Substituted heterocyclic compounds as HSET inhibitors

Abstract

The present invention relates to substituted heterocyclic compounds of general formula (I) wherein W is a thiazole, thiophene, pyrazole, imidazole or isoxazole, as well as to the use of compounds of the invention for the treatment and / or prophylaxis of hyperproliferative diseases and conditions in mammals, in particular humans, and to pharmaceutical compositions containing such compounds. # imgabs0 #

Description

[0001] The present invention relates to substituted heterocyclic compounds of the following general formula I,

[0002]

[0003] The invention also relates to the use of the compounds of the present invention for treating and / or preventing hyperproliferative diseases and disorders such as cancer in mammals (especially humans), and pharmaceutical compositions containing such compounds. Background Art

[0004] DNA replication, followed by allele 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 serves as the primary site for spindle pole formation (Meunier and Vernos, 2012). Centrosome duplication is also tightly controlled and occurs concurrently with DNA replication, ensuring the generation of two functional centrosomes, which form the mitotic spindle poles (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, HSET (encoded by KIFC1 in humans and Kifc5a in mice), a minus-end MT motor, has garnered attention in cancer due to its effects on cell division (Cai et al., 2010; Goshima et al., 2005).

[0005] In recent years, the importance of centrosomes, and in particular HSET, to bipolar spindle formation has attracted much attention, but the exact role of HSET in this process remains a controversial topic (Mahoney et al., 2006; Tillement et al., 2009). Recent reports have linked centrosome amplification and high HSET expression to chromosome segregation errors and aneuploidy, which are hallmarks of human cancer (Marx et al., 2009). Centrosome amplification disrupts asymmetric cell division in neuroblastoma cells and leads to tumorigenesis in fly models (Basto et al., 2008), and supernumerary centrosomes have also been found in most solid tumor types, forming a marker of aggressiveness in breast, brain, prostate, cervical, kidney, and bladder cancers (Chan, 2011). Therefore, it is becoming increasingly clear that supernumerary centrosomes are not only a sign of malignancy, but may also drive malignant transformation (Ogden et al., 2013). However, not all cells with centrosome amplification undergo multipolar mitosis, and a key mechanism by which cells with extra centrosomes achieve pseudobipolar spindles is centrosome clustering (Basto et al., 2008; Ganem et al., 2009).

[0006] Although centrosome clustering prevents multipolar mitosis and cell death, it prolongs mitosis and increases the frequency of chromosome segregation errors 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 has been shown to be the Achilles' heel of cancer cells with supernumerary centrosomes (Basto et al., 2008), and increasing evidence suggests that inhibiting centrosome clustering may provide a new therapeutic strategy for tumors with a high incidence of centrosome amplification (Jordan and Wilson, 2004; Ogden et al., 2012).

[0007] A key protein known to be crucial for centrosome clustering is HSET (Ncd in flies). Tumor cells require HSET to cluster 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 promotes movement along MTs within the cell (Mountain et al., 1999), and transports organelles, protein complexes, and mRNA along microtubules in an ATP-dependent manner. HSET is a minus-end-directed motor protein that can exert inward forces to crosslink and slide microtubules (Walczak et al., 1997; Cai et al., 2009; Rath et al., 2012). Although the exact role of HSET in cell division is unclear, previous evidence suggests that it is crucial for the survival of cancer cells, but not for normal cells (Ganem et al., 2009; Kwon et al., 2008). High HSET expression levels are strongly correlated with metastasis of non-small cell lung cancer to the brain, which points to an association between HSET, centrosome amplification, and tumorigenesis (Cai et al., 2010; Gordon et al., 2001; Grinberg-Rashi et al., 2009). Knocking down HSET in normal retinal pigment epithelial 1 (RPE-1) cells or the breast cancer cell line MCF-7 (which does not have a high incidence of centrosome amplification) does not inhibit the formation of bipolar spindles, and cells undergo normal division (Kleylein-Sohn et al., 2012; Kwon et al., 2008). In contrast, knocking down HSET in breast cancer and neuroblastoma cell lines MDA-MB-231 and N1E-115 containing supernumerary centrosomes, respectively, prevents centrosome clustering and induces cell death through multipolar anaphase (Kwon et al., 2008). Therefore, the above findings point to HSET as an interesting target in cancer therapy (Basto et al., 2008; Kraljevic Pavelic et al., 2011; et al., 2011; Kwon et al., 2008).

[0008] Numerous studies have demonstrated that HSET depletion increases cell death and the frequency of multipolarity in cells with abnormal centrosomes, but not in cells with normal centrosomes. For example, HSET depletion induces spindle multipolarity and selectively sensitizes centrosome-amplified ER-positive breast cancer cell lines, including triple-negative breast cancer (TNBC), to cell death (Patel et al., 2018). HSET depletion has been shown to induce selective cytotoxicity in cancer cells with centrosome amplification (Drosopoulos et al., 2014). Furthermore, HSET overexpression is associated with poor prognosis and docetaxel resistance in breast cancer (De et al., 2009; Li et al., 2015), observed in patients with ovarian adenocarcinoma (Pawar et al., 2014), and in many other cancer types (Pannu et al., 2015). Furthermore, in non-small cell lung cancer (NSCLC), HSET expression is highly predictive of the presence of brain metastases in both early-stage and advanced disease (Grinberg-Rashi et al., 2009).

[0009] A variety of tumors, including those with centrosome amplification, are treated with cytotoxic microtubule-targeting drugs (e.g., paclitaxel, eribulin). Although these drugs induce temporary remissions, they typically exhibit severe side effects and the development of drug resistance, which leads to early relapse. More recently, agents targeting kinesin motor proteins, such as Eg5 inhibitors, have been explored for the treatment of a variety of human tumors. These agents induce monopolar spindles (the opposite phenotype of HSET inhibition) and target all rapidly dividing cells, including myeloid cells. Therefore, they share the dose-limiting toxicity of other antimitotic therapies. Conversely, by selectively killing cells with centrosome amplification while leaving cells with a normal number of centrosomes unaffected, HSET inhibitors are expected to show reduced toxicity (Ganem et al., 2009; Patel et al., 2015). Together, these data support the development of agents that selectively inhibit HSET to target tumors with centrosome amplification (Myers and Collins, 2016).

[0010] Examples of small molecule HSET inhibitors are described in the literature. AZ82 is an ADP / ATP competitive inhibitor that exhibits selectivity against nine other kinesins, including Eg5 (Wu et al., 2013). In biochemical assays, AZ82 inhibits microtubule-stimulated HSET ATPase activity (IC 50=0.3 μM) and induces multipolar spindle formation and mitotic catastrophe in cells with amplified centrosomes. CW069 is an inhibitor of HSET in biochemical assays (IC 50 =75 μM) (Watts et al., 2013). SR31527 also showed biochemical inhibition of HSET (IC 50 =6.6 μM) (Zhang et al., 2016). More information can be found in WO09155025 and WO15085088.

[0011] Therefore, there remains a need for therapies for the treatment and prevention of hyperproliferative diseases and disorders such as cancer.It is therefore an object to discover HSET inhibitors for use as potential therapeutics for the treatment of cancer diseases. Summary of the Invention

[0012] Surprisingly, it has been found that the compounds according to the present invention are highly selective and potent inhibitors of HSET and that the compounds of the present invention may therefore be useful in the treatment of hyperproliferative diseases and disorders, such as cancer.

[0013] The present invention relates to compounds of the general formula I and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

[0014]

[0015] in

[0016] W stands for

[0017]

[0018] R 1 Indicates Hal, CN, A, COOR 7 、CON(R 7 )2、COA' or Het 1 ,

[0019] R 2 Indicates H, Hal, A',

[0020] R 3 express

[0021]

[0022] R 4 、R 8 independently of one another represent H, an unbranched or branched alkyl group having 1 to 3 C atoms,

[0023] R 5represents H or one or more substituents selected from Hal, A, OH, OCH3, NH2, NHCH3, N(CH3)2 and CH2CN,

[0024] Het1 represents oxadiazolyl, which is unsubstituted or substituted by unbranched or branched alkyl having 1 to 4 C atoms,

[0025] A denotes an unbranched or branched alkyl or cycloalkyl radical having 1 to 10 C atoms, wherein two adjacent CH- and / or CH2- groups may form a double bond, and wherein one or two non-adjacent CH- and / or CH2- groups may be replaced by an N-, O- and / or S-atom, and wherein 1 to 7 H atoms may be replaced by F or Cl,

[0026] A' represents an unbranched or branched alkyl group having 1 to 4 C atoms, of which 1 to 7 H atoms may be replaced by F or Cl,

[0027] Het 1 represents oxadiazolyl, which is unsubstituted or substituted by unbranched or branched alkyl having 1 to 4 C atoms,

[0028] Het 2 represents oxadiazolyl, tetrazolyl, pyrazolyl or oxazolyl, which is unsubstituted or substituted by unbranched or branched alkyl having 1 to 4 C atoms,

[0029] R 7 Indicates H or A,

[0030] Hal represents F, Cl, Br or I.

[0031] The present invention preferably relates to compounds according to formula I, wherein W represents

[0032]

[0033] 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 same meaning as in claim 1.

[0034] The present invention more preferably relates to compounds according to formula I and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, wherein W represents

[0035]

[0036] 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 same meaning as in claim 1.

[0037] The present invention particularly preferably relates to compounds according to formula I, wherein W represents

[0038]

[0039] 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 same meaning as in claim 1.

[0040] The present invention preferably relates to compounds according to formula I and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, in which 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 Has the same meaning as in claim 1.

[0041] The present invention more preferably relates to compounds according to formula I and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, wherein R2 represents 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 same meaning as in claim 1.

[0042] The present invention preferably relates to compounds according to formula I and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, in which R 3 express

[0043]

[0044] 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 same meaning as in claim 1.

[0045] The present invention particularly preferably relates to compounds according to formula I and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, in which R 3 express

[0046] 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 same meaning as in claim 1.

[0047] The present invention particularly preferably relates to compounds according to formula I and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, in which R 6 represents benzoyl or 2-isoquinolinyl, and W, R 1 、R 2 、R 3 、R 4 、R5 、R 7 、R 8 、A、A'、Het 1 and Het 2 Has the same meaning as in claim 1.

[0048] The present invention preferably relates to compounds according to formula I and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, wherein Het 2 represents an oxadiazolyl group or a tetrazolyl group, 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 same meaning as in claim 1.

[0049] The present invention particularly preferably relates to compounds according to formula I and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, wherein Het 2 represents a methyl-oxadiazolyl group or a methyl-tetrazolyl group, 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 same meaning as in claim 1.

[0050] The present invention preferably relates to compounds selected from the group consisting of the following compounds and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios:

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071] In addition, the abbreviations below have the following meanings:

[0072] Boc tert-butyloxycarbonyl

[0073] CBZ benzyloxycarbonyl

[0074] DNP 2,4-Dinitrophenyl

[0075] FMOC 9-Fluorenylmethoxycarbonyl

[0076] imi-DNP is a 2,4-dinitrophenyl group at position 1 of the imidazole ring

[0077] OMe methyl ester

[0078] POA phenoxyacetyl

[0079] DCCI dicyclohexylcarbodiimide

[0080] HOBt 1-Hydroxybenzotriazole

[0081] The 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, including mixtures thereof in all ratios.

[0082] The present invention also relates to pharmaceutical preparations of this type according to the invention, which comprise further excipients and / or adjuvants.

[0083] Furthermore, the present invention relates to the above pharmaceutical preparations according to the invention, which comprise at least one further pharmaceutically active compound.

[0084] Pharmaceutically or physiologically acceptable derivatives mean, for example, salts of the compounds of the present invention, and so-called prodrug compounds. Prodrug compounds mean derivatives of the compounds of the present invention that are modified by, for example, alkyl or acyl groups (see also amino and hydroxyl protecting groups below), sugars or oligopeptides, and that are rapidly cleaved or released in vivo to form effective molecules. These also include biodegradable polymer derivatives of the compounds of the present invention, such as described in Int. J. Pharm. 115 (1995), 61-67.

[0085] 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 pharmaceutically acceptable salts of the compounds of the present invention, which can be derived from various organic and inorganic bases by procedures known in the art. Pharmaceutically acceptable salt forms of the compounds of the present invention are mostly prepared by conventional methods. If the compound of the present invention contains a carboxyl group, a suitable salt of the compound of the present invention can be formed by reacting the compound of the present invention with a suitable base to obtain the corresponding base addition salt. Such bases include alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, such as potassium ethoxide and sodium propoxide; and various organic bases, such as piperidine, diethanolamine and N-methylglutamine. Aluminum salts of the compounds of the present invention are also included.

[0086] Additionally, base salts of the compounds of the present invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium, and zinc salts, but this is not intended to represent a limitation.

[0087] Among the salts mentioned above, preference is given to ammonium; alkali metal sodium and potassium salts and alkaline earth metal calcium and magnesium salts. Salts of the compounds of the present invention derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, 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 penicillin), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris(hydroxymethyl)methylamine (tromethamine), but this is not intended to represent a limitation.

[0088] 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.

[0089] The base addition salts of the compounds of the present invention are prepared by contacting the free acid form with a sufficient amount of the desired base to cause salt formation in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form differs from its corresponding salt form in certain respects with respect to certain physical properties (e.g., solubility in polar solvents); however, for the purposes of the present invention, the salts correspond to their respective free acid forms.

