 2.19 mmol) and 2-amino-4-methylthiazole-5-carboxylic acid (381 mg, 2.41 mmol). Purification by reverse-phase flash chromatography. Yield: 69 mg (12%) off-white solid. HPLC / MS m / z: 255.0418 [M+H] + , Rt (U): 2.55 min.

[0419] Example 115.2.: Prepared as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [0] (30 mg, 0.093 mmol) and [(1S)-2,2,2-trifluoro-1-methyl-ethyl]2-amino-4-methyl-thiazole-5-carboxylate (26 mg, 0.102 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration. Yield: 41 mg (75%) off-white solid. HPLC / MS m / z: 561.1528 [M+H] + , Rt (U): 2.92 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.02-8.99 (m, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 8.09 (d, J = 7.0 Hz, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 5.9, 0.8 Hz, 1H), 5.67-5.59 (m, 1H), 4.74-4.65 (m, 1H), 3.16-3.08 (m, 1H), 2.71 (s, 3H), 2.64-2.58 (m, 2H), 2.57 (s, 3H), 2.46-2.38 (m, 2H), 1.46 (d, J = 6.6 Hz, 3H).

[0420] Example 116: Ethyl-4-(difluoromethyl)-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate [ka]

[0421] Example 116.1.: Ethyl 2-chloro-4,4-difluoroacetoacetate (200 mg, 1.00 mmol) and thiourea (151 mg, 2.00 mmol) were mixed in absolute EtOH (1.00 mL) in a microwave vial under an argon atmosphere. The reaction mixture was heated at 100° C. by microwave irradiation for 1 h. The reaction mixture was concentrated under reduced pressure and mixed with diethyl ether. The formed precipitate was filtered off, washed with diethyl ether, and dried under reduced pressure to yield 111 mg (50%) of ethyl 2-amino-4-(difluoromethyl)thiazole-5-carboxylate as an off-white solid. HPLC / MS m / z: 223.0349 [M+H] + , Rt (X): 2.04 min.

[0422] Example 116.2.: Prepared as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [0] (30 mg, 0.093 mmol) and ethyl 2-amino-4-(difluoromethyl)thiazole-5-carboxylate (23 mg, 0.102 mmol). Purification by reverse-phase flash chromatography. Yield: 31 mg (63%) colorless powder. HPLC / MS m / z: 529.1456 [M+H] + , Rt (X): 2.86 min. 1H NMR (600 MHz, DMSO-d6) δ 12.93 (br s, 1H), 9.02-8.99 (m, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 8.09 (d, J = 7.0 Hz, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 53.7 Hz, 1H), 6.97 (d, J = 5.7 Hz, 1H), 4.74-4.67 (m, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.16-3.09 (m, 1H), 2.71 (s, 3H), 2.65-2.59 (m, 2H), 2.47-2.41 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0423] Example 117: N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[(7-methyl-1-isoquinolyl)amino]cyclobutanecarboxamide [ka]

[0424] Example 117.1: cis-3-Aminocyclobutanecarboxylic acid hydrochloride (463 mg, 3.05 mmol) and sodium carbonate (1.08 g, 10.2 mmol) were mixed in anhydrous NMP (4.07 mL) under an argon atmosphere and stirred at rt for 10 min. 1-Chloro-7-methylisoquinoline (362 mg, 2.04 mmol) was added and the reaction mixture was heated at 170 °C. The reaction was stopped after 48 h due to the formation of a by-product. The reaction mixture was purified by reverse-phase flash chromatography (5–50% MeOH in water [0.1% FA]) to yield 98 mg (17%) of 3-[(7-methyl-1-isoquinolyl)amino]cyclobutanecarboxylic acid as an off-white solid. HPLC / MS m / z: 257.1 [M+H] + , Rt (U): 1.71 min.

[0425] Example 117.2.: Prepared as described in 0 using 3-[(7-methyl-1-isoquinolyl)amino]cyclobutanecarboxylic acid (30 mg, 0.117 mmol) and 5-tert-butyl-4-methyl-thiazol-2-ylamine (40 mg, 0.234 mmol). Purification by reverse-phase flash chromatography followed by SCX-2 filtration. Yield: 17 mg (35%) colorless amorphous solid. HPLC / MS m / z: 409.2048 [M+H] + , Rt (U): 2.90 min. 1 H NMR (600 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.13 (s, 1H), 7.78 (d, J = 5.8 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.47-7.41 (m, 2H), 6.85 (d, J = 5.8 Hz, 1H), 4.65-4.56 (m, 1H), 3.06-2.97 (m, 1H), 2.59-2.51 (m, 3H), 2.47 (s, 3H), 2.35-2.26 (m, 5H), 1.36 (s, 9H).

[0426] Example 118: 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(3-((4-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)thiazol-2-yl)amino)-3-oxopropyl)benzamide [ka]

[0427] Example 118.1.: Methyl 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate[0] (60.00 mg, 0.1397 mmol) was suspended in MeOH (1.00 mL) and water (1.00 mL) before adding sodium hydroxide (111.77 mg, 2.7943 mmol). The reaction was heated to 55 °C, but did not dissolve. Upon addition of THF (1.00 mL), the reaction mixture became homogenous and was stirred at 55 °C for 1 hr 20 min. LCMS indicated nearly complete conversion and some degradation products. The mixture was cooled in an ice bath, acidified with 1 M HCl (~4 mL), and concentrated in vacuo. The crude product was partitioned between EtOAc (25 mL) and water (25 mL). The organic layer was washed with brine and dried over MgSO. Concentration in vacuo gave 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylic acid (14 mg, 24%, 0.0337 mmol) as a colorless powder. Purity 90% (UV). This material was used in the next step without further purification. HPLC / MS m / z: 416.1 [M+H] + , Rt (P): 1.81 min.

[0428] Example 118.2.: To 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylic acid (14.00 mg, 0.0337 mmol) in anhydrous DMF (0.70 mL) was added EDC.HCl (7.43 mg, 0.0388 mmol) and HOBt (5.46 mg, 0.0404 mmol). The reaction mixture was stirred at rt under nitrogen for 30 min before the addition of acetamide oxime (3.25 mg, 0.0438 mmol). The reaction mixture was stirred at rt for 17 h, at which time LCMS showed good conversion to [(Z)-1-aminoethylideneamino]4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate. A condenser was added, and the reaction was then heated to 100° C. under nitrogen behind a blast shield for 21 h to effect cyclization. Volatiles were removed in vacuo, and the crude material was purified by reverse-phase column chromatography (eluent: 20-100% MeOH in water (both + 0.1% formic acid modifier)) to provide 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(3-((4-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)thiazol-2-yl)amino)-3-oxopropyl)benzamide (1.2 mg, 8%, 0.0026 mmol). HPLC / MS m / z: 454.1 [M+H] + , Rt (R): 1.31 min. 1H NMR (500 MHz, Acetone-d6) δ 11.42 (broad s, 1H), 8.54 (td, J = 1.8, 0.6 Hz, 1H), 8.30 (s, 1H), 8.18 (ddd, J = 7.7, 1.7, 1.1 Hz, 1H), 8.09 (ddd, J = 7.8, 1.9, 1.2 Hz, 1H), 7.65 (td, J = 7.8, 0.6 Hz, 1H), 3.90-3.80 (m, 2H), 3.02 (t, J = 6.5 Hz, 2H), 2.68 (s, 3H), 2.64 (s, 3H), 2.38 (s, 3H).