[0090] In view of the above, it can be seen that the term "pharmaceutically acceptable salt" according to the present invention is intended to include an active compound of the compound of the present invention in the form of one of its salts, particularly if this salt form confers improved pharmacokinetic properties on the active compound compared to the free form of the active compound or any other salt form of the active compound previously used. A pharmaceutically acceptable salt form of an active compound may also provide this active compound with desirable pharmacokinetic properties that it did not previously possess for the first time, and may even have a positive effect on the pharmacokinetics of this active compound with respect to its therapeutic efficacy in vivo.

[0091] Solvates of the compounds according to the invention are understood to be addition products formed between inert solvent molecules and the compounds according to the invention due to their mutual attractive force. For example, solvates are hydrates, such as monohydrates or dihydrates, or alcoholates, i.e. addition compounds with alcohols, such as methanol or ethanol.

[0092] All physiologically acceptable salts, derivatives, solvates and stereoisomers of these compounds, including mixtures thereof in all ratios, also conform to the invention.

[0093] The compounds of the present invention may contain one or more chiral centers, such that all stereoisomers, enantiomers, diastereomers, etc. of the compounds of the present invention are also claimed in the present invention.

[0094] The invention also relates to the optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds.

[0095] According to the present invention, the compounds of the present invention may be chiral due to their molecular structure, and may therefore appear in various enantiomeric forms. Therefore, they can be racemic or optically active forms. Since the pharmaceutical efficacy of the racemate or stereoisomer of the compound according to the present invention may be different, it is desirable to use enantiomers. In these cases, the final product may be separated into enantiomeric compounds by chemical or physical means known to those skilled in the art or having been adopted (such as the one in the synthesis).

[0096] Pharmaceutically or physiologically acceptable derivatives are understood to include, for example, salts of the compounds according to the invention and so-called prodrug compounds. Prodrug compounds are understood to include compounds according to the invention that have been modified, for example, by alkyl or acyl groups (see also amino and hydroxyl protecting groups below), sugars or oligopeptides, and which are rapidly cleaved or released in vivo to form the active compounds according to the invention. These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115 (1995), 61-67.

[0097] Suitable acid addition salts are all inorganic or organic salts of physiologically or pharmaceutically acceptable acids, such as halides, in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methanesulfonates or p-toluenesulfonates.

[0098] Very particular preference is given to the hydrochlorides, trifluoroacetates or bistrifluoroacetates of the compounds according to the invention.

[0099] Solvates of the compounds according to the invention are understood to be addition products formed between inert solvent molecules and the compounds according to the invention due to their mutual attractive force. For example, solvates are hydrates, such as monohydrates or dihydrates, or alcoholates, i.e. addition compounds with alcohols, such as methanol or ethanol.

[0100] Furthermore, the compounds of the present invention are also intended to include isotopically labeled forms thereof. Isotopically labeled forms of the compounds of the present invention are identical to the compounds of the present invention except for the fact that one or more atoms of the compound are replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. 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 invention, their prodrugs or pharmaceutically acceptable salts containing 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 invention can be used in a variety of advantageous ways. For example, into which have been incorporated, for example, 3 H or 14 The isotope-labeled compounds of the present invention containing radioactive isotopes such as tritium (C) are suitable for drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) are particularly preferred due to their ease of preparation and excellent detectability. Heavier isotopes such as deuterium ( 2 The incorporation of isotopically labeled compounds into the compounds of the present invention has therapeutic advantages due to the higher metabolic stability of this isotope. Higher metabolic stability can directly translate into increased in vivo half-life or lower dosage, which in most cases will represent a more preferred embodiment of the present invention. The isotopically labeled compounds of the present invention can generally be prepared by following the procedures disclosed in the synthetic schemes and related descriptions in the Examples and Preparations sections herein, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0101] In order to manipulate the oxidative metabolism of the compound through the primary kinetic isotope effect, the compound of the present invention may also be incorporated with deuterium ( 2H). The primary kinetic isotope effect is a change in the rate of a chemical reaction caused by the exchange of isotopic nuclei, which in turn causes a change in the ground state energy required for covalent bond formation after this isotopic exchange. Exchange of heavier isotopes generally causes a decrease in the ground state energy of a chemical bond and, therefore, a decrease in the rate of the rate-limiting bond. If bond breakage occurs in or near a saddle point region along the coordinates of a multi-product reaction, the product distribution ratio may be substantially altered. This is illustrated as follows: If deuterium is bonded to a carbon atom at a non-exchangeable position, the typical rate difference is k M / k D = 2-7. If this rate difference is successfully applied to a compound of the present invention that is susceptible to oxidation, the distribution of the compound in the body can be greatly modified and improved pharmacokinetic properties can be obtained.

[0102] 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 properties are susceptible to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information about the processes of such oxidative metabolism, which in turn allows for the rational design of deuterated compounds of the present invention with improved stability by resisting such oxidative metabolism. Significant improvements in the pharmacokinetic properties of the compounds of the present invention are thereby achieved, and can be seen in terms of in vivo half-life (T / 2), maximum therapeutic concentration (C max ), area under the dose-response curve (AUC), and F-angle; and quantitatively expressed in terms of reduction in clearance, dose, and material cost.

[0103] The following is intended to illustrate the above: Compounds of the present invention having multiple potential attack sites for oxidative metabolism, such as nitrogen-bonded hydrogen atoms and benzylic hydrogen atoms, are prepared as a series of analogs in which various combinations of hydrogen atoms are replaced with deuterium atoms, such that some, most, or all of these hydrogen atoms are replaced with deuterium atoms. Half-life determinations enable the degree of improved resistance to oxidative metabolism to be advantageously and accurately determined. In this manner, it has been determined that the half-life of the parent compound can be extended by up to 100% as a result of such deuterium-hydrogen exchange.

[0104] The replacement of hydrogen with deuterium in the compounds of the present invention can also be used to achieve advantageous modifications to the metabolite profile of the starting compound, so as to reduce or eliminate undesirable toxic metabolites. For example, if the toxic metabolite is produced by oxidative carbon-hydrogen (CH) bond cleavage, it is reasonable to assume that the deuterated analog will greatly reduce or eliminate the production of the undesirable metabolite, even if the specific oxidation is not the rate-determining step. Further information on the prior art of 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.

[0105] The present invention also relates to mixtures of the compounds according to the invention, for example, mixtures of two diastereomers in a ratio of 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. These are particularly preferred mixtures of two stereoisomeric compounds. However, mixtures of two or more compounds according to the invention are also preferred.

[0106] Furthermore, the present invention relates to a process for preparing the compounds according to the invention, characterized in that

[0107] a) a base of a compound of the invention is converted into one of its salts by treatment with an acid, or

[0108] b) An acid of the compound of the present invention is converted into one of its salts by treating with a base.

[0109] It is also possible in each case to carry out the reactions stepwise and to modify the order of the linking reactions of the building blocks with accompanying changes in the protecting group concept.

[0110] The starting materials or starting compounds are generally known. If they are novel, they can be prepared by methods known per se.

[0111] If desired, the starting materials can also be formed in situ by not isolating them from the reaction mixture but instead immediately converting them further into the compounds according to the invention.

[0112] Compound of the present invention is preferably by solvolysis, particularly by hydrolysis, or by hydrogenolysis, discharges and obtains from their functional derivatives.Preferred starting material for solvolysis or hydrogenolysis is to contain corresponding protection amino, carboxyl and / or hydroxyl rather than one or more free amino, carboxyl and / or hydroxyl those, preferably carries amino protecting group rather than those of the H atom that is connected with the N atom.Further preferably carries the starting material of the H atom of hydroxyl protecting group rather than hydroxyl.Also preferably carries protected carboxyl rather than the starting material of free carboxyl.Also may there be a plurality of identical or different protected amino, carboxyl and / or hydroxyl in the starting material molecule.If the protecting group that exists is different from each other, their selective cleavage can be removed in many cases.

[0113] The term "amino protecting group" is generally known and relates to a group that is suitable for protecting (blocking) an amino group from chemical reactions, but that can be easily removed after the desired chemical reaction is performed elsewhere in the molecule. Typical such groups are in particular unsubstituted or substituted acyl groups, and unsubstituted or substituted aryl groups (e.g., 2,4-dinitrophenyl) or aralkyl groups (e.g., benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protecting group is removed after the desired reaction or reaction sequence, its type and size are not otherwise critical, but amino protecting groups with 1-20 carbon atoms, in particular those with 1-8 carbon atoms, are preferred. The term "acyl" should be understood in the broadest sense in conjunction with the present method. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl, and especially aralkyloxycarbonyl. Examples of such acyl groups are alkanoyl groups such as acetyl, propionyl, butyryl, aralkanoyl groups such as phenylacetyl, aryl groups such as benzoyl or toluoyl, aryloxyalkanoyl groups such as phenoxyacetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, aralkyloxycarbonyl groups such as CBZ, 4-methoxybenzyloxycarbonyl or FMOC. Preferred acyl groups are CBZ, FMOC, benzyl and acetyl.

[0114] The term "acid protecting group" or "carboxyl protecting group" is likewise generally known and relates to a group which is suitable for protecting a -COOH group from chemical reactions but which can be easily removed after the desired chemical reaction has been carried out elsewhere in the molecule. It is typical to use an ester rather than a free acid, such as a substituted and unsubstituted alkyl ester (e.g. methyl, ethyl, tert-butyl and substituted derivatives thereof), a substituted and unsubstituted benzyl ester or a silyl ester. The type and size of the acid protecting group are not critical, but preference is given to those having 1 to 20 C atoms, in particular those having 1 to 10 C atoms.

[0115] The term "hydroxy protecting group" is likewise generally known and relates to a group which is suitable for protecting a hydroxy group from chemical reactions but which can be easily removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical groups of this type are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and in addition alkyl groups. The type and size of the hydroxy protecting group are crucial, but preference is given to those having 1 to 20 carbon atoms, in particular those having 1 to 10 carbon atoms. Examples of hydroxy protecting groups are especially benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, with benzyl and acetyl being preferred.

[0116] Further typical examples of amino, acidic and hydroxyl protecting groups are found in, for example, “Greene's Protective Groups in Organic Synthesis”, 4th edition, Wiley-Interscience, 2007.

[0117] Functional derivatives of the compounds of the invention to be used as starting materials can be prepared by known methods of amino acid and peptide synthesis, as described, for example, in the aforementioned authoritative works and patent applications.

[0118] The compounds of the invention are, depending on the protecting group used, released from their functional derivatives, for example, with the aid of a strong acid, advantageously trifluoroacetic acid or perchloric acid, but also other strong mineral 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. The presence of additional inert solvents and / or catalysts is possible but not always necessary.

[0119] Depending on the respective synthesis route, the starting materials can optionally be reacted in the presence of an inert solvent.

[0120] Suitable inert solvents are, for example, heptane, hexane, petroleum ether, DMSO, benzene, toluene, xylene, trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, for example methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, for example diethyl ether, diisopropyl ether (preferably for substitution of the indole nitrogen), tetrahydrofuran (THF) or dioxane; glycol ethers, for example ethylene glycol monomethyl ether or ethylene glycol monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, for example acetone or butanone; amides, for example acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitriles, for example acetonitrile; esters, for example ethyl acetate; carboxylic acids or anhydrides, for example, acetic acid or acetic anhydride; nitro compounds, for example nitromethane or nitrobenzene, optionally also mixtures of the solvents with one another or with water.

[0121] The amount of solvent used is not critical; preferably 10 g to 500 g of solvent are added per g of compound of the invention to be reacted.

[0122] It may be advantageous to add acid binders, for example alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates or other alkali or alkaline earth metal salts of weak acids, preferably potassium, sodium or calcium salts, or organic bases, for example triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine component.

[0123] The compounds obtained according to the present invention can be separated from the corresponding solutions in which they are prepared (e.g. by centrifugation and washing) and can be stored in another composition after separation, or they can also be retained directly in the prepared solution. The compounds obtained according to the present invention can also be absorbed in the desired solvent for a specific application.

[0124] The reaction time depends on the reaction conditions selected. Generally speaking, the reaction time is 0.5 hours to 10 days, preferably 1 to 24 hours. When using a microwave oven, the reaction time can be reduced to 1 to 60 minutes.

[0125] Furthermore, the compounds according to the invention and also the starting materials for their preparation are prepared by known methods, as described in the literature (e.g. authoritative works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), for example under reaction conditions known and suitable for the reactions described. It is also possible to use variants known per se, which are not described in more detail here.

[0126] Conventional workup steps, such as addition of water to the reaction mixture and extraction, make it possible to obtain the compound after removal of the solvent. For further purification of the product, it may be advantageous to subsequently carry out a distillation or crystallization or a chromatographic purification.

[0127] The acids of the present invention can be converted into the relevant addition salts using a base, for example by reacting equal amounts of the acid and base in an inert solvent such as ethanol and including evaporation. Suitable bases for this reaction are in particular those which give physiologically acceptable salts. Thus, the acids of the present invention can be converted into the corresponding metal salts, in particular alkali or alkaline earth metal salts, or into the corresponding ammonium salts using a base (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate). Organic bases which give physiologically acceptable salts such as ethylamine are also suitable for this reaction.

[0128] On the other hand, alkali of the present invention can use acid to be converted into relevant acid addition salt, for example, by the alkali of equivalent and acid in inert solvents such as ethanol, react and subsequent evaporation.The acid that is applicable to this reaction is the acid that obtains physiologically acceptable salt especially.Therefore, may use mineral acid, for example sulfuric acid, nitric acid, hydrohalic acid for example hydrochloric acid or Hydrobromic acid, phosphoric acid for example orthophosphoric acid, sulfanilic acid, for example organic acid in addition, particularly aliphatic series, alicyclic series, arylaliphatic series, aromatic or heterocyclic series, monobasic or polycarboxylic acid, sulfonic acid or sulfuric acid, for example formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic 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, methanesulfonic acid or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxy sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, naphthalenesulfonic acid and naphthalenedisulfonic acid or lauryl sulfuric acid. The compounds of the invention can be isolated and / or purified using salts of physiologically unacceptable acids, such as picrates.

[0129] The compounds of the present invention were found to be well tolerated and to possess valuable pharmacological properties.

[0130] The present invention therefore also relates to the use of the compounds according to the invention for the preparation of medicaments for the treatment and / or prevention of diseases which are caused, contributed to and / or propagated by HSET.

[0131] The present invention therefore also relates in particular to medicaments comprising at least one compound according to the invention and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios) for the treatment and / or prevention of physiological and / or pathological states.

[0132] Particularly preferred are physiological and / or pathological conditions associated with HSET.

[0133] Physiological and / or pathological state means a medically relevant physiological and / or pathological state, such as, for example, a disease or illness as well as a medical disorder, condition, symptom or complication etc., in particular a disease.

[0134] The present invention also relates to medicaments comprising at least one compound according to the invention and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for the treatment and / or prevention of physiological and / or pathological states selected from hyperproliferative diseases and disorders.

[0135] 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, including mixtures thereof in all ratios, for the treatment and / or prophylaxis of physiological and / or pathological states selected from hyperproliferative and infectious diseases and disorders, wherein the hyperproliferative disease or disorder is cancer.

[0136] The present invention therefore particularly preferably relates to a medicament comprising at least one compound according to the invention and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios), wherein the cancer is selected from the group consisting of acute and chronic lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, bladder cancer, brain cancer, breast cancer, cervical hyperplasia, cervical cancer, choriocarcinoma cancer), chronic myeloid leukemia, chronic lymphocytic leukemia, colon cancer, endometrial cancer, esophageal cancer, essential thrombocythemia, genitourinary cancer, glioma, glioblastoma, hairy cell leukemia, head and neck cancer, Hodgkin's disease, Kaposi's sarcoma, lung cancer, lymphoma, malignant carcinoid, malignant hypercalcemia, malignant melanoma, malignant pancreatic insulinoma, medullary thyroid cancer, melanoma, multiple myeloma, mycosis fungoides, myeloid and lymphocytic leukemia, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, polycythemia vera, primary brain cancer, essential macroglobulinemia, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, skin cancer, small cell lung cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, testicular cancer, thyroid cancer, and Wilms' tumor.

[0137] The present invention further preferably relates to a medicament comprising at least one compound according to the invention and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios) for the treatment and / or prophylaxis of physiological and / or pathological states selected from hyperproliferative and infectious diseases and disorders, wherein the hyperproliferative diseases or disorders are selected from age-related macular degeneration, Crohn's disease, cirrhosis, conditions associated with chronic inflammation, proliferative diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, granulomatous diseases, organ or tissue transplant-related immune hyperproliferation, and immunoproliferative diseases or disorders selected from inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), vascular hyperproliferation secondary to retinal hypoxia and vasculitis.

[0138] The medicaments disclosed above are intended to include the corresponding use of the compounds according to the present invention for the preparation of medicaments for the treatment and / or prevention of the above physiological and / or pathological conditions.

[0139] Furthermore, the medicaments disclosed above are intended to encompass corresponding methods for the treatment and / or prevention of the above physiological and / or pathological conditions, wherein at least one compound according to the invention is administered to a patient in need of such treatment.

[0140] The compounds according to the invention preferably exhibit advantageous biological activities, which can be readily 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 induce an inhibitory effect, which is generally indicated by an IC in a suitable range, preferably in the micromolar range, and more preferably in the nanomolar range. 50 Value record.

[0141] The compounds according to the invention can be administered to humans or animals, in particular mammals, such as apes, dogs, cats, rats or mice, and can be used for therapeutic treatment of the human or animal body and for preventing and treating the diseases mentioned above. They can also be used as diagnostic agents or as reagents.

[0142] In addition, the compounds according to the present invention can be used to isolate and study the activity or expression of HSET. In addition, they are particularly suitable for use in diagnostic methods for diseases associated with disturbed HSET activity. Therefore, the present invention also relates to using the compounds according to the present invention for isolating and studying the activity or expression of HSET or as binding agents and inhibitors of HSET.

[0143] For diagnostic purposes, the compounds according to the invention may, for example, be radiolabeled. Examples of radiolabeled 3 H. 14 C. 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 also be labeled by enzymes, fluorophores and chromophores. Examples of enzymes are alkaline phosphatase, β-galactosidase and glucose oxidase, examples of fluorophores are fluorescein, examples of chromophores are luminol, and automated detection systems, such as for fluorescent staining, are described in, for example, US 4,125,828 and US 4,207,554.

[0144] The present invention also relates to pharmaceutical compositions containing the compounds of the invention and their use for the treatment and / or prevention of diseases and conditions in which partial or complete inactivation of HSET may be beneficial.

[0145] The compounds of the present invention can be used for the preparation of pharmaceutical preparations, in particular by non-chemical methods. In this case, they are combined with at least one solid, liquid and / or semi-liquid excipient or adjuvant, and optionally with one or more other active compounds, to make suitable dosage forms.

[0146] Therefore, the present invention also relates to pharmaceutical preparations comprising at least one compound of the present invention and / or its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including medicaments of mixtures thereof in all proportions). In particular, the present invention also relates to pharmaceutical preparations comprising other excipients and / or adjuvants, and also relates to pharmaceutical preparations comprising at least one other pharmaceutically active compound.

[0147] In particular, the present invention also relates to a process for the preparation of a pharmaceutical preparation, characterized in that one of the compounds according to the invention and / or one of its physiologically acceptable salts, derivatives, solvates and stereoisomers (including mixtures thereof in all ratios) is combined with solid, liquid and / or semi-liquid excipients or adjuvants, and optionally with further pharmaceutically active compounds, into a suitable dosage form.

[0148] The pharmaceutical formulations according to the present invention can be used as medicaments in humans or veterinary medicine. The patient or host can be of 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 in experimental research, where they provide models for treating human diseases.

[0149] Suitable carrier material is applicable to enteral (for example oral), parenteral or topical application and the organic or inorganic substance that does not react with novel compound, for example water, vegetable oil (for example sunflower oil or cod liver oil), benzyl alcohol, polyethylene glycol, gelatin, carbohydrate such as lactose or starch, magnesium stearate, talc, lanolin or vaseline.Due to the professional knowledge of those skilled in the art, he is familiar with which adjuvant is applicable to required pharmaceutical preparation.Except solvent, described solvent such as water, physiological saline solution or for example such as alcohol such as ethanol, propyl alcohol or glycerol, such as mixture, gelling agent, tablet auxiliary agent and other active ingredient carriers of sugar solution such as glucose or mannitol solution or described solvent, may also use such as lubricant, stabilizer and / or wetting agent, emulsifier, for affecting salt, antioxidant, dispersant, defoamer, buffer substance, flavoring and / or aromatic or flavoring agent, preservative, solubilizing agent or dyestuff of osmotic pressure.If desired, according to preparation of the present invention or medicine, can comprise one or more other reactive compounds, for example one or more vitamins.

[0150] If desired, the preparations or medicaments according to the invention can contain one or more additional active compounds and / or one or more action enhancers (auxiliaries).

[0151] The terms "pharmaceutical formulation" and "pharmaceutical composition" are used synonymously for the purposes of the present invention.

[0152] As used herein, "pharmaceutically tolerable" refers to drugs, precipitants, excipients, adjuvants, stabilizers, solvents and other agents that facilitate administration of the pharmaceutical formulations obtained therefrom to mammals without undesirable physiological side effects, such as nausea, dizziness, digestive problems, and the like.

[0153] In pharmaceutical preparations for parenteral administration, there are requirements for isotonicity of the preparation (low toxicity), normal hydration and tolerability and safety, for the auxiliary agents used and for the primary packaging. Surprisingly, the compounds according to the invention preferably have the advantage that direct use is possible and therefore no further purification steps for removing toxicologically unacceptable agents, such as, for example, high concentrations of organic solvents or other toxicologically unacceptable auxiliary agents, are necessary before using the compounds according to the invention in pharmaceutical preparations.

[0154] The present invention particularly preferably also 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 auxiliaries and / or further pharmaceutically active compounds.

[0155] The compounds according to the invention preferably enable the preparation of highly concentrated formulations without disadvantageous undesirable aggregation of the compounds according to the invention. Thus, ready-to-use solutions with a high active ingredient content can be prepared with the aid of the compounds according to the invention with aqueous solvents or in aqueous media.

[0156] It is also possible to lyophilize the compounds and / or their physiologically acceptable salts and solvates and use the resulting lyophilizates, for example, for the preparation of injection preparations.

[0157] Aqueous formulations can be prepared by dissolving or suspending the compound according to the invention in an aqueous solution and optionally adding adjuvants. To this end, a defined volume of a stock solution containing a defined concentration of the additional adjuvant is advantageously added to a solution or suspension of the compound according to the invention having a defined concentration, and the mixture is optionally diluted with water to a pre-calculated concentration. Alternatively, the adjuvant can be added in solid form. The required amount of stock solution and / or water in each case can then be added to the resulting aqueous solution or suspension. The compound according to the invention can also advantageously be dissolved or suspended directly in a solution containing all the additional adjuvants.

[0158] Advantageously, solutions or suspensions comprising the compounds according to the invention and having a pH of 4 to 10, preferably a pH of 5 to 9 and an osmotic pressure of 250 to 350 mosmol / kg can be prepared. Thus, the pharmaceutical preparations can be administered directly without substantial pain, intravenously, intra-arterially, intra-articularly, subcutaneously or transcutaneously. Furthermore, the preparations can also be added to infusion solutions, such as, for example, glucose solutions, isotonic saline solutions or Ringer's solutions, which can also contain additional active compounds, thereby also enabling the administration of relatively large amounts of active compounds.

[0159] The pharmaceutical preparations according to the invention may also comprise mixtures of a plurality of compounds according to the invention.

[0160] The formulations according to the invention are physiologically well tolerated, easy to prepare, can be accurately dispensed, and are preferably stable with respect to assays, decomposition products, and aggregates throughout storage and transport, as well as during multiple freezing and thawing processes. Preferably, they can be stored stably at refrigerator temperature (2-8° C.) and at room temperature (23-27° C.) and 60% relative humidity (RH) for a period of at least three months to two years.

[0161] For example, the compound according to the present invention can be stored in a stable manner by drying and, when necessary, converted into a ready-to-use pharmaceutical preparation by dissolving or suspending. Without being limited to these examples, possible drying methods are, for example, nitrogen drying, vacuum oven drying, freeze drying, washing with an organic solvent and subsequent air drying, liquid bed drying, fluidized bed drying, spray drying, roller drying, layer drying, air drying at room temperature and other methods.

[0162] The term "effective amount" means that amount of a drug or pharmaceutically active compound that elicits in a tissue, system, animal or human the biological or medicinal response that is sought or desired, for example, by a researcher or physician.

[0163] Additionally, the term "therapeutically effective amount" refers to an amount that improves the treatment, cure, prevention, or elimination of a disease, syndrome, disease state, condition, or disorder, or prevents side effects, or reduces the progression of a disease, condition, or disorder, as compared to a corresponding subject that has not received such amount. The term "therapeutically effective amount" also encompasses an amount effective to enhance normal physiological function.

[0164] When using the preparation or medicine according to the present invention, the compound according to the present invention and / or its physiologically acceptable salt and solvate are generally used similar to known commercially available preparations or preparations, preferably with a dosage of 0.1 to 500 mg / use unit, particularly 5 to 300 mg / use unit. The daily dose is preferably 0.001 to 250 mg / kg body weight, particularly 0.01 to 100 mg / kg body weight. The preparation can be administered once or multiple times a day, for example twice, three times or four times a day. However, the individual dosage of the patient depends on a large number of individual factors, for example, depending on the efficacy of the specific compound used, depending on age, weight, general health, sex, nutrition, depending on the time and method of administration, depending on the excretion rate, depending on the combination with other drugs and depending on the severity and duration of the specific disease.

[0165] The measure of the intake of pharmaceutically active compounds in an organism is its bioavailability. If the pharmaceutically active compound is delivered intravenously to an organism in the form of an injection solution, its absolute physiological availability, i.e., the ratio of the drug in the unchanged form that reaches the systemic blood, i.e., the main circulation, is 100%. In the case of oral administration of therapeutically active compounds, the active compound is generally in the solid form in the preparation, and therefore must first be dissolved so that it can overcome entry barriers, such as the gastrointestinal tract, oral mucosa, nasal mucosa or skin, particularly the stratum corneum, or can be absorbed by the body. Data on pharmacokinetics, i.e., data on bioavailability, can be obtained with a method similar to J.Shaffer et al., J.Pharm.Sciences, 88 (1999), 313-318.

[0166] Furthermore, a medicament of this type can be prepared by one of the methods generally known in the pharmaceutical art.

[0167] The drug may be suitable 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 particularly intraarticular) administration. Drugs of this type may be prepared by all methods known in the pharmaceutical art, for example by combining the active compound with an excipient or adjuvant.