[0429] Example 119: 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(5-(5-propyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)propenamide [ka]

[0430] Example 119.1.: N-(5-cyanothiazol-2-yl)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide [0] (37.40 mg, 0.0922 mmol) and TEA (0.01 mL, 0.0922 mmol) were heated in [bmim]OAc (0.18 mL) at 80 °C. Hydroxylamine hydrochloride (12.82 mg, 0.1845 mmol) was then added, and the resulting solution was stirred for 1.5 h. The solution was cooled to rt and partitioned between water (15 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford N-[5-[(Z)-N'-hydroxycarbamimidoyl]thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide (40 mg, 99%, 0.0912 mmol) as a colorless solid. HPLC / MS m / z: 439.14, [M+H] + , Rt (P): 1.00 min.

[0431] Example 119.2.: Butyric acid (0.01 mL, 0.0597 mmol), N-[5-[(Z)-N'-hydroxycarbamimidoyl]thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide (21.80 mg, 0.0497 mmol), and EDC.HCl (11.44 mg, 0.0597 mmol) were suspended in a mixture of MeCN (0.17 mL) and THF (0.17 mL) under a nitrogen atmosphere. The resulting solution was stirred at rt for 17 h. Removal of the volatiles under reduced pressure provided N-[(Z)-N-hydroxy-C-[2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoylamino]thiazol-5-yl]carbonimidoyl]butanamide. HPLC / MS m / z: 509.18, [M+H] + , Rt (P): 1.25 min.

[0432] Example 119.3.: To a solution of N-[(Z)-N-hydroxy-C-[2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoylamino]thiazol-5-yl]carbonimidoyl]butanamide (25.29 mg, 0.0497 mmol) in DMSO (0.30 mL) was added potassium hydroxide (11.16 mg, 0.1989 mmol). The resulting solution was stirred at rt for 1.5 h. Additional potassium hydroxide (4 eq.) was added and the resulting solution was stirred at rt for 1.5 h. Purification by reverse-phase column chromatography (eluent: 30-80% MeOH in water (+0.1% formic acid)) followed by ion-exchange SCX-II column chromatography, washing with MeOH before eluting with 2M NH in MeOH, provided 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(5-(5-propyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)propanamide (7 mg, 29%, 0.0143 mmol) as a colorless solid. HPLC / MS m / z: 491.16, [M+H] + , Rt (U): 2.62 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.91-8.87 (m, 1H), 8.16 (dd, J = 8.5, 1.5 Hz, 1H), 8.11 (s, 1H), 8.06 (t, J = 5.5 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.00-6.97 (m, 1H), 3.84 (q, J = 6.4 Hz, 2H), 2.95 (dt, J = 10.0, 7.1 Hz, 4H), 2.70 (s, 3H), 1.80 (sext, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H).

[0433] Example 120: Propyl-1-methyl-3-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-1H-pyrazole-5-carboxylate [ka] 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid [0] (49.58 mg, 0.1801 mmol), propyl 5-amino-2-methylpyrazole-3-carboxylate (30.00 mg, 0.1637 mmol), and HATU (87.17 mg, 0.2292 mmol) were dissolved in dry DMF (1.09 mL) at rt. DIPEA (0.04 mL, 0.2456 mmol) was added, and the reaction mixture was stirred at rt overnight. The mixture was diluted with EtOAc, washed with a solution of NH4Cl and water (2 x), dried over MgSO4, and concentrated in vacuo. Purification by reverse-phase column chromatography (eluent: 30–100% MeOH / HO + 0.1% formic acid) gave propyl 1-methyl-3-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-1H-pyrazole-5-carboxylate (54 mg, 75%, 0.1226 mmol) as a colorless powder. HPLC / MS m / z: 441.2, [M+H] + , Rt (R): 1.29 min. 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H, NH), 8.81 (t, J = 5.5 Hz, 1H, NH), 8.47 (t, J = 1.8 Hz, 1H), 8.12 (dt, J = 7.8, 1.4 Hz, 1H), 8.03 (dt, J = 7.9, 1.5 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.05 (s, 1H), 4.20 (t, J = 6.5 Hz, 2H), 3.98 (s, 3H), 3.58-3.51 (m, 2H), 2.68 (s, 3H), 2.63 (t, J = 7.0 Hz, 2H), 1.73-1.65 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).

[0434] The following examples were prepared similarly: Example 121: Propyl-4-methyl-2-(N-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 15 mg (14%), colorless powder. HPLC / MS m / z: 472.2, [M+H] + , Rt (R): 1.42 min. 1 H NMR (500 MHz, DMSO-d6) δ 8.85-8.79 (m, 1H), 8.50-8.45 (m, 1H), 8.13 (dt, J = 7.8, 1.5 Hz, 1H), 8.04 (dt, J = 7.9, 1.4 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 4.16 (t, J = 6.5 Hz, 2H), 3.66 (s, 3H), 3.64-3.59 (m, 2H), 3.07 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.57 (s, 3H), 1.74-1.60 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0435] Example 122: Cyclopentyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 4-Methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylic acid [0] (30.00 mg, 0.0722 mmol) was dissolved in dry DCM (1.00 mL) at rt. Oxalyl dichloride (0.06 mL, 0.7222 mmol) was added, followed by a few drops of DMF. The reaction mixture was stirred at rt for 2 h before the solvent was removed under reduced pressure and cyclopentanol (1.00 mL) was added. The reaction mixture was stirred at rt for 4 h. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase column chromatography (eluent: 30-100% MeOH / HO + 0.1% formic acid) to provide cyclopentyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate (8 mg, 23%, 0.0165 mmol) as an off-white powder. HPLC / MS m / z: 484.2, [M+H] + , Rt (R): 1.43 min. 1 H NMR (500 MHz, Acetone-d6) δ 11.27 (s, 1H), 8.53 (t, J = 1.5 Hz, 1H), 8.29-8.21 (m, 1H), 8.20-8.14 (m, 1H), 8.09-8.04 (m, 1H), 7.66-7.59 (m, 1H), 5.34-5.28 (m, 1H), 3.86-3.80 (m, 2H), 3.00-2.93 (m, 2H), 2.67 (s, 3H), 2.51 (s, 3H), 1.96-1.89 (m, 2H), 1.81-1.74 (m, 4H), 1.68-1.62 (m, 2H).

[0436] Example 123: Hexyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka]

[0437] Example 123.1.: 4-Methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylic acid [0] (60.00 mg, 0.1444 mmol) was dissolved in dry DMF (1.00 mL) at rt. Pyridine (0.07 mL, 0.1733 mmol) and (2,3,4,5,6-pentafluorophenyl) 2,2,2-trifluoroacetate (0.03 mL, 0.1733 mmol) were added, and the mixture was stirred at rt for 1 h and at 60 °C overnight. The reaction mixture was diluted with EtOAc, washed with water, dried over MgSO4, and concentrated under reduced pressure. Purification by reverse-phase column chromatography (eluent: 30–100% MeOH / HO + 0.1% formic acid) gave (2,3,4,5,6-pentafluorophenyl)4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate (28 mg, 33%, 0.0482 mmol) as a colorless powder. HPLC / MS m / z: 582.1, [M+H] + , Rt (Q): 3.29 min.

[0438] Example 123.2.: Hexan-1-ol (0.60 mL, 4.7803 mmol) was added to (2,3,4,5,6-pentafluorophenyl) 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate (20.00 mg, 0.0344 mmol) at rt. DMF (0.50 mL) was added. The reaction mixture was stirred at rt for 20 min, at 65°C for 2 h, and at 100°C for 3 h. DMAP (3 mg) was added, and the reaction mixture was stirred at 100°C for 1 h. The reaction mixture was diluted with EtOAc, washed with water, dried over MgSO4, and concentrated under reduced pressure. Purification by reverse-phase column chromatography (eluent: 30-100% MeOH / HO + 0.1% formic acid) provided hexyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate (14 mg, 81%, 0.0280 mmol) as a colorless powder. HPLC / MS m / z: 500.2, [M+H] + , Rt (R): 1.54 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.13 (dt, J = 7.7, 1.4 Hz, 1H), 8.02 (dt, J = 8.0, 1.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.19 (t, J = 6.5 Hz, 2H), 3.65-3.56 (m, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.53 (s, 3H), 1.69-1.60 (m, 2H), 1.40-1.33 (m, 2H), 1.33-1.24 (m, 4H), 0.90-0.82 (m, 3H).

[0439] The following examples were prepared similarly: Example 124: Cyclohexyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 11 mg (36%), colorless powder. HPLC / MS m / z: 498.2, [M+H] + , Rt (R): 1.49 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.46 (t, J = 1.8 Hz, 1H), 8.13 (dt, J = 7.7, 1.4 Hz, 1H), 8.02 (dt, J = 7.9, 1.3 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.92-4.84 (m, 1H), 3.64-3.56 (m, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.53 (s, 3H), 1.87-1.78 (m, 2H), 1.72-1.63 (m, 2H), 1.56-1.45 (m, 3H), 1.44-1.31 (m, 3H).

[0440] Example 125: 4-Aminobutyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate hydrochloride [ka] tert-Butyl N-(4-hydroxybutyl)carbamate was used in a similar procedure, followed by 3 h deprotection at rt using HCl in dioxane (1.04 mL, 50 eq., 4.1762 mmol). Removal of the solvent under reduced pressure provided 4-aminobutyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate (43 mg, 98%, 0.0822 mmol) hydrochloride as a cream-colored powder. HPLC / MS m / z: 487.2, [M+H] + , Rt (R): 0.98 min. 1 H NMR (500 MHz, Methanol-d4) δ 8.49 (t, J = 1.7 Hz, 1H), 8.19 (dt, J = 7.8, 1.4 Hz, 1H), 7.99-7.94 (m, 1H), 7.61 (t, J = 7.8 Hz, 1H), 4.32 (t, J = 5.8 Hz, 2H), 3.77 (t, J = 6.8 Hz, 2H), 3.05-2.97 (m, 2H), 2.88 (t, J = 6.8 Hz, 2H), 2.66 (s, 3H), 2.59 (s, 3H), 1.88-1.77 (m, 4H).

[0441] Example 126: 3-(4-Methoxyphenyl)propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 20 mg (67%), colorless powder. HPLC / MS m / z: 564.2 [M+H] + , Rt (R): 1.52 min. 1H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.87 (t, J = 5.6 Hz, 1H), 8.48-8.43 (m, 1H), 8.15-8.09 (m, 1H), 8.06-7.99 (m, 1H), 7.69-7.61 (m, 1H), 7.16-7.09 (m, 2H), 6.88-6.81 (m, 2H), 4.16 (t, J = 6.4 Hz, 2H), 3.71 (s, 3H), 3.60 (q, J = 6.5 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.66-2.59 (m, 2H), 2.54 (s, 3H), 1.97-1.89 (m, 2H).

[0442] Example 127: 4-(2-Methoxyethoxy)butyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 23 mg (61%), cream powder. HPLC / MS m / z: 546.2, [M+H] + , Rt (R): 1.35 min. 1 H NMR (500 MHz, Methanol-d4) δ 8.49-8.47 (m, 1H), 8.19-8.15 (m, 1H), 7.96 (ddd, J = 7.9, 1.9, 1.2 Hz, 1H), 7.60 (td, J = 7.8, 0.6 Hz, 1H), 4.27 (t, J = 6.4 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.60-3.56 (m, 2H), 3.55-3.51 (m, 4H), 3.35 (s, 3H), 2.86 (t, J = 6.7 Hz, 2H), 2.66 (s, 3H), 2.56 (s, 3H), 1.84-1.77 (m, 2H), 1.74-1.67 (m, 2H).

[0443] Example 128: Methyl-2-methyl-5-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]pyrazole-3-carboxylate [ka] 42 mg (56%), colorless fluffy powder. HPLC / MS m / z: 413.16 [M+H] + , Rt (R): 1.15 min. 1 H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.82 (t, J = 5.5 Hz, 1H), 8.52-8.43 (m, 1H), 8.16-8.10 (m, 1H), 8.03 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.05 (s, 1H), 3.99 (s, 3H), 3.83 (s, 3H), 3.55 (q, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.63 (t, J = 7.1 Hz, 2H).

[0444] Example 129: 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(3-((4-methyl-5-(pentan-2-yl)thiazol-2-yl)amino)-3-oxopropyl)benzamide [ka]

[0445] Example 129.1.: A mixture of 4-methylheptan-2-one (100.00 mg, 0.7800 mmol), thiourea (118.74 mg, 1.5599 mmol), and molecular iodine (197.96 mg, 0.7800 mmol) was dissolved in EtOH (1.56 mL) and heated at 80 °C overnight. The reaction mixture was diluted with EtOAc, washed with an aqueous solution of NaOH (1 M) and an aqueous solution of NaSO, dried over MgSO, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: 20-40% EtOAc in cyclohexane) provided 4-methyl-5-(1-methylbutyl)thiazol-2-amine (20 mg, 14%, 0.1085 mmol) as a yellow oil. HPLC / MS m / z: 185.1, [M+H] + , Rt (R): 0.92 min.