[0168] Parenteral administration is preferably suitable for administering the medicament according to the invention. In the case of parenteral administration, intra-articular administration is particularly preferred.

[0169] The compounds according to the invention are also suitable for the preparation of medicaments to be administered parenterally with a slow, sustained and / or controlled release of the active compound. Therefore, they are also suitable for the preparation of delayed-release formulations, which are advantageous to the patient owing to the fact that they only need to be administered within relatively large time intervals.

[0170] Suitable drugs for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, antibacterial agents and solutes, by which the preparation is made isotonic with the blood or synovial fluid of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may contain a suspending medium and a thickening agent. The preparation can be delivered in single-dose or multi-dose containers, such as sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state so that only a sterile carrier liquid, such as water for injection purposes, needs to be added immediately before use. Injection solutions and suspensions prepared according to the preparation can be prepared from sterile powders, granules and tablets.

[0171] The compounds according to 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 a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

[0172] Compound according to the present invention can also be coupled to the soluble polymer as target drug excipient.Such polymer can encompass polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamidophenol, polyhydroxyethyl aspartamide or polyethylene oxide polylysine (substituted by palmitoyl / root).Compound according to the present invention can also be coupled to the biodegradable polymer classification that is applicable to realizing sustained-release drug, such as polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoester (polyorthoester), polyacetal, polydihydroxypyran, polycyanoacrylate, polylactic acid-to-glycolic acid, polymer, such as the conjugate of dextran and methacrylate, polyphosphate, various polysaccharides and polyamines and poly-ε-caprolactone, albumin, chitosan, collagen or modified gelatin and hydrogel crosslinked or the amphiphilic block copolymer.

[0173] Suitable for enteral administration (oral or rectal) are in particular tablets, dragees, capsules, syrups, juices, drops or suppositories, and suitable for topical administration are ointments, creams, pastes, emulsions, gels, sprays, foams, aerosols, solutions (for example in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propylene glycol or mixtures thereof with one another and / or with water) or powders. Also particularly suitable for topical use are liposomal preparations.

[0174] In the case of a formulation providing an ointment, the active compound may be employed with a paraffinic or a water-miscible cream base. Alternatively, the active compound may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

[0175] Drugs suitable for transdermal administration may be delivered as a separate patch intended to remain in close contact with the epidermis of the recipient. Thus, for example, the active compound may be supplied from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[0176] It goes without saying that, in addition to the components specifically mentioned above, the medicament according to the invention may also contain other agents which are customary in the art with regard to a particular type of pharmaceutical preparation.

[0177] The present invention also relates to a set (kit) consisting of the following individual packages:

[0178] a) an effective amount of a compound according to the invention and / or physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and

[0179] b) an effective amount of an additional pharmaceutically active compound.

[0180] The set comprises suitable containers, such as boxes or cartons, individual bottles, bags or ampoules. The set may, for example, comprise separate ampoules, each containing an effective amount of a compound of the invention and / or pharmaceutically acceptable derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of another pharmaceutically active compound in dissolved or lyophilized form.

[0181] Furthermore, the medicaments according to the present invention may also be used to provide additive or synergistic effects on certain known therapies and / or may be used to restore the efficacy of certain existing therapies.

[0182] In addition to the compounds according to the invention, the pharmaceutical preparations according to the invention may also contain further pharmaceutically active compounds, for example pharmaceutically active compounds for 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 further pharmaceutically active compounds known to those skilled in the art in addition to the compounds according to the invention in their treatment.

[0183] In a main embodiment, a method for enhancing the immune response of a host in need is provided. The immune response can be enhanced by reducing T cell tolerance, including by increasing the release of IFN-γ of the host, by reducing the production or activation of regulatory T cells of the host, or by increasing the production of antigen-specific memory T cells of the host. In one embodiment, the method includes combining or alternating administration of a compound of the present invention with an antibody to the host. In a specific sub-embodiment, the antibody is a therapeutic antibody. In a specific embodiment, a method for enhancing the efficacy of passive antibody therapy is provided, including combining or alternating administration of a compound of the present invention with one or more passive antibodies. This method can enhance the efficacy of antibody therapy for treating abnormal cell proliferative disorders such as cancer, or can enhance the efficacy of therapy in treating or preventing infectious diseases. The compound of the present invention can be combined or alternating administration with antibodies such as rituximab, Herceptin or Erbitux.

[0184] In another principal embodiment, there is provided a method of treating or preventing abnormal cell proliferation comprising administering to a host in need thereof a compound of the present invention in the substantial absence of another anticancer agent.

[0185] In another major embodiment, a method for treating or preventing abnormal cell proliferation in a host in need thereof is provided, comprising administering to the host a first compound of the present invention substantially in combination with a first anticancer agent, and subsequently administering to the host a second compound of the present invention that is a receptor antagonist. In a sub-embodiment, the second antagonist is administered substantially in the absence of another anticancer agent. In another major embodiment, a method for treating or preventing abnormal cell proliferation in a host in need thereof is provided, comprising administering to the host a compound of the present invention substantially in combination with a first anticancer agent, and subsequently administering to the host a second anticancer agent in the absence of an antagonist.

[0186] Thus, the cancer treatments disclosed herein can be performed as a therapy with the compounds of the present invention or in combination with surgery, radiation, or chemotherapy. This type of chemotherapy can include the use of one or more active compounds from the following classes of anti-tumor active compounds:

[0187] (i) Antiproliferative / antitumor / DNA damaging active compounds and combinations thereof as used in medical oncology, such as alkylating active compounds (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (e.g., antifolates, such as fluoropyrimidines, such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea and gemcitabine); antitumor antibiotics (e.g., anthracyclines, such as doxorubicin, bleomycin, , doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin D and mithramycin); antimitotic active compounds (e.g. vinca alkaloids, such as vincristine, vinblastine, vindesine and vinorelbine, and taxanes, such as paclitaxel 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);

[0188] (ii) active compounds that inhibit cell growth, such as antiestrogens (e.g. tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptor modulators (e.g. fulvestrant), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprorelin and buserelin), progestins (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, vorazole and exemestane) and 5α-reductase inhibitors, such as finasteride;

[0189] (iii) active compounds that inhibit cancer invasion, including, for example, metalloproteinase inhibitors, such as marimastat, and inhibitors of urokinase-type plasminogen activator receptor function;

[0190] (iv) inhibitors of growth factor function, such as growth factor antibodies, growth factor receptor antibodies such as the anti-erbB2 antibody trastuzumab [Herceptin TM] and the anti-erbBl antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine / threonine kinase inhibitors such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (C1 1033), inhibitors of the platelet-derived growth factor family and inhibitors of the hepatocyte growth factor family, for example);

[0191] (v) anti-angiogenic active compounds, for example, bevacizumab, angiostatin, endostatin, linomide, batimastat, captopril, chondroitin, genistein, interleukin 12, lavender, medroxyprogesterone acetate, recombinant human platelet factor 4, teicogalan, thrombospondin, TNP-470, anti-VEGF monoclonal antibodies, soluble VEGF receptor chimeric proteins, anti-VEGF receptor antibodies, anti-PDGF receptors, integrin inhibitors, tyrosine kinase inhibitors, serine / threonine kinase inhibitors, antisense oligonucleotides, antisense oligodeoxynucleotides, siRNA, anti-VEGF aptamers, pigment epithelium-derived factor and compounds disclosed in International Patent Applications WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354;

[0192] (vi) Vascular disrupting agents, such as Compretin A4 and the compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;

[0193] (vii) antisense therapies, such as those directed to the targets mentioned above, e.g., ISIS2503, an anti-Ras antisense;

[0194] (viii) gene therapy approaches, including, for example, approaches for replacing abnormal modified genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT approaches (gene-directed enzyme prodrug therapy), such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and approaches to increasing a patient's tolerance to chemotherapy or radiation therapy, such as multidrug resistance therapy; and

[0195] (ix) immunotherapy methods, including, for example, ex vivo and in vivo methods for increasing the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte macrophage colony-stimulating factor, methods for reducing T-cell anergy, methods using transfected immune cells, such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cells, and methods using anti-idiotypic antibodies;

[0196] (x) Chemotherapeutic agents, including, for example, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, amifostine, anastrozole, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, bleomycin, bortezomib, busulfan, calutrone, camptothecin, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, phenylbutyric acid Nitrogen mustard, cinacalcet, cisplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin, drostanolone, epirubicin, epoetin alfa, estramustine, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, and gemcitabine

[0197] Drugs from Table 1 may preferably, but not exclusively, be combined with the compounds of the present invention.

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] Even without further embodiments, it is assumed that a person skilled in the art will be able to use the above description in the broadest possible scope.The preferred embodiments should therefore be regarded only as a descriptive disclosure which is absolutely not limiting in any way.

[0207] The following examples are therefore intended to illustrate the invention without limiting it. Unless otherwise indicated, percentage data represent percentages by weight. All temperatures are expressed in degrees Celsius. "Conventional workup": if necessary, water is added, if necessary, the pH is adjusted to a value between 2 and 10, depending on the composition of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate or magnesium sulfate, filtered and evaporated, and the product is purified by chromatography on silica gel and / or by crystallization.

[0208] 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).

[0209] List of abbreviations

[0210] AUC Area under the plasma drug concentration-time curve

[0211] C max Maximum plasma concentration

[0212] CL clearance

[0213] CV coefficient of variation

[0214] CYP cytochrome P450

[0215] DMSO dimethyl sulfoxide

[0216] F Bioavailability

[0217] f a Absorption fraction

[0218] iv intravenous

[0219] LC-MS / MS liquid chromatography tandem mass spectrometry

[0220] LLOQ Lower limit of quantification

[0221] NC Not calculated

[0222] ND Not determined

[0223] PEG polyethylene glycol

[0224] Pgp permeability glycoprotein

[0225] PK pharmacokinetics

[0226] Poorally (orally)

[0227] rt room temperature

[0228] t 1 / 2 half life

[0229] t max Time to reach maximum drug plasma concentration

[0230] UPLC ultra-high performance liquid chromatography

[0231] V ss Volume of distribution (at steady state)

[0232] v / vVolume ratio

[0233] Preparation and analysis methods of the compounds of the present invention

[0234] The present invention relates in particular to the compounds of the following examples and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios.

[0235] All solvents used were commercially available and used without further purification. Reactions were typically run under an inert atmosphere of nitrogen or argon using anhydrous solvents. Flash column chromatography was performed using silica gel 60 (0.035-0.070 mm particle size). Flash column chromatography can also be performed using a Biotage purification system using a SNAP KP-Sil column or a SNAP Ultra C18 column in reverse phase mode. Microwave-assisted reactions were performed using a Biotage Initiator microwave system.

[0236] 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 an internal reference. Chemical shifts (δ) are reported in ppm relative to tetramethylsilane (TMS) and are referenced to the internal deuterated solvent. 1 H NMR data are reported as follows: chemical shift (multiplicity, coupling constant, and number of hydrogens). Multiplicity abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), sext (sextet), hept (septet), m (multiplet), br (broad).

[0237] The HPLC / MS spectrum of product is recorded on the Agilent1100HPLC system (1100 high pressure gradient pumps, 1100 diode array detectors, wavelength: 220nm) that is connected with Agilent1100 mass spectrometer detectors (positive ion mode).On the SHIMADZU LC-MS machine being made up of UFLC 20-AD system and LCMS2020MS detector, carry out LC-MS analysis.

[0238] Details of the conditions applied for the HPLC / MS spectra recorded on a Shimadzu LCMS-2020 system or on an Agilent 1100 HPLC system were:

[0239] (A): Column: HALO C18, 3.0*30 mm, 2.0 μm; Mobile phase A: Water with 0.05% TFA, Mobile phase B: ACN with 0.05% TFA; Gradient: 5% B to 100% B until 0.70 min, maintained until 1.10 min, 100% B to 5% B until 1.12 min, stopped after 1.20; Flow rate: 1.5 mL / min.

[0240] (B): Column: Titank C18 2.1*30 mm, 1.8 μm; Mobile phase A: Water with 0.04% NH4OH, Mobile phase B: ACN; Gradient: 10% B to 95% B in 1.4 min, maintained until 1.90 min, 95% B to 10% B until 1.92 min, stopped after 2.00; Flow rate: 0.8 mL / min.

[0241] (C): Column: HALO C18, 3.0*30 mm, 2.0 μm; Mobile phase A: Water with 0.05% TFA, Mobile phase B: ACN with 0.05% TFA; Gradient: 5% B to 100% B until 1.20 min, maintained until 1.80 min, 100% B to 5% B until 1.82 min, stopped after 2.00; Flow rate: 1.5 mL / min.

[0242] (D): Column: HALO C18, 3.0*30 mm, 2.0 μm; Mobile phase A: Water with 0.05% TFA, Mobile phase B: ACN with 0.05% TFA; Gradient: 5% B to 50% B until 1.80 min, 50% B to 95% B until 2.50 min, maintain until 2.80 min, 95% B to 5% B until 2.81 min, stop after 3.00; Flow rate: 1.5 mL / min.

[0243] (E): Column: HALO C18, 3.0*30 mm, 2.0 μm; Mobile phase A: Water with 0.1% FA, Mobile phase B: ACN with 0.1% FA; Gradient: 10% B to 95% B until 1.20 min, maintained until 1.80 min, 95% B to 10% B until 1.82 min, stopped after 2.00; Flow rate: 1.5 mL / min.