[0446] Example 129.2.: 3-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(3-((4-methyl-5-(pentan-2-yl)thiazol-2-yl)amino)-3-oxopropyl)benzamide was prepared as a brown powder using 4-methyl-5-(1-methylbutyl)thiazol-2-amine (12 mg, 28%, 0.0272 mmol) in a procedure similar to that of Example 0. HPLC / MS m / z: 442.2, [M+H] + , Rt (R): 1.49 min. 1 H NMR (500 MHz, Chloroform-d) δ 8.41 (t, J = 1.8 Hz, 1H), 8.17 (dt, J = 7.7, 1.4 Hz, 1H), 7.93 (dt, J = 8.0, 1.5 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.13-7.07 (m, 1H), 3.89-3.81 (m, 2H), 3.01-2.93 (m, 1H), 2.84-2.79 (m, 2H), 2.66 (s, 3H), 2.21 (s, 3H), 1.62-1.46 (m, 2H), 1.31-1.19 (m, 5H), 0.87 (t, J = 7.3 Hz, 3H) (1 x NH not observed).

[0447] Example 130: 4-Acetamidobutyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] Acetyl acetate (6.58 μL, 0.0696 mmol) and 4-aminobutyl 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate hydrochloride [0] (28.00 mg, 0.0535 mmol) were dissolved in dry THF (0.50 mL) at rt. TEA (22.39 μL, 0.1606 mmol) was added, and the reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure, and the residue was dissolved in DMSO (0.5 mL + 0.3 mL) and purified by reverse-phase column chromatography (eluent: 30-100% MeOH / HO + 0.1% formic acid) to give 4-acetamidobutyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate (20 mg, 71%, 0.0378 mmol) as a colorless powder. HPLC / MS m / z: 529.2, [M+H] + , Rt (R): 1.23 min. 1H NMR (500 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.86 (t, J = 5.6 Hz, 1H), 8.46 (t, J = 1.8 Hz, 1H), 8.13 (dt, J = 7.7, 1.4 Hz, 1H), 8.02 (dt, J = 8.0, 1.4 Hz, 1H), 7.84 (t, J = 5.6 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.19 (t, J = 6.5 Hz, 2H), 3.64-3.56 (m, 2H), 3.09-3.01 (m, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.53 (s, 3H), 1.78 (s, 3H), 1.69-1.60 (m, 2H), 1.52-1.44 (m, 2H).

[0448] Example 131: Propyl-1-methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamido)-1H-pyrazole-5-carboxylate formate [ka] 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid [0] (16.05 mg, 0.0538 mmol), HOBt (14.54 mg, 0.1076 mmol), EDC.HCl (20.63 mg, 0.1076 mmol), and propyl 5-amino-2-methylpyrazole-3-carboxylate (11.83 mg, 0.0646 mmol) were dissolved in dry DMF (0.29 mL). The reaction mixture was warmed to 60 °C and stirred overnight. Purification by reverse-phase column chromatography (eluent: 30-100% MeOH / HO + 0.1% formic acid) provided propyl 1-methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamido)-1H-pyrazole-5-carboxylate formate (11 mg, 44%, 0.0237 mmol) as a yellow powder. HPLC / MS m / z: 464.2, [M+H] + , Rt (R): 1.18 min. 1 H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.90-8.87 (m, 1H), 8.23-8.18 (m, 1H), 8.14 (dd, J = 8.5, 1.5 Hz, 1H), 8.00-7.94 (m, 2H), 7.84 (d, J = 8.5 Hz, 1H), 7.06 (s, 1H), 6.96 (d, J = 5.7 Hz, 1H), 4.20 (t, J = 6.5 Hz, 2H), 3.98 (s, 3H), 3.80-3.73 (m, 2H), 2.74 (t, J = 7.0 Hz, 2H), 2.70 (s, 3H), 1.74-1.66 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).

[0449] The following examples were also prepared by similar procedures: Example 132: Tert-butyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate [ka] 13 mg (36%), slightly yellow powder. HPLC / MS m / z: 472.17, [M+H] + , Rt (Z): 2.80 min. 1 H NMR (600 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 8.47 (t, J = 1.8 Hz, 1H), 8.14 (dt, J = 7.7, 1.4 Hz, 1H), 8.04 (ddd, J = 7.9, 1.8, 1.2 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 3.63-3.58 (m, 2H), 2.79 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 2.51 (d, J = 1.0 Hz, 3H), 1.52 (s, 9H).

[0450] Example 133: Ethyl-3-methyl-5-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiophene-2-carboxylate [ka] 6.8 mg (8%), amorphous colorless solid. HPLC / MS m / z: 443.14 [M+H] + , Rt (R): 1.32 min. 1H NMR (500 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.88 (t, J = 5.6 Hz, 1H), 8.46 (d, J = 1.8 Hz, 1H), 8.13 (dt, J = 7.9, 1.4 Hz, 1H), 8.03 (dt, J = 7.7, 1.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 6.52 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.58 (q, J = 6.5 Hz, 2H), 2.71 (t, J = 6.9 Hz, 2H), 2.68 (s, 3H), 2.40 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).

[0451] Example 134: Ethyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)-N-propylpropanamido)thiazole-5-carboxylate [ka]

[0452] Example 134.1.: Sodium triacetoxyborohydride (227.61 mg, 1.0739 mmol) was added to a solution of ethyl 2-amino-4-methylthiazole-5-carboxylate (100.00 mg, 0.5370 mmol) and propanal (0.12 mL, 1.6109 mmol) in DCE (3.58 mL). Acetic acid (0.05 mL, 0.8055 mmol) was added and the solution was heated at 80 °C for 30 min under microwave irradiation. The reaction mixture was quenched with saturated bicarbonate solution (20 mL) and extracted with DCM (20 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure to provide ethyl 4-methyl-2-(propylamino)thiazole-5-carboxylate (129 mg, 105%, 0.5650 mmol) as a yellow oil, which was used in the next step without further purification. HPLC / MS m / z: 229.10, [M+H] +, Rt (P): 1.38 min.

[0453] Example 134.2.: Ethyl 4-methyl-2-(propylamino)thiazole-5-carboxylate was used in a procedure similar to that of 0 to provide ethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)-N-propylpropanamido)thiazole-5-carboxylate (15 mg, 11%, 0.0309 mmol) as a colorless solid. HPLC / MS m / z: 486.18, [M+H] + , Rt (S): 3.16 min. 1 H NMR (500 MHz, DMSO-d6) δ 8.81 (t, J = 5.4 Hz, 1H), 8.47 (d, J = 1.8 Hz, 1H), 8.13 (dt, J = 7.7, 1.4 Hz, 1H), 8.04 (dt, J = 7.9, 1.5 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.11 (t, J = 7.9 Hz, 2H), 3.64 (q, J = 6.5 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.56 (s, 3H), 1.72 (sext, J = 7.5 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H).

[0454] Example 135: Ethyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamido)-1H-pyrazole-5-carboxylate. [ka] To 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid [0] (30.00 mg, 0.1006 mmol) and PyBrop (93.77 mg, 0.2011 mmol), ethyl 5-amino-1h-pyrazole-3-carboxylate (18.72 mg, 0.1207 mmol) dissolved in anhydrous DMF (0.63 mL) was added. DIPEA (70.07 μL, 0.4023 mmol) was added to the solution, which was then stirred at room temperature for 3 days. Purification by reverse-phase column chromatography (eluent: 20-100% MeOH in water (both + 0.1% formic acid modifier)), followed by ion-exchange column SCX-II eluting with 2M NH3 in MeOH, provided ethyl 3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamido)-1H-pyrazole-5-carboxylate (13 mg, 30%, 0.0299 mmol). HPLC / MS m / z: 436.2 [M+H] + , Rt (U): 2.12 min. 1 H NMR (500 MHz, DMSO-d6) δ 13.49 (s, 1H), 10.68 (s, 1H), 8.91-8.86 (m, 1H), 8.14 (dd, J = 8.5, 1.6 Hz, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 5.7 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.77 (q, J = 6.9, 6.5 Hz, 2H), 2.75 (t, J = 7.0 Hz, 2H), 2.70 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0455] Example 136: 6-Hydroxyhexyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzamido)propanamido)thiazole-5-carboxylate [ka]

[0456] Example 136.1.: Nitrogen was bubbled through a mixture of methyl 3-bromo-5-(trifluoromethyl)benzoate (5.50 g, 19.432 mmol) and zinc cyanide (2.97 g, 25.261 mmol) in DMF (97.16 mL) for 15 min. Palladium tetrakis(triphenylphosphine) (1347.28 mg, 1.1659 mmol) was added, purged with nitrogen for 5 min, and heated at 100 °C for 3 h. Brine (800 mL) was added, extracted with diethyl ether (2 x 100 mL), and the combined organic layers were washed with brine (2 x 250 mL). The mixture was dried over magnesium sulfate. Purification by silica gel column chromatography (eluent: 0-10% EtOAc in cyclohexane) provided methyl 3-cyano-5-(trifluoromethyl)benzoate (4.03 g, 90%, 17.564 mmol). 1 H NMR (500 MHz, Chloroform-d) δ 8.53-8.48 (m, 2H), 8.09 (td, J = 1.6, 0.8 Hz, 1H), 4.01 (s, 3H).

[0457] Example 136.2.: Methyl 3-cyano-5-(trifluoromethyl)benzoate (533.60 mg, 2.3285 mmol) and TEA (0.32 mL, 2.3285 mmol) were heated in [bmim]OAc (2.33 mL) at 80 °C, and hydroxylamine hydrochloride (323.62 mg, 4.657 mmol) was added. The solution was stirred at 80 °C for 15 min. The mixture was cooled to rt, and water (50 mL) was added. The residue was extracted with EtOAc (3 × 25 mL). The organic layers were combined, washed with brine (25 mL), dried over MgSO4, and concentrated under reduced pressure. Purification by reverse-phase column chromatography (eluent: 10-100% MeOH in water (both + 0.1% formic acid)) provided methyl 3-[(Z)-N'-hydroxycarbamimidoyl]-5-(trifluoromethyl)benzoate (390 mg, 64%, 1.4875 mmol) as a colorless solid. HPLC / MS m / z: 263.1, [M+H] + , Rt (P): 0.95 min.

[0458] Example 136.3.: Acetic acid (0.08 mL, 1.4722 mmol), methyl 3-(N-hydroxycarbamimidoyl)-5-(trifluoromethyl)benzoate (386.00 mg, 1.4722 mmol), and EDC.HCl (310.45 mg, 1.6194 mmol) were dissolved in MeCN (4.82 mL) and THF (4.82 mL) under a nitrogen atmosphere. The solution was stirred at rt overnight. Starting material was still present. EDC.HCl (0.2 eq) and acetic acid (0.2 eq) were added, and the solution was stirred at rt for an additional 3 h. Removal of volatiles under reduced pressure provided methyl 3-(N-acetoxycarbamimidoyl)-5-(trifluoromethyl)benzoate (450 mg, 100%, 1.4792 mmol) as a colorless oil, which was used in the next step without further purification. HPLC / MS m / z: 305.1, [M+H] + , Rt (P): 1.32 min.

[0459] Example 136.4.: To a solution of methyl 3-(N-acetoxycarbamimidoyl)-5-(trifluoromethyl)benzoate (447.87 mg, 1.4722 mmol) in DMSO (1.47 mL) was added potassium hydroxide (272.60 mg, 4.8583 mmol). The solution was stirred at rt for 60 min. Water (1 mL) was added to effect saponification. The solution was then stirred at rt for an additional 1 h. LC / MS showed complete conversion to the expected carboxylic acid. Water (20 mL) was added and the aqueous layer was washed with EtOAc (20 mL). The aqueous layer was acidified (to pH approximately 1) by adding a few drops of fuming HCl (37%). The residue was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, and concentrated under reduced pressure to provide 3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzoic acid (360 mg, 90%, 1.3227 mmol) as a colorless solid. HPLC / MS m / z: 273.0 [M+H] + , Rt (P): 1.49 min.

[0460] Example 136.5.: 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzoyl]amino]propanoic acid was prepared using a procedure similar to 0, using 3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzoic acid. HPLC / MS m / z: 344.1, [M+H] + , Rt (R): 1.21 min.

[0461] Example 136.6.: Analogous Procedure A procedure similar to that of Example 0 using hexane-1,6-diol provided 6-hydroxyhexyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzamido)propanamido)thiazole-5-carboxylate (43 mg, 80%, 0.0737 mmol) as a cream-colored powder. HPLC / MS m / z: 584.2, [M+H] +, Rt (R): 1.46 min. 1 H NMR (500 MHz, Methanol-d4) δ 8.75-8.70 (m, 1H), 8.46-8.40 (m, 1H), 8.31-8.25 (m, 1H), 4.25 (t, J = 6.5 Hz, 2H), 3.79 (t, J = 6.6 Hz, 2H), 3.56 (t, J = 6.6 Hz, 2H), 2.87 (t, J = 6.6 Hz, 2H), 2.68 (s, 3H), 2.55 (s, 3H), 1.78-1.70 (m, 2H), 1.61-1.52 (m, 2H), 1.51-1.40 (m, 4H).