[0244] (F): Column: Kinetex EVO C18, 4.6x50 mm, 5.0 μm; Mobile phase A: Water with 0.05% FA, Mobile phase B: ACN with 0.04% FA and 1% water; Gradient: 1% B to 99% B until 0.8 min, 99% B to 1% B until 1.1 min, stop after 1.50; Flow rate: 3.3 mL / min.

[0245] (G): Column: Kinetex EVO C18, 3.0x50 mm, 2.6 μm; Mobile phase A: Water with 5 mM NH4HCO3, Mobile phase B: ACN; Gradient: 10% B to 95% B in 2.0 min, maintained until 2.7 min, 95% B to 10% B until 2.75 min, stopped after 3.0; Flow rate: 1.2 mL / min; Wavelength: 254 nm.

[0246] (H): Column: Chromolith HR C18, 4.6x50 mm, 5.0 μm; Mobile phase A: Water with 0.1% TFA, Mobile phase B: ACN with 0.1% TFA; Gradient: 1% B to 99% B until 2.0 min, hold until 2.5 min, 99% B to 1% B until 2.51 min, stop after 2.95; Flow rate: 3.3 mL / min.

[0247] (I): Column: Shim-pack velox, 3.0*30 mm, 2.7 μm; Mobile phase A: Water with 0.1% FA, Mobile phase B: ACN with 0.1% FA; Gradient: 5% B to 100% B until 1.50 min, maintained until 1.80 min, 100% B to 5% B until 1.81 min, stopped after 2.00; Flow rate: 1.5 mL / min.

[0248] (J): Column: HALO C18, 3.0*30 mm, 2.0 μm; Mobile phase A: Water with 0.05% TFA, Mobile phase B: ACN with 0.05% TFA; Gradient: 5% B to 95% B until 2.50 min, maintained until 2.80 min, 95% B to 5% B until 2.81 min, stopped after 3.00; Flow rate: 1.5 mL / min.

[0249] (K): Column: HALO C18, 3.0*30 mm, 2.0 μm; Mobile phase A: Water with 0.1% FA, Mobile phase B: ACN with 0.1% FA; Gradient: 5% B to 95% B until 2.50 min, maintain until 2.80 min, 95% B to 5% B until 2.81 min, stop after 3.00; Flow rate: 1.5 mL / min.

[0250] (L): Column: HALO C18, 3.0*30 mm, 2.0 μm; Mobile phase A: Water with 0.1% FA, Mobile phase B: ACN with 0.1% FA; Gradient: 5% B to 100% B until 1.50 min, maintained until 1.80 min, 100% B to 5% B until 1.81 min, stopped after 2.00; Flow rate: 1.5 mL / min.

[0251] (M): Column: Chromolith HR C18RP-18e, 4.6x50 mm; Mobile phase A: Water with 0.05% FA, Mobile phase B: ACN with 0.04% FA; Gradient: 0% B to 100% B until 2.0 min, hold until 2.5 min, 100% B to 0% B until 2.51 min, stop after 2.95; Flow rate: 3.3 mL / min.

[0252] (N): Column: Titank C18 2.1*30 mm, 1.8 μm; Mobile phase A: Water with 0.04% NH4OH, Mobile phase B: ACN; Gradient: 10% B to 95% B in 2.0 min, maintained until 2.80 min, 95% B to 10% B until 2.81 min, stopped after 3.00; Flow rate: 0.8 mL / min.

[0253] (O): Column: HALO C18, 3.0*30 mm, 2.0 μm; Mobile phase A: Water with 0.1% FA, Mobile phase B: ACN with 0.1% FA; Gradient: 5% B to 95% B until 2.10 min, maintain until 2.75 min, 95% B to 5% B until 2.81 min, stop after 3.00; Flow rate: 1.5 mL / min.

[0254] Details of the conditions used for HPLC / MS spectra on an Agilent 1200 series HPLC and diode array detector coupled to a 6210 time-of-flight mass spectrometer with a dual multimode APCI / ESI source.

[0255] (P): Analytical separation was performed at 40°C on a Merck Chromolith flash column (RP-18e, 25x2 mm) using a flow rate of 1.5 mL / min in a 2 min gradient elution 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) in 1.25 min, 100:0 (A / B) for 0.5 min, and then reversed back to 5:95 (A / B) in 0.05 min, with a final 5:95 (A / B) for 0.2 min.

[0256] (Q): Analytical separation was performed at 30°C on a Merck Chromolith Flash column (RP-18e, 25x2 mm) using a flow rate of 0.75 mL / min in a 4 min gradient elution 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) in 2.5 min, 100:0 (A / B) for 1 min, and then reversed back to 5:95 (A / B) in 0.1 min, with a final 5:95 (A / B) for 0.4 min.

[0257] Details of the conditions applied for HPLC / MS spectra on a Waters Acquity UPLC and a diode array detector coupled to a Waters G2 QToF mass spectrometer equipped with a multimode ESI / APCI source.

[0258] (R): Analytical separation was performed at 30°C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a 2 min gradient elution at a flow rate of 0.5 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: 10:90 (A / B) to 90:10 (A / B) in 1.25 min, 90:10 (A / B) for 0.5 min, and then reversed back to 10:90 (A / B) in 0.15 min, and finally 10:90 (A / B) for 0.1 min.

[0259] (S): Analytical separation was performed at 30°C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a 4 min gradient elution at a flow rate of 0.3 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: 10:90 (A / B) to 90:10 (A / B) in 3 min, 90:10 (A / B) for 0.5 min, and then reversed back to 10:90 (A / B) in 0.3 min, with a final 10:90 (A / B) for 0.2 min.

[0260] (T): Analytical separation was performed at 30°C on an Agilent Poroshell C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a 2 min gradient elution at a flow rate of 0.5 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: 10:90 (A / B) to 90:10 (A / B) in 1.25 min, 90:10 (A / B) for 0.5 min, and then reversed back to 10:90 (A / B) in 0.15 min, with a final 10:90 (A / B) for 0.1 min.

[0261] (U): Analytical separation was performed at 30°C on an Agilent Poroshell C18 column (30x2.1 mm, 2.6 u, 100 A) using a flow rate of 0.3 mL / min in a 4 min gradient elution 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: 10:90 (A / B) to 90:10 (A / B) in 3 min, 90:10 (A / B) for 0.5 min, and then reversed back to 10:90 (A / B) in 0.3 min, with a final 10:90 (A / B) for 0.2 min.

[0262] Details of the conditions applied for HPLC / MS spectra on an Agilent 1260 Infinity II Series UPLC and a diode array detector coupled to a 6530 quadrupole time-of-flight mass spectrometer with an Agilent Jet Stream ESI source.

[0263] (V): Analytical separation was performed at 40°C on an Agilent Poroshell C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a flow rate of 0.6 mL / min in a 2 min gradient elution with detection at 254, 280, and 214 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient elution was as follows: 10:90 (A / B) to 90:10 (A / B) in 1.25 min, 90:10 (A / B) for 0.5 min, and then reversed back to 10:90 (A / B) in 0.15 min, with a final 10:90 (A / B) for 0.1 min.

[0264] (X): Analytical separation was performed at 40°C on an Agilent Poroshell C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a flow rate of 0.4 mL / min in a 4 min gradient elution with detection at 254, 280, and 214 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient elution was as follows: 10:90 (A / B) to 90:10 (A / B) in 2.5 min, 90:10 (A / B) for 1 min, and then reversed back to 10:90 (A / B) in 0.3 min, with a final 10:90 (A / B) for 0.2 min.

[0265] (Y): Analytical separation was performed at 40°C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a flow rate of 0.6 mL / min in a 2 min gradient elution with detection at 254, 280, and 214 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient elution was as follows: 10:90 (A / B) to 90:10 (A / B) in 1.25 min, 90:10 (A / B) for 0.5 min, and then reversed back to 10:90 (A / B) in 0.15 min, and finally 10:90 (A / B) for 0.1 min.

[0266] (Z): Analytical separation was performed at 40°C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6 u, 100 A) using a flow rate of 0.4 mL / min in a 4 min gradient elution with detection at 254, 280, and 214 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient elution was as follows: 10:90 (A / B) to 90:10 (A / B) in 2.5 min, 90:10 (A / B) for 1 min, and then reversed back to 10:90 (A / B) in 0.3 min, with a final 10:90 (A / B) for 0.2 min.

[0267] Example 1: Ethyl 4-methyl-2-(3-(3-methylbenzamido)propionamido)thiazole-5-carboxylate

[0268]

[0269] 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 room temperature under a nitrogen atmosphere were added EDC (4.05 g, 21.14 mmol) and ethyl 2-amino-4-methylthiazole-5-carboxylate (2.165 g, 11.63 mmol) in sequence. 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, saturated aqueous bicarbonate solution 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):1.32min.

[0270] 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)propionylamino]-4-methyl-thiazole-5-carboxylate (1.28 g, 3.5811 mmol) in EtOH (35.81 mL). The reaction mixture was stirred at room temperature for 2 h before concentration in vacuo. Purification by ion exchange SCX-II column chromatography, washing with MeOH and then eluting with 2M NH3, gave ethyl 2-(3-aminopropionylamino)-4-methyl-thiazole-5-carboxylate (867.4 mg, 94%, 3.371 mmol) as a light yellow solid. HPLC / MS m / z: 258.1 [M+H] + , Rt(S):1.52min.

[0271] Example 1.3.: HATU (110 mg, 0.466 mmol) was added to 3-methylbenzoic acid (38.1 mg, 0.280 mmol), 2-(3-aminopropionylamino)-4-methyl-thiazole-5-carboxylic acid ethyl ester (80 mg, 0.311 mmol) and DIPEA (163 μl, 0.933 mmol) in DMF (3109 μl), and the reaction mixture was stirred at room temperature overnight. The crude product was dissolved in EtOAc and washed with 1N HCl, saturated aqueous bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo, and purified by reverse column chromatography (eluent: 0-80% methanol / water + 0.1% formic acid, respectively) to obtain 83 mg (71%, 0.221 mmol) of 4-methyl-2-(3-(3-methylbenzamido)propionylamino)thiazole-5-carboxylic acid ethyl ester as a colorless solid. HPLC / MS m / z:376.2[M+H] + , Rt(P):1.50min. 1 H NMR (500MHz, DMSO-d6) δ12.51 (s, 1H), 8.55 (t, J=5.6Hz, 1H), 7.64 (h, J=0.9Hz, 1H), 7.60 (ddd, J=5.8, 3.4, 1.8Hz, 1H), 7.34-7 .31 (m, 2H), 4.23 (q, J=7.1Hz, 2H), 3.60-3.51 (m, 2H), 2.75 (t, J=6.9Hz, 2H), 2.53 (s, 3H), 2.34 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0272] The following examples were prepared similarly:

[0273] Example 2: Ethyl 4-methyl-2-(3-(3-(pyrrolidin-1-yl)benzamido)propionamido)thiazole-5-carboxylate

[0274]

[0275] 14 mg (26%, 0.0325 mmol) yellow solid. HPLC / MS m / z: 431.2 [M+H] + , Rt(S):3.05min. 1 HNMR (500MHz, DMSO-d6) δ12.46 (s, 1H), 8.45 (t, J=5.6Hz, 1H), 7.20 (t, J=7.9Hz, 1H), 7.01 (d, J=7.9Hz, 1H), 6.95-6.91 (m, 1H), 6.64 (dd, J=8.2, 1.9H z, 1H), 4.23 (q, J=7.1Hz, 2H), 3.54 (q, J=6.7Hz, 2H), 3.26-3.18 (m, 4H), 2. 74 (t, J=6.9Hz, 2H), 2.53 (s, 3H), 2.00-1.90 (m, 4H), 1.27 (t, J=7.1Hz, 3H).

[0276] Example 3: Ethyl 2-(3-(3-(1H-pyrazol-1-yl)benzamido)propionamido)-4-methylthiazole-5-carboxylate

[0277]

[0278] 27 mg (51%, 0.0632 mmol) colorless solid. HPLC / MS m / z: 428.1 [M+H] + , Rt(S):2.70min. 1 HNMR (500MHz, DMSO-d6) δ12.53 (s, 1H), 8.78 (t, J=5.5Hz, 1H), 8.56-8.52 (m, 1H), 8.26 (t, J=1.8Hz, 1H), 7.98 (ddd, J=8.1, 2.2, 0.9Hz, 1H), 7.78 (d, J=1.4Hz, 1H), 7.74 (dt, J =7.7, 1.1Hz, 1H), 7.58 (t, J = 7.9Hz, 1H), 6.57 (dd, J = 2.5, 1.8Hz, 1H), 4.23 (q, J = 7.1Hz , 2H), 3.60 (q, J=6.7Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0279] Example 4: Ethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0280]

[0281] 47 mg (68%, 0.1060 mmol) off-white solid. HPLC / MS m / z: 444.1 [M+H] + , Rt(S):2.77min. 1 H NMR (500MHz, DMSO-d6) δ12.53 (s, 1H), 8.78 (t, J=5.5Hz, 1H), 8.56-8.52 (m, 1H), 8.26 ( t, J=1.8Hz, 1H), 7.98 (ddd, J=8.1, 2.2, 0.9Hz, 1H), 7.78 (d, J=1.4Hz, 1H), 7.74 (dt, J= 7.7, 1.1Hz, 1H), 7.58 (t, J=7.9Hz, 1H), 6.57 (dd, J=2.5, 1.8Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.60 (q, J=6.7Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0282] Example 5: 4-methyl-2-(3-(5,6,7,8-tetrahydronaphthalene-2-carboxamido)propionamido)thiazole-5-carboxylic acid ethyl ester

[0283]

[0284] 24 mg (37%, 0.0578 mmol) colorless solid. HPLC / MS m / z: 416.2 [M+H] + , Rt(S):3.14min. 1 HNMR (500MHz, DMSO-d6) δ12.50 (s, 1H), 8.46 (t, J=5.5Hz, 1H), 7.52 (d, J=7.2Hz, 2H), 7.10 (d, J=8.2H z, 1H), 4.23 (q, J=7.1Hz, 2H), 3.54 (q, J=6.8Hz, 2H), 2.74 (t, J=6.8Hz, 6H), 2.53 (s, 3H), 1.73 (quint J=3.4Hz, 4H), 1.27 (t, J=7.1Hz, 3H).