[0462] Example 137: 5-butyl-4-methyl-N-(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)thiazole-2-carboxamide formate [ka] To a stirred solution of 5-butyl-4-methyl-thiazole-2-carboxylic acid (16.82 mg, 0.0844 mmol), HATU (48.13 mg, 0.1266 mmol), and DIPEA (29.40 μL, 0.1688 mmol) in DMF (0.30 mL) was added N'-[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]ethane-1,2-diamine[0] (25.00 mg, 0.0928 mmol). The resulting solution was stirred at rt overnight. Purification by reverse-phase column chromatography (eluent: 40-90% MeOH / HO + 0.1% formic acid) provided 5-butyl-4-methyl-N-(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)thiazole-2-carboxamide formate (8 mg, 19%, 0.0178 mmol) as a cream-colored powder. HPLC / MS m / z: 451.2, [M+H] + , Rt (T): 1.28 min. 1H NMR (600 MHz, Methanol-d4) δ 8.79 (s, 1H), 8.35-8.22 (m, 1H), 8.17 (dd, J = 8.5, 1.8 Hz, 1H), 7.86 (d, J = 6.1 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 6.0 Hz, 1H), 3.84-3.76 (m, 2H), 3.76-3.69 (m, 2H), 2.75 (t, J = 7.5 Hz, 2H), 2.65 (s, 3H), 2.32 (s, 3H), 1.62-1.52 (m, 2H), 1.40-1.30 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0463] Example 138: Cyclopentyl-1-methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamido)-1H-pyrazole-5-carboxylate [ka]

[0464] Example 138.1.: To a solution of 3-amino-1-methyl-1H-pyrazole-5-carboxylic acid (50.00 mg, 0.3543 mmol) and DMAP (4.33 mg, 0.0354 mmol) in DCM (3.31 mL) was added 1 M DCC (0.43 mL, 0.4251 mmol) and cyclopentanol (0.32 mL, 3.5428 mmol) sequentially. The resulting solution was stirred at rt overnight. LCMS showed complete conversion. The volatiles were removed in vacuo, and the crude product was purified by reverse-phase chromatography. The residue was dissolved in DMSO (0.8 mL, RBF washed with 0.3 mL DMSO) and loaded onto a 12 g C18 SNAP Ultra column. The column was eluted with 20–70% MeOH in water (+0.1% formic acid). Tubes 7–10 were passed through an SCX-II cartridge (5 g). The column was eluted with MeOH, followed by a 2M ammonia solution in MeOH. The basic fractions were concentrated under reduced pressure to afford cyclopentyl 5-amino-2-methyl-pyrazole-3-carboxylate (35 mg, 47%, 0.1673 mmol) as a colorless oil. HPLC / MS m / z: 210.13, [M+H] + , Rt (T): 1.22 min.

[0465] Example 138.2.: Cyclopentyl 5-amino-2-methyl-pyrazole-3-carboxylate was used in a procedure similar to that of 0 to provide cyclopentyl 2-methyl-5-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoylamino]pyrazole-3-carboxylate (8.8 mg, 27%, 0.0180 mmol) as a colorless solid. HPLC / MS m / z: 490.22, [M+H] + , Rt (U): 2.67 min. 1H NMR (600 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.91-8.85 (m, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 7.99 (d, J = 5.7 Hz, 1H), 7.96 (t, J = 5.5 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.02 (s, 1H), 6.97 (d, J = 5.7 Hz, 1H), 5.29 (dq, J = 6.1, 3.0 Hz, 1H), 3.97 (s, 3H), 3.77 (td, J = 7.0, 5.2 Hz, 2H), 2.74 (t, J = 7.0 Hz, 2H), 2.71 (s, 3H), 1.96-1.86 (m, 2H), 1.74 (dddd, J = 20.9, 11.9, 6.5, 3.5 Hz, 4H), 1.65-1.56 (m, 2H).

[0466] Example 139: 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-[4-methyl-5-(trifluoromethyl)-1,3-thiazol-2-yl]propenamide [ka]

[0467] Example 139.1.: 4-Methyl-5-(trifluoromethyl)-1,3-thiazol-2-amine (142.5 mg, 0.782 mmol), Boc-β-alanine (177.6 mg, 0.939 mmol), and HATU (446.0 mg, 1.173 mmol) were dissolved in DMF (2.0 mL). N-Ethyldiisopropylamine (202.1 mg, 1.564 mmol) was added, and the brown solution was stirred at rt for 3 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water and brine, dried over sodium sulfate, filtered, and evaporated to dryness. The oily residue was purified by flash chromatography to produce 199 mg of a light brown solid, which was suspended in dioxane (3.0 mL), treated with HCl in 1,4-dioxane (4 M, 3.2 mL), and stirred at rt for 2 h. The reaction mixture was evaporated to dryness to give 184 mg of 3-amino-N-[4-methyl-5-(trifluoromethyl)-1,3-thiazol-2-yl]propanamide dihydrochloride as a yellow solid. HPLC / MS m / z: 254.1 [M+H] + , Rt (M): 1.18 min.

[0468] Example 139.2: 3-amino-N-[4-methyl-5-(trifluoromethyl)-1,3-thiazol-2-yl]propanamide dihydrochloride (184.0 mg, 0.564 mmol), 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (138.2 mg, 0.677 mmol), and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate (257.4 mg, 0.677 mmol) were placed in a vial and suspended in DMF (2.5 mL). N-ethyldiisopropylamine (310.0 μL, 1.805 mmol) was added, and the clear brown solution was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate (40 mL), washed with water and brine, dried over sodium sulfate, filtered, and evaporated to dryness. The oily residue was purified by flash chromatography, and the resulting solid was triturated with acetonitrile, suction filtered, washed with a small amount of acetonitrile and tert-butyl methyl ether, and dried overnight under vacuum at 60 °C to give 167 mg (67%) of 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-[4-methyl-5-(trifluoromethyl)-1,3-thiazol-2-yl]propenamide as a colorless solid. HPLC / MS m / z: 440.1 [M+H] + , Rt (M): 1.60 min. 1 H NMR (500 MHz, DMSO-d6): δ 12.62 (s, 1H), 8.83 (t, J = 5.5 Hz, 1H), 8.45 (t, J = 1.7 Hz, 1H), 8.12 (dt, J = 7.7, 1.4 Hz, 1H), 8.03-8.00 (m, 1H), 7.65 (t, J = 7.8 Hz, 1H), 3.61 (q, J = 6.6 Hz, 2H), 2.80 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.40-2.37 (m, 3H).