[0285] Example 6: Ethyl 4-methyl-2-(3-(3-(oxazol-5-yl)benzamido)propionamido)thiazole-5-carboxylate

[0286]

[0287] 40 mg (60%, 0.0934 mmol) yellow solid. HPLC / MS m / z: 429.1 [M+H] + , Rt(S):2.67min. 1 HNMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.77 (t, J=5.5Hz, 1H), 8.50 (s, 1H), 8.16 (t, J=1.6Hz, 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=7.7Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.59 (q , J=6.7Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0288] Example 7: Ethyl 4-methyl-2-(3-(3-morpholinobenzamido)propionamido)thiazole-5-carboxylate

[0289]

[0290] 22 mg (32%, 0.0493 mmol) off-white solid. HPLC / MS m / z: 447.2 [M+H] + , Rt(S):2.67min. 1 H NMR (500MHz, DMSO-d6) δ12.52 (s, 1H), 8.54 (t, J=5.6Hz, 1H), 7.35-7.32 (m, 1H), 7.29 (t, J=7.8Hz, 1H), 7.25 (d, J=7.7Hz, 1H), 7.08 (ddd, J=8.1, 2.5, 1. 1Hz, 1H), 4.24 (q, J=7.1Hz, 2H), 3.80-3.69 (m, 4H), 3.55 (q, J=6.7Hz, 2H), 3 .17-3.07 (m, 4H), 2.75 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.28 (t, J=7.1Hz, 3H).

[0291] Example 8: (S)-2-(2-hydroxy-3-(3-methylbenzylamino)propionylamino)-4-methylthiazole-5-carboxylic acid ethyl ester

[0292]

[0293] (S)-3-((tert-Butoxycarbonyl)amino)-2-hydroxypropanoic acid was used to obtain 16 mg (12%, 0.041 mmol) of (S)-ethyl 2-(2-hydroxy-3-(3-methylbenzamido)propionamido)-4-methylthiazole-5-carboxylate as a colorless solid. HPLC / MS m / z: 392.1 [M+H] + , Rt(S):2.69min. 1 H NMR (500MHz, DMSO-d6) δ12.13 (s, 1H), 8.46 (t, J=5.8Hz, 1H), 7.62 (quint, J=1.0Hz, 1H), 7.61-7.57 (m, 1H), 7.33 (dd, J=5.0 , 0.9Hz, 2H), 5.96 (s, 1H), 4.40 (s, 1H), 4.24 (q, J=7.1Hz, 2H), 3.56 (s, 2H), 2.55 (s, 3H), 2.34 (s, 3H), 1.28 (t, J=7.1Hz, 3H).

[0294] Example 9: 2-[3-[(3-methoxycarbonylbenzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0295]

[0296] 3-Carbomethoxybenzoic acid (35mg, 0.19mmol), ethyl 2-(3-aminopropionyl-amino)-4-methyl-thiazole-5-carboxylate (50mg, 0.19mmol) and DIPEA (103uL, 0.58mmol) were dissolved in DMF (1.94mL). HATU (215.17mg, 0.9100mmol) was added and the reaction mixture was stirred at room temperature over the weekend. The reaction mixture was then diluted with EtOAc (40mL) and washed with water (40mL). The aqueous layer was re-extracted with EtOAc (40mL). The organic layers were combined and washed with saturated sodium bicarbonate aqueous solution (50mL) and brine (50mL). The organic layer was dried (MgSO ), filtered and concentrated in vacuo. Reverse phase column chromatography was used, and the crude product was purified by 12g C18Biotage ULTRA column. The column was eluted with 30-100% MeOH in water (both + 0.1% formic acid modifier) ​​to give 16 mg (20%, 0.04 mmol) of ethyl 2-[3-[(3-methoxycarbonylbenzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylate as a colorless fluffy solid. HPLC / MS m / z: 420.07 [M+H] + , Rt(R):1.29min. 1 H NMR (500MHz, DMSO-d6) δ12.53 (s, 1H), 8.85 (t, J=5.5Hz, 1H), 8.42 (t, J=1.8Hz, 1H), 8.09 (dd, J=7.8, 1.8Hz, 2H), 7.62 (t, J=7. 8Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.88 (s, 3H), 3.59 (q, J=6.6Hz, 2H), 2.77 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0297] The following examples were prepared in a similar manner:

[0298] Example 10: 2-[3-[(3-Fluoro-5-methoxycarbonyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0299]

[0300] 43 mg (51%) colorless fluffy solid. HPLC / MS m / z: 438.11 [M+H] + , Rt(R):1.35min. 1HNMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.93 (t, J=5.5Hz, 1H), 8.28 (t, J=1.5Hz, 1H), 7.92 (ddd, J=9.4, 2.6, 1.5Hz, 1H), 7.85 (ddd, J=8 .8, 2.6, 1.4Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.89 (s, 3H), 3.66-3.47 (m, 2H), 2.77 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0301] Example 11: 2-[3-[(2-Fluoro-3-methoxycarbonyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0302]

[0303] 26 mg (31%) colorless fluffy solid. HPLC / MS m / z: 438.11 [M+H] + , Rt(R):1.23min. 1 HNMR (500MHz, DMSO-d6) δ12.52 (s, 1H), 8.62 (t, J=5.4Hz, 1H), 7.95 (ddd, J=7.7, 6.8, 1.9Hz, 1H), 7.78 (ddd, J=8.0, 6.3, 1.9Hz, 1H), 7.3 8 (t, J=7.7Hz, 1H), 4.24 (q, J=7.1Hz, 2H), 3.86 (s, 3H), 3.57 (q, J=6.5Hz, 2H), 2.75 (t, J=6.8Hz, 2H), 2.54 (s, 3H), 1.28 (t, J=7.1Hz, 3H).

[0304] Example 12: 2-[3-[(2-chloro-5-methoxycarbonyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0305]

[0306] 41 mg (46%) fine colorless powder. HPLC / MS m / z: 454.08 [M+H] + , Rt(R):1.27min. 1H NMR (500MHz, DMSO-d6) δ12.53 (s, 1H), 8.72 (t, J=5.6Hz, 1H), 7.96 (dd, J=8.4, 2.2Hz, 1H), 7.91 (d, J=2.1Hz, 1H), 7.64 (d, J=8. 4Hz, 1H), 4.24 (q, J=7.1Hz, 2H), 3.86 (s, 3H), 3.56 (q, J=6.4Hz, 2H), 2.77 (t, J=6.7Hz, 2H), 2.54 (s, 3H), 1.28 (t, J=7.1Hz, 3H).

[0307] Example 13: 2-[3-[(3-chloro-5-methoxycarbonyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0308]

[0309] 37 mg (42%) colorless granular solid. HPLC / MS m / z: 454.08 [M+H] + , Rt(R):1.41min. 1 HNMR (500MHz, DMSO-d6) δ12.53 (s, 1H), 8.95 (t, J=5.5Hz, 1H), 8.35 (t, J=1.5Hz, 1H), 8.14 (dd, J=2.1, 1.6Hz, 1H), 8.06 (dd, J=2.1 , 1.5Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.90 (s, 3H), 3.59 (q, J=6.5Hz, 2H), 2.77 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0310] Example 14: 2-[3-[(3-methoxycarbonyl-4-methyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0311]

[0312] 56 mg (66%) colorless solid. HPLC / MS m / z: 434.14 [M+H] + , Rt(R):1.33min. 1HNMR (500MHz, DMSO-d6) δ12.52 (s, 1H), 8.73 (t, J = 5.5Hz, 1H), 8.28 (d, J = 2.0Hz, 1H), 7.92 (dd, J = 7.9, 2.0Hz, 1H), 7.42 (d, J = 8.0Hz, 1 H), 4.23 (q, J=7.1Hz, 2H), 3.85 (s, 3H), 3.57 (q, J=6.7Hz, 2H), 2.76 (t, J=6.8Hz, 2H), 2.55 (s, 3H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0313] Example 15: 2-[3-[(3-methoxycarbonyl-5-methyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0314]

[0315] 56 mg (67%) colorless solid. HPLC / MS m / z: 434.14 [M+H] + , Rt(R):1.35min. 1 HNMR (500MHz, DMSO-d6) δ12.53 (s, 1H), 8.78 (t, J=5.5Hz, 1H), 8.30-8.10 (m, 1H), 7.91 (dd, J=1.6, 0.8Hz, 2H), 4.24 (q, J =7.1Hz, 2H), 3.87 (s, 3H), 3.57 (q, J = 6.5Hz, 2H), 2.76 (t, J = 6.8Hz, 2H), 2.54 (s, 3H), 2.41 (s, 3H), 1.27 (t, J = 7.1Hz, 3H).

[0316] Example 16: 2-[3-[(3-methoxy-5-methoxycarbonyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0317]

[0318] 35 mg (40%) colorless solid. HPLC / MS m / z: 450.13 [M+H] + , Rt(R):1.33min. 1HNMR (500MHz, DMSO-d6) δ12.51 (s, 1H), 8.81 (t, J = 5.5Hz, 1H), 8.02 (t, J = 1.4Hz, 1H), 7.64 (dd, J = 2.6, 1.5Hz, 1H), 7.57 (dd, J = 2.6, 1.4Hz , 1H), 4.24 (q, J=7.1Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.58 (q, J=6.6Hz, 2H), 2.77 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.28 (t, J=7.1Hz, 3H).

[0319] Example 17: 2-[3-[(3-cyano-5-methoxycarbonyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0320]

[0321] 32 mg (37%) colorless amorphous solid. HPLC / MS m / z: 445.12 [M+H] + , Rt(R):1.30min. 1 H NMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 9.02 (t, J = 5.5Hz, 1H), 8.64 (t, J = 1.7Hz, 1H), 8.50 (t, J = 1.6Hz, 1H), 8.47 (t, J = 1.6Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.92 (s, 3H), 3.60 (q, J=6.4Hz, 2H), 3.32 (s, 4H), 2.78 (t, J=6.7Hz, 2H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0322] Example 18: 2-[3-[(3-Bromo-5-methoxycarbonyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0323]

[0324] 163 mg (47%) amorphous colorless solid. HPLC / MS m / z: 498.03 [M+H] + , Rt(R):1.43min. 1HNMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.96 (t, J = 5.5Hz, 1H), 8.39 (s, 1H), 8.27 (t, J = 1.8Hz, 1H), 8.18 (t, J = 1.7Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.89 (s, 3H), 3.58 (q, J=6.4Hz, 2H), 2.76 (q, J=5.7, 4.7Hz, 2H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0325] Example 19: 2-[3-[(3-ethyl-5-methoxycarbonyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0326]

[0327] 3 mg (7%) colorless amorphous solid. HPLC / MS m / z: 448.15 [M+H] + , Rt(R):1.40min. 1 HNMR (500MHz, MeOD-d4) δ8.28 (t, J=1.7Hz, 1H), 8.03-7.99 (m, 1H), 7.90 (dt, J=2.3, 1.1Hz, 1H), 4.31 (q, J=7.1Hz, 2H), 3.93 (s, 3H ), 3.76 (t, J=6.7Hz, 2H), 2.85 (t, J=6.7Hz, 2H), 2.77 (q, J=7.6Hz, 2H), 2.58 (s, 3H), 1.36 (t, J=7.1Hz, 3H), 1.28 (t, J=7.6Hz, 3H).

[0328] Example 20: 2-[3-[(3-Hydroxy-5-methoxycarbonyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0329]

[0330] 20 mg (12%) colorless amorphous solid. HPLC / MS m / z: 436.12 [M+H] + , Rt(R):1.26min. 1H NMR (500MHz, DMSO-d6) δ12.52 (s, 1H), 10.12 (s, 1H), 8.73 (t, J = 5.6Hz, 1H), 7.86 (t, J = 1.6Hz, 1H), 7.53-7.34 (m, 2H), 4.24 (q, J=7.1Hz, 2H), 3.85 (s, 3H), 3.55 (q, J=6.5Hz, 2H), 2.75 (t, J=6.8Hz, 2H), 2.54 (s, 3H), 1.28 (t, J=7.1Hz, 3H).

[0331] Example 21: 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propylamino]thiazole-5-carboxylic acid ethyl ester

[0332]

[0333] 50 mg (51%) colorless amorphous solid. HPLC / MS m / z: 430.15 [M+H] + , Rt(R):1.31min. 1 H NMR (500MHz, DMSO-d6) δ8.74 (t, J=5.6Hz, 1H), 8.47 (dt, J=1.8, 1.0Hz, 1H), 8.36 (t, J=5.5Hz, 1H), 8.16-8.10 (m, 1H), 8.04 (ddd, J=7.8, 1.8, 1.2H z, 1H), 7.70-7.61 (m, 1H), 4.14 (q, J=7.1Hz, 2H), 3.33 (m, 4H, H2O peak added), 2.69 (s, 3H), 2.39 (s, 3H), 1.83 (quint, J=6.9Hz, 2H), 1.21 (t, J=7.1Hz, 3H).

[0334] Example 22: 2-[3-[[3-methoxycarbonyl-5-[(E)-phenylvinyl]benzoyl]amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0335]

[0336] 15 mg (24%) colorless amorphous solid. HPLC / MS m / z: 522.17 [M+H] + , Rt(R):1.56min. 1H NMR (500MHz, DMSO-d6) δ12.55 (s, 1H), 8.90 (t, J=5.5Hz, 1H), 8.34 (t, J=1.7H z, 1H), 8.29 (t, J=1.6Hz, 1H), 8.27 (t, J=1.7Hz, 1H), 7.72-7.59 (m, 2H), 7.48 -7.37 (m, 4H), 7.31 (t, J=7.4Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.91 (s, 3H), 3.6 2 (q, J=6.4Hz, 2H), 2.79 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0337] Example 23: Ethyl 2-(3-(3-(1,2,4-oxadiazol-3-yl)benzamido)propionamido)-4-methylthiazole-5-carboxylate

[0338]

[0339] 51 mg (75%). HPLC / MS m / z: 430.1[M+H] + , Rt(U):2.77min. 1 H NMR (600MHz, DMSO-d6) δ12.53 (s, 1H), 9.76 (s, 1H), 8.87 (t, J = 5.5Hz, 1H), 8.50 (t, J = 1.7Hz, 1H), 8.18 (dt, J = 7.7, 1.4Hz, 1H), 8.07-8.0 2 (m, 1H), 7.68 (t, J=7.8Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.60 (q, J=6.6Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0340] Example 24: Ethyl 2-(3-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)-4-methylthiazole-5-carboxylate

[0341]

[0342] Example 24.1.: 3-Chloro-5-cyano-benzoic acid methyl ester (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 room temperature overnight. The solvent was removed to give 264 mg (90%, 1.1547 mmol) of 3-chloro-5-[(Z)-N'-hydroxycarbamimidoyl]benzoic acid methyl ester as a brown oil, which was used without further purification. HPLC / MS m / z: 229.04, [M+H] + , Rt(P):0.59min.

[0343] Example 24.2.: In a microwave vial under N2, 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). The reaction mixture was stirred at room temperature overnight. DIPEA (0.38 mL, 2.1652 mmol) was added and the solution was heated at 150°C under microwave irradiation for 30 min. The solvent was evaporated and EtOAc was added. The residue was washed twice with 0.1N HCl, once with saturated NaHCO3 solution, brine, and dried over MgSO4. Purification by silica gel column chromatography (eluent: 0-4% EtOAc in cyclohexane) gave 50 mg (26%, 0.1979 mmol) of methyl 3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate as a light brown oil. HPLC / MS m / z: 253.04, [M+H] + , Rt(R):1.54min.

[0344] Example 24.3: To 3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid methyl ester (50.00 mg, 0.1979 mmol) in TNF (0.99 mL) was added water (0.99 mL) followed by LiOH hydrate (24.91 mg, 0.5937 mmol). After stirring at room temperature, the volatiles were removed in vacuo and the crude product was partitioned between EtOAc (15 mL) and 1M HCl (15 mL). The organic phase was retained and the aqueous phase was extracted with additional EtOAc (10 mL). The organic phases 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. This was used in the next step without further purification. HPLC / MS m / z: 239.02, [M+H] + , Rt(R):1.44min.

[0345] Example 24.4.: A procedure similar to the preparation of Example 0 using 3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid and ethyl 2-(3-aminopropionylamino)-4-methylthiazole-5-carboxylate gave 26 mg (52%, 0.0544 mmol) of ethyl 2-(3-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionylamino)-4-methylthiazole-5-carboxylate as a colorless solid. HPLC / MS m / z: 478.09, [M+H] + , Rt(S):3.06min. 1 H NMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.98 (t, J = 5.5Hz, 1H), 8.40 (t, J = 1.6Hz, 1H), 8.08 (dt, J = 9.4, 1.9Hz, 2H), 4. 23 (q, J=7.1Hz, 2H), 3.60 (q, J=6.4Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.69 (s, 3H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0346] The following examples were prepared in a similar manner using 2-amino-4-methyl-thiazole-5-carboxylic acid propyl ester.

[0347] Example 25: Propyl 2-(3-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)-4-methylthiazole-5-carboxylate

[0348]

[0349] 31 mg (60%) colorless solid. HPLC / MS m / z: 492.11, [M+H] + , Rt(S):3.20min. 1 HNMR (500MHz, DMSO-d6) δ12.55 (s, 1H), 8.98 (t, J = 5.6Hz, 1H), 8.40 (t, J = 1.5Hz, 1H), 8.08 (dt, J = 7.6, 1.9Hz, 2H), 4.15 (t, J = 6.5 Hz, 2H), 3.60 (q, J=6.5Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.69 (s, 3H), 2.53 (s, 3H), 1.67 (sext, J=7.1Hz, 2H), 0.93 (t, J=7.4Hz, 3H).

[0350] Example 26: 4-methyl-2-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylic acid propyl ester

[0351]

[0352] Prepared by a similar procedure from 3-cyano-5-methyl-benzoic acid methyl ester to give 58 mg (73%) of 4-methyl-2-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylic acid propyl ester as a colorless solid. HPLC / MS m / z: 472.16, [M+H] + , Rt(S):3.04min. 1 HNMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.80 (t, J=5.5Hz, 1H), 8.25 (t, J=1.6H z, 1H), 7.95 (td, J=1.6, 0.8Hz, 1H), 7.85 (td, J=1.7, 0.8Hz, 1H), 4.15 (t, J=6.5 Hz, 2H), 3.59 (q, J=6.5Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.67 (s, 3H), 2.53 (s, 3H) , 2.44-2.41 (m, 3H), 1.67 (dtd, J=13.8, 7.4, 6.4Hz, 2H), 0.94 (t, J=7.4Hz, 3H).

[0353] Example 27: 1-methyl-3-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)-1H-pyrazole-5-carboxylic acid propyl ester

[0354]

[0355] 1-Methyl-3-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)-1H-pyrazole-5-carboxylic acid propyl ester (20 mg, 21%, 0.0440 mmol) was prepared as a colorless solid from 3-cyano-5-methyl-benzoic acid methyl ester and 5-amino-2-methyl-pyrazole-3-carboxylic acid propyl ester by a similar procedure. HPLC / MS m / z: 455.20, [M+H] + , Rt(S):2.86min. 1 H NMR (500MHz, DMSO-d6) δ10.68 (s, 1H), 8.75 (t, J=5.5Hz, 1H), 8.26 (d, J=1.7H z, 1H), 7.95 (td, J=1.7, 0.8Hz, 1H), 7.86 (td, J=1.7, 0.8Hz, 1H), 7.05 (s, 1H), 4.20 (t, J=6.5Hz, 2H), 3.98 (s, 3H), 3.54 (td, J=7.0, 5.4Hz, 2H), 2.67 (s, 3H), 2.62 (t, J=7.1Hz, 2H), 2.43 (s, 3H), 1.76-1.65 (m, 2H), 0.94 (t, J=7.4Hz, 3H).

[0356] Example 28: Propyl 2-(3-(3-cyano-5-(trifluoromethyl)benzamido)propionamido)-4-methylthiazole-5-carboxylate

[0357]

[0358] 40.5 mg (53%) yellow solid. HPLC / MS m / z: 469.12, [M+H] + , Rt(S):3.09min. 1 HNMR (500MHz, DMSO-d6) δ12.55 (s, 1H), 9.04 (t, J = 5.5Hz, 1H), 8.54 (d, J = 1.8Hz, 2H), 8.43 (s, 1H), 4.15 (t, J = 6.5 Hz, 2H), 3.61 (q, J=6.4Hz, 2H), 2.78 (t, J=6.7Hz, 2H), 2.54 (s, 3H), 1.67 (h, J=7.0Hz, 2H), 0.94 (t, J=7.4Hz, 3H).

[0359] Example 29: Propyl 2-(3-(3-(tert-butyl)-5-(methoxycarbonyl)benzamido)propionamido)-4-methylthiazole-5-carboxylate

[0360]

[0361] 23 mg (36%) colorless solid. HPLC / MS m / z: 490.20, [M+H] + , Rt(R):3.31min. 1 HNMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.86 (t, J = 5.6Hz, 1H), 8.25 (t, J = 1.6Hz, 1H), 8.11 (t, J = 1.8Hz, 1H), 8.07 (t, J = 1.7Hz, 1H), 4.15 (t, J = 6.5Hz, 2H), 3.88 (s, 3H), 3.59 (q, J=6.5Hz, 2H), 2.77 (t, J=6.8Hz, 2H), 2.53 (s, 3H ), 1.67 (dtd, J=13.7, 7.4, 6.5Hz, 2H), 1.32 (s, 9H), 0.94 (t, J=7.4Hz, 3H).

[0362] Example 30: Propyl 2-(3-(3-cyano-5-(methoxycarbonyl)benzamido)propionamido)-4-methylthiazole-5-carboxylate

[0363]

[0364] 15 mg (10%) colorless solid. HPLC / MS m / z: 459.13, [M+H] + , Rt(S):2.94min. 1 H NMR (500MHz, DMSO-d6) δ 12.54 (s, 1H), 9.02 (t, J = 5.5Hz, 1H), 8.64 (t, J = 1.7Hz, 1H), 8.50 (t, J = 1.7Hz, 1H), 8.47 (t, J = 1.6Hz, 1H), 4.15 (t , J=6.5Hz, 2H), 3.92 (s, 3H), 3.60 (q, J=6.4Hz, 2H), 2.78 (t, J=6.6Hz, 2H), 2.53 (s, 3H), 1.67 (sext, J=7.0Hz, 2H), 0.94 (t, J=7.4Hz, 3H).

[0365] 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

[0366]

[0367] Example 31.1.: A similar procedure to Example 0 was used using 3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid [0] to give 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):1.21min.

[0368] 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 uL, 0.2325 mmol). The resulting solution was stirred at room temperature overnight. The crude product was partitioned between water (14 mL) and EtOAc (35 mL), and after separation, the organic layer was washed with brine (40 mL), dried (MgSO4), 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 (each + 0.1% formic acid)) gave 3.97 mg (13%, 0.0086 mmol) of 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 as a colorless solid. HPLC / MS m / z: 462.14 [M+H] + , Rt(T):1.58min. 1 HNMR (600MHz, DMSO-d6) δ11.85 (s, 1H), 8.95 (t, J = 5.5Hz, 1H), 8.41 (t, J = 1.6Hz, 1H), 8.10 (t, J = 1.8Hz, 1H), 8.08 (t, J=1.8Hz, 1H), 3.56 (q, J=6.7Hz, 2H), 2.69 (s, 3H), 2.68 (d, J=7.0Hz, 2H), 2.30 (s, 3H), 1.35 (s, 9H).

[0369] Example 32: Propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzamido)propionamido)thiazole-5-carboxylate

[0370]

[0371] Example 32.1.: 2-[3-[[3-Cyano-5-(trifluoromethyl)benzoyl]amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid propyl ester [0] (105.00 mg, 0.2241 mmol) and TEA (0.03 mL, 0.2241 mmol) in [bmim]OAc (0.22 mL) were heated 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 in EtOAc (30 mL) and washed with water (3 x 20 mL), brine (30 mL), then dried over MgSO4 and concentrated in vacuo to give 115 mg (102%, 0.2293 mmol) of 2-[3-[[3-(N-hydroxycarbamimidoyl)-5-(trifluoromethyl)benzoyl]amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid propyl ester as a colorless solid, which was used in the next step without further purification. HPLC / MS m / z: 502.14, [M+H] + , Rt(R):1.46min.

[0372] Example 32.2.: To a solution of 2-[3-[[3-(N-hydroxycarbamimidoyl)-5-(trifluoromethyl)benzoyl]amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid propyl ester (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 room temperature 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 (0.1% formic acid as buffer in both)) gave propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzamido)propionamido)thiazole-5-carboxylate (6 mg, 31%, 0.0114 mmol) as a colorless solid. HPLC / MS m / z: 527.14, [M+H] + , Rt(S):3.27min.1 HNMR (500MHz, 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=6.6Hz, 2H), 3.79 (t, J=6.7Hz, 2H), 2.87 (t, J=6.7Hz, 2H), 2.68 (s, 3H), 2.56 (d, J=1.2Hz, 3H), 1.75 (dtd, J=14.0, 7.4, 6.5Hz, 2H), 1.01 (t, J=7.4Hz, 3H).

[0373] Example 33: 2-[3-[(3-Methoxycarbonyl-5-nitro-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid propyl ester

[0374]

[0375] 134 mg (58%) light yellow powder (134 mg, 58%, 0.28 mmol). HPLC / MS m / z: 479.12 [M+H] + , Rt(R):1.42min. 1 H NMR (500MHz, DMSO-d6) δ12.56 (s, 1H), 9.23 (t, J=5.5Hz, 1H), 8.90 (dd, J=2.2, 1.6Hz, 1H), 8.79 (t, J=1.6Hz, 1H), 8.72 (dd, J=2.2, 1.4Hz, 1H), 4.15 ( t, J=6.5Hz, 2H), 3.95 (s, 3H), 3.63 (q, J=6.4Hz, 2H), 2.80 (t, J=6.7Hz, 2H ), 2.53 (s, 3H), 1.67 (dtd, J=13.8, 7.4, 6.4Hz, 2H), 0.94 (t, J=7.4Hz, 3H).