[0469] Example 140: Ethyl-2-((2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzamido)ethyl)-carbamoyl)-4-methylthiazole-5-carboxylate [ka]

[0470] Example 140.1.: A solution of chloro(isopropyl)magnesium; chlorolithium (3.60 mL, 4.6779 mmol) was added to a solution of ethyl 2-bromo-4-methyl-thiazole-5-carboxylate (0.90 g, 3.5984 mmol) in dry THF (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 10 min before the addition of morpholine-4-carbaldehyde (0.90 mL, 8.996 mmol). After 25 min, the reaction mixture was quenched with NH4Cl (10 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL), dried over MgSO4, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: 0-20% EtOAc in cyclohexane) provided ethyl 2-formyl-4-methyl-thiazole-5-carboxylate (495 mg, 69%, 2.4846 mmol) as a colorless oil. HPLC / MS m / z: 200.0, [M+H] + , Rt (Q): 2.33 min.

[0471] Example 140.2.: 2-Methylbut-2-ene (7.82 mL, 73.784 mmol) was added to a solution of ethyl 2-formyl-4-methylthiazole-5-carboxylate (490.00 mg, 2.4595 mmol) in THF (8.20 mL) and t-BuOH (8.20 mL) at rt. After 5 min, a solution of sodium dihydrogen phosphate (885.26 mg, 7.3784 mmol) and sodium chlorite (734.03 mg, 8.1162 mmol) in HO (4 mL) was added dropwise. The reaction mixture was stirred at rt for 1.5 h. The reaction mixture was quenched with a saturated solution of NaSO. The aqueous layer was extracted with EtOAc, then acidified with 2N HCl to pH 1-2, and extracted again with EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure to provide 5-ethoxycarbonyl-4-methyl-thiazole-2-carboxylic acid (382 mg, 72%, 1.7748 mmol), which was used without further purification.

[0472] Example 140.3.: tert-Butyl N-(2-aminoethyl)carbamate (0.09 mL, 0.5766 mmol) was added to a solution of 5-ethoxycarbonyl-4-methyl-thiazole-2-carboxylic acid (73.00 mg, 0.3392 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine, HCl (135.00 mg, 0.8696 mmol), and 1-hydroxybenzotriazole (117.00 mg, 0.8659 mmol) in dry DMF at rt. The reaction mixture was stirred at rt overnight. The mixture was diluted with EtOAc (10 mL), washed with a saturated solution of NaHCO3 (2 x 5 mL) and water (2 x 5 mL), dried over MgSO4, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: 5-50% EtOAc in cyclohexane) gave ethyl 2-[2-(tert-butoxycarbonylamino)ethylcarbamoyl]-4-methyl-thiazole-5-carboxylate (50 mg, 41%, 0.1399 mmol) as a colorless powder. HPLC / MS m / z: 358.1, [M+H] +, Rt (R): 2.84 min.

[0473] Example 140.4.: HCl in dioxane (0.59 mL, 2.3501 mmol) was added to a solution of ethyl 2-[2-(tert-butoxycarbonylamino)ethylcarbamoyl]-4-methyl-thiazole-5-carboxylate (42.00 mg, 0.1175 mmol) in dry dioxane (0.59 mL) at rt. The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure to give ethyl 2-(2-aminoethylcarbamoyl)-4-methyl-thiazole-5-carboxylate as a colorless solid. No further purification was performed.

[0474] Example 140.5.: Ethyl 2-(2-aminoethylcarbamoyl)-4-methyl-thiazole-5-carboxylate (28.00 mg, 0.1088 mmol), 3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzoic acid (28.49 mg, 0.1306 mmol), HOBt (29.41 mg, 0.2176 mmol), and EDC (33.79 mg, 0.2176 mmol) were dissolved in dry DMF (0.54 mL) at rt. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc, washed with NaHCO (2 x 8 mL) and water (8 mL), dried over MgSO, concentrated under reduced pressure, and dissolved in DMSO (0.5 mL + 0.3 mL). Purification by reverse-phase column chromatography (eluent: 30-100% MeOH / HO + 0.1% formic acid) provided ethyl 2-((2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzamido)ethyl)carbamoyl)-4-methylthiazole-5-carboxylate (30 mg, 57%, 0.0623 mmol). HPLC / MS m / z: 458.1, [M+H] + , Rt (S): 2.96 min. 1H NMR (500 MHz, DMSO-d6) δ 9.17-9.09 (m, 1H), 8.85-8.78 (m, 1H), 8.45 (t, J = 1.8 Hz, 1H), 8.14 (dt, J = 7.8, 1.4 Hz, 1H), 8.02 (dt, J = 8.0, 1.4 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.53-3.45 (m, 4H), 3.08-2.99 (m, 2H), 2.69 (s, 3H), 1.36 (t, J = 7.6 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0475] The following examples were prepared similarly: Example 141: Ethyl-4-methyl-2-((2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)ethyl)carbamoyl)thiazole-5-carboxylate [ka] 48 mg (51%), colorless solid. HPLC / MS m / z: 444.1, [M+H] + , Rt (R): 1.32 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.16-9.10 (m, 1H), 8.83-8.79 (m, 1H), 8.45 (t, J = 1.7 Hz, 1H), 8.12 (dt, J = 7.8, 1.4 Hz, 1H), 8.02 (dt, J = 7.9, 1.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.52-3.43 (m, 4H), 2.69 (s, 3H), 2.68 (s, 3H), 1.30 (t, J = 7.1Hz, 3H).

[0476] Example 142: Ethyl-(R)-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)butanamido)thiazole-5-carboxylate [ka]

[0477] Example 142.1.: To tert-butyl (3R)-3-aminobutanoate (155.97 mg, 0.9795 mmol) was added anhydrous DMF (4.90 mL), 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (200.00 mg, 0.9795 mmol), DIPEA (0.51 mL, 2.9386 mmol), and HATU (345.68 mg, 1.47 mmol). The reaction mixture was stirred at rt overnight. Water (70 mL) was added, and the mixture was extracted with EtOAc (2 x 60 mL). The combined organics were washed with saturated NaHCO, brine, and dried over MgSO before concentrating in vacuo to give tert-butyl (3R)-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]butanoate (335 mg, 99%, 0.9699 mmol) as a clear viscous oil. Used without further purification. HPLC / MS m / z: 368.1 [M+Na] + , Rt (P): 1.45 min.

[0478] Example 142.2.: To tert-butyl (3R)-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]butanoate (167.00 mg, 0.4835 mmol) in DCM (1.50 mL) was added TFA (0.37 mL, 4.8351 mmol) and the mixture was stirred for 2 h. Volatiles were removed in vacuo. Traces of high-boiling TFA and by-products were removed by adding toluene followed by evaporation. Using a high vacuum +45°C water bath, (3R)-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]butanoic acid (142 mg, 102%, 0.4909 mmol) remained as a colorless solid. No further purification was performed. HPLC / MS m / z: 458.1 [M+H] + , Rt (P): 1.51 min.

[0479] Example 142.3.: A 50 mL RBF was charged with (3R)-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]butanoic acid (140.00 mg, 0.4839 mmol), ethyl 2-amino-4-methyl-thiazole-5-carboxylate (90.12 mg, 0.4839 mmol), HOBt (130.78 mg, 0.9679 mmol), and dry DMF (2.42 mL). To this mixture was added EDC (185.54 mg, 0.9679 mmol). A condenser, needle, and empty balloon were added and the mixture was stirred at 60 °C for 18 h. LCMS indicated the presence of the desired product. Water (50 mL) was added. This was extracted with EtOAc (2 x 35 mL), and the organics were combined, washed with saturated NaHCO3 (25 mL), brine (25 mL), dried over MgSO4, and concentrated in vacuo to give a colorless solid. Purification by reverse-phase column chromatography (eluent: 20-80% MeOH in water (both + 0.1% formic acid modifier)) provided ethyl (R)-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)butanamido)thiazole-5-carboxylate (10 mg, 5%, 0.0219 mmol). HPLC / MS m / z: 458.1 [M+H]+ , Rt (P): 1.51 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.44 (t, J = 1.8 Hz, 1H), 8.12 (dt, J = 7.8, 1.4 Hz, 1H), 8.01 (dt, J = 7.9, 1.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 4.57-4.44 (m, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.78 (dd, J = 14.9, 7.2 Hz, 1H), 2.72 (dd, J = 14.9, 6.8 Hz, 1H), 2.69 (s, 3H), 2.53 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.23 (d, J = 6.7 Hz, 3H).

[0480] The following examples were also prepared in a similar manner: Example 143: Ethyl-(S)-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)butanamido)thiazole-5-carboxylate [ka] 15mg (10%). HPLC / MS m / z: 458.1 [M+H] + , Rt (S): 2.82 min. 1H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.44 (dt, J = 1.7, 1.0 Hz, 1H...

Claims

1. Formula I, 【Chemistry 1】 During the ceremony W is 【Chemistry 2】 Display R 1 Hal, CN, A, COOR 7 , CON(R 7 ) 2 , COA', or Het 1 Display R 2 displays H, Hal, A', R 3 teeth, 【Chemistry 3】 Display R 4 , R 8 denote, independently of one another, H, unbranched or branched alkyl having 1 to 3 C atoms, R 5 is H, or Hal, A, OH, OCH 3 , N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , and C.H. 2 Representing one or more substituents selected from the group: CN; R 6 is unsubstituted or is Hal, A, OH, N(R 7 ) 2 , COOR 7 , CN, NO 2 and / or Het 2 benzoyl, 2-isoquinolinyl, or 4-quinazolinyl, each of which is substituted 1-, 2-, or 3 times with A represents an unbranched or branched alkyl or cycloalkyl group having 1 to 10 C atoms, where two adjacent CH groups and / or CH 2 The group may form a double bond and may contain one or two non-adjacent CH groups and / or CH 2 the group may be replaced by N, O and / or S atoms, and in which 1 to 7 H atoms may be replaced by F or CI; A' denotes unbranched or branched alkyl having 1 to 4 C atoms, in which 1 to 7 H atoms may be replaced by F or Cl, Het 1 denotes oxadiazolyl which is unsubstituted or substituted at its C atoms by 1 to 4 unbranched or branched alkyl, Het 2 denotes oxadiazolyl, tetrazolyl, pyrazolyl or oxazolyl which is unsubstituted or substituted at its C atoms by 1 to 4 unbranched or branched alkyl, R 7 displays H or A, Hal denotes F, Cl, Br, or I. and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any ratio.

2. W is 【Chemistry 4】 Display the following information and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 , and Het 2 has the meaning as in claim 1, 10. The compound according to claim 1, and its physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any ratio.

3. W is 【Chemistry 5】 Display the following information and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 , and Het 2 has the meaning as in claim 1, 3. Compounds according to claim 1 or 2, and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio.

4. W is 【Chemistry 6】 Display the following information and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 , and Het 2 has the meaning 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 ratio.

5. R 2 denotes H or A', and W, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 , and Het 2 has the meaning as in claim 1, Compounds according to any one of claims 1 to 4, as well as their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio.

6. R 2 denotes H or methyl, and W, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 , and Het 2 has the meaning as in claim 1, Compounds according to any one of claims 1 to 5, as well as their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio.

7. R 3 teeth, 【Chemistry 7】 Display the following information and W, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 , and Het 2 has the meaning 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 3 teeth, 【Chemistry 8】 Display the following information and W, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 , and Het 2 has the meaning as in claim 1, Compounds according to any one of claims 1 to 7, as well as their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio.

9. R 6 denotes benzoyl or 2-isoquinolinyl, and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , A, A', Het 1 , and Het 2 has the meaning as in claim 1, Compounds according to any one of claims 1 to 8, as well as their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio.

10. Het 2 denotes oxadiazolyl or tetrazolyl, and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', and Het 1 has the meaning as in claim 1, Compounds according to any one of claims 1 to 9, as well as their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio.

11. Het 2 denotes methyl-oxadiazolyl or methyl-tetrazolyl, and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', and Het 1 has the meaning as in claim 1, Compounds according to any one of claims 1 to 10, as well as their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, and mixtures thereof in any ratio.

12. 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】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 and their physiologically acceptable salts, derivatives, solvates, prodrugs, and stereoisomers, and mixtures thereof in any proportion.

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

14. 14. The pharmaceutical preparation according to claim 13, further comprising an excipient and / or an adjuvant.

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

16. A process for the preparation of a pharmaceutical preparation, characterized in that the compound according to any one of claims 1 to 12, and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, as well as mixtures thereof in any ratio, is brought into a suitable dosage form together with solid, liquid or semi-liquid excipients or adjuvants.

17. A medicament comprising at least one compound according to any one of claims 1 to 12, and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, as well as mixtures thereof in any ratio, for use in a method for the treatment and / or prophylaxis of physiological and / or pathophysiological conditions.

18. A medicament comprising at least one compound according to any one of claims 1 to 12, 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.

19. 19. The method of claim 18, wherein the hyperproliferative disease or disorder is cancer.

20. Cancers include acute and chronic lymphocytic leukemia, acute granulocytic leukemia, adrenal cortical carcinoma, bladder cancer, brain cancer, breast cancer, cervical hyperplasia, cervical cancer, choriocarcinoma, chronic granulocytic 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, medullary thyroid carcinoma, 20. The medicament for use according to claim 19, selected from the group consisting of 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 tumors, 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.

21. The following separate packs: a) an effective amount of a compound according to any one of claims 1 to 12, 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 pharma- ceutical active compound; A set (kit) consisting of:

Images