[0376] Example 34: Ethyl 4-methyl-2-(3-(3-methyl-1,2,4-oxadiazol-5-yl)benzamido)propionamido)thiazole-5-carboxylate

[0377]

[0378] 3-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (31.74 mg, 0.1555 mmol), ethyl 2-(3-aminopropionylamino)-4-methyl-thiazole-5-carboxylate (40.00 mg, 0.1555 mmol) and DIPEA (81.45 uL, 0.4664 mmol) were dissolved in DMF (1.55 mL). HATU (54.86 mg, 0.2332 mmol) was added and stirred at room temperature for 18 h. The mixture was diluted with EtOAc and washed with water, saturated aqueous bicarbonate solution 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 from warm DMSO to give ethyl 4-methyl-2-(3-(3-(3-methyl-1,2,4-oxadiazol-5-yl)benzamido)propionamido)thiazole-5-carboxylate (8 mg, 12%, 0.0180 mmol) as colorless needles. HPLC / MS m / z: 444.1 [M+H] + , Rt(P):1.49min. 1 H NMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.93 (t, J=5.5Hz, 1H), 8.54 (dt, J=1.8, 1.0Hz, 1H), 8.22 (ddd, J=7.8, 1.8, 1.1Hz, 1H), 8.13 (ddd, J=7.9, 1.9, 1.2Hz, 1H), 7.76-7.69 (m, 1H), 4.23 (q, J=7.1Hz, 2H), 3.61 (q, J=6.5Hz, 2H ), 2.79 (t, J=6.8Hz, 2H), 2.54 (s, 3H), 2.44 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0379] The following examples were prepared by similar procedures:

[0380] Example 35: Cyclopropylmethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0381]

[0382] 30 mg (57%) colorless powder. HPLC / MS m / z: 470.15, [M+H] + , Rt(S):2.93min. 1H NMR (500MHz, methanol-d4) δ8.49 (t, J=1.8Hz, 1H), 8.18 (dt, J=7.7, 1.4Hz, 1H), 7.96 (dt, J=7.8, 1.5Hz, 1H), 7.61 (t, J=7.8Hz, 1H), 4.09 (d, J=7. 2Hz, 2H), 3.77 (t, J=6.7Hz, 2H), 2.86 (t, J=6.7Hz, 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).

[0383] Example 36: Ethyl 2-(3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)-4-methylthiazole-5-carboxylate

[0384]

[0385] To ethyl 2-(3-aminopropionylamino)-4-methyl-thiazole-5-carboxylate (40.00 mg, 0.1555 mmol) and 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 uL, 0.4664 mmol) followed by HATU (54.86 mg, 0.2332 mmol). The reaction was stirred at room temperature for 18 h. The mixture was diluted with EtOAc and washed with water, saturated aqueous bicarbonate solution, 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 with 0.1% formic acid modifier)) gave ethyl 2-(3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)-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):3.00min. 1H NMR (500MHz, DMSO-d6) δ12.53 (s, 1H), 8.86 (t, J = 5.5Hz, 1H), 8.45 (t, J = 1.7Hz , 1H), 8.14 (dt, J=7.7, 1.3Hz, 1H), 8.02 (dt, J=7.9, 1.3Hz, 1H), 7.65 (t, J=7.8H z, 1H), 4.23 (q, J=7.1Hz, 2H), 3.60 (q, J=6.5Hz, 2H), 3.03 (q, J=7.6Hz, 2H), 2. 78 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.35 (t, J=7.6Hz, 3H), 1.27 (t, J=7.1Hz, 3H).

[0386] Example 37: Ethyl 4-methyl-2-(3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)benzamido)propionamido)thiazole-5-carboxylate

[0387]

[0388] To ethyl 2-(3-aminopropionylamino)-4-methyl-thiazole-5-carboxylate (40.00 mg, 0.1555 mmol) and 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 room temperature overnight and allowed to stand at room temperature over the weekend. The mixture was diluted with EtOAc (25 mL) and washed with water (25 mL) and saturated aqueous bicarbonate solution (10 mL). 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 with 0.1% formic acid modifier)) gave ethyl 4-methyl-2-(3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)benzamido)propionamido)thiazole-5-carboxylate (10 mg, 15%, 0.0225 mmol) as a colorless powder. HPLC / MS m / z: 444.1 [M+H] + , Rt(S):2.73min. 1H NMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.90 (t, J = 5.5Hz, 1H), 8.42 (t, J = 1.8Hz, 1H), 8.14-8.09 (m, 1H), 8.05 (dt, J = 7.9, 1.3Hz, 1H), 7.69 (t, J=7.8Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.60 (td, J=6.6Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.60 (s, 3H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0389] Example 38: Ethyl 4-methyl-2-(3-(3-(2-methyl-2H-tetrazol-5-yl)benzamido)propionamido)thiazole-5-carboxylate

[0390]

[0391] To ethyl 2-(3-aminopropionylamino)-4-methyl-thiazole-5-carboxylate (40.00 mg, 0.1555 mmol) and 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 room temperature overnight. The mixture was diluted with EtOAc and washed with water, saturated aqueous bicarbonate solution, 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 give ethyl 4-methyl-2-(3-(3-(2-methyl-2H-tetrazol-5-yl)benzamido)propionamido)thiazole-5-carboxylate (21 mg, 30%, 0.0474 mmol) as a colorless powder. HPLC / MS m / z: 444.1 [M+H] + , Rt(R):1.59min. 1HNMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.86 (t, J=5.5Hz, 1H), 8.52 (t, J=1.7Hz, 1H), 8.19 (dt, J=7.7, 1.3Hz, 1H), 7.98 (dt, J=7.9, 1.3Hz, 1 H), 7.66 (t, J=7.8Hz, 1H), 4.45 (s, 3H), 4.23 (q, J=7.1Hz, 2H), 3.60 (q, J=6.5Hz, 2H), 2.79 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.32-1.24 (m, 3H).

[0392] Example 39: tert-Butyl 4-methyl-2-[3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylate

[0393]

[0394] Example 39.1.: To 3-aminopropionic acid methyl ester hydrochloride (100.00 mg, 0.7164 mmol) and 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 yellow solution obtained was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (120 mL). Water was extracted with fresh EtOAc (100 mL). The organic phases were combined and washed with saturated aqueous bicarbonate solution (150 mL) and brine (200 mL) and then dried over MgSO4. After filtration and concentration in vacuo, methyl 3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propanoate (170 mg, 82%, 0.5876 mmol) was obtained as a light yellow thin layer and used in the next step without further purification. HPLC / MS m / z: 290.13, [M+H] + , Rt(P):1.15min.

[0395] 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 showed 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 (2x60 mL). The organic phases were combined, washed with brine (60 mL) and dried over MgSO4 to afford 3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propanoic acid (137 mg, 85%, 0.4977 mmol) as a colorless solid. HPLC / MS m / z: 276.11, [M+H] + , Rt(P):1.03min.

[0396] Example 39.3.: To a solution of HOBt (29.45 mg, 0.2180 mmol) and 3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propionic 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-methylthiazole-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) ​​gave tert-butyl (4-methyl-2-[3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylate) as a colorless solid (41 mg, 80%, 0.0870 mmol). HPLC / MS m / z: 472.12 [M+H] + , Rt(R):1.41min. 1 HNMR (600MHz, DMSO-d6) δ12.46 (s, 1H), 8.86 (t, J = 5.5Hz, 1H), 8.53 (t, J = 1.8Hz, 1H), 8.19 (dt, J = 7.7, 1.4Hz, 1H), 7.99 (dt, J=7.8, 1.5Hz, 1H), 7.66 (t, J=7.8Hz, 1H), 4.45 (s, 3H), 3.61 (q, J=6.5Hz, 2H), 2.79 (t, J=6.8Hz, 2H), 1.51 (s, 9H).

[0397] The following examples were prepared similarly.

[0398] Example 40: Isopropyl 4-methyl-2-[3-[[3-(2-methyltetrazol-5-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylate

[0399]

[0400] 27 mg (54%) colorless amorphous solid. HPLC / MS m / z: 458.16 [M+H] + , Rt(R):1.36min. 1 H NMR (500MHz, DMSO-d6) δ12.51 (s, 1H), 8.86 (t, J = 5.5Hz, 1H), 8.52 (t, J = 1.8Hz, 1H), 8.19 (dt, J = 7.7, 1.4Hz, 1H), 7.98 (dt, J = 7.9, 1.4Hz, 1H), 7 .66 (t, J=7.8Hz, 1H), 5.05 (hept, J=6.3Hz, 1H), 4.45 (s, 3H), 3.60 (q, J=6.5Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.53 (s, 3H), 1.28 (d, J=6.2Hz, 6H).

[0401] Example 41: N-[3-[(5-tert-Butyl-4-methyl-thiazol-2-yl)amino]-3-oxo-propyl]-3-(2-methyltetrazol-5-yl)benzamide

[0402]

[0403] 7 mg (24%) colorless solid. HPLC / MS m / z: 428.19 [M+H] + , Rt(T):1.40min. 1 HNMR (500MHz, DMSO-d6) δ11.85 (s, 1H), 8.83 (t, J=5.5Hz, 1H), 8.62-8.47 (m, 1H), 8.27-8.14 (m, 1H), 7.98 (ddd, J=7.9, 1. 9, 1.2Hz, 1H), 7.65 (t, J=7.8Hz, 1H), 4.45 (s, 3H), 3.57 (q, J=6.6Hz, 2H), 2.69 (t, J=6.9Hz, 2H), 2.29 (s, 3H), 1.35 (s, 9H).

[0404] Example 42: Ethyl 2-(3-(3-(ethoxycarbonyl)benzamido)propionamido)-4-methylthiazole-5-carboxylate

[0405]

[0406] To 3-ethoxycarbonylbenzoic acid (37.73 mg, 0.1943 mmol) and ethyl 2-(3-aminopropionylamino)-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 room temperature overnight. The mixture was diluted with EtOAc and washed with water, saturated aqueous bicarbonate solution, and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification was performed 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% MeCN in DCM) to give ethyl 2-(3-(3-(ethoxycarbonyl)benzamido)propionamido)-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):2.90min. 1 H NMR (500MHz, acetone-d6) δ11.34 (s, 1H), 8.50 (td, J=1.9, 0.6Hz, 1H), 8.22 (s, 1H ), 8.15 (d, J = 1.7Hz, 1H), 8.13 (d, J = 1.8Hz, 1H), 7.61 (td, J = 7.8, 0.6Hz, 1H) , 4.37 (q, J=7.1Hz, 2H), 4.28 (q, J=7.1Hz, 2H), 3.82 (q, J=6.3Hz, 2H), 2.97 ( t, J=6.5Hz, 2H), 2.53 (s, 3H), 1.37 (t, J=7.1Hz, 3H), 1.33 (t, J=7.1Hz, 3H).

[0407] Example 43: Ethyl 4-methyl-2-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0408]

[0409] Example 43.1.: 3-Cyano-5-methyl-benzoic acid methyl ester (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 room temperature overnight. The solvent was removed in vacuo to give 3-[(Z)-N'-hydroxycarbamimidoyl]-5-methyl-benzoic acid methyl ester (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):1.10min.

[0410] Example 43.2.: In a microwave vial under nitrogen atmosphere, acetic acid (0.06 mL, 1.0827 mmol), 3-[(Z)-N'-hydroxycarbamimidoyl]-5-methyl-benzoic acid methyl ester (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). The reaction mixture was stirred at room temperature overnight. DIPEA (0.38 mL, 2.1601 mmol) was added and the solution was heated at 150 ° C for 1 h under microwave irradiation. 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)) gave methyl 3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate (25 mg, 13%, 0.0980 mmol). 1 HNMR (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).

[0411] Example 43.3.: To 3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid methyl ester (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 product was partitioned between EtOAc (15 mL) and 1M HCl (15 mL). The organic phase was retained and the aqueous phase was extracted with additional EtOAc (10 mL). The organic phases 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. Used in the next step without further purification. HPLC / MS m / z:219.1[M+H] + , Rt(R):1.18min.

[0412] Example 43.4.: To 3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (17.00 mg, 0.0779 mmol) and ethyl 2-(3-aminopropionylamino)-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 room temperature for 1.5 h, the volatiles were removed in vacuo. Purification was performed by silica gel column chromatography (eluent: EtOH in DCM gradient) followed by reverse phase column chromatography (eluent: MeCN in DCM gradient). Final purification by semi-preparative HPLC (65%-80% MeOH in water) gave ethyl 4-methyl-2-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate (4 mg, 11%, 0.0087 mmol) as a clear glass. HPLC / MS m / z: 458.1 [M+H] + , Rt(S):2.90min. 1H 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).

[0413] Example 44: 2-(3-(3-(methoxycarbonyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)-4-methylthiazole-5-carboxylic acid propyl ester

[0414]

[0415] Example 44.1.: 2-[3-[(3-cyano-5-methoxycarbonyl-benzoyl)amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid propyl ester [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 room temperature and water (15 mL) was added. The residue was extracted with DCM (3×20 mL). The organic layers were combined, washed with brine (30 mL), dried over MgSO4 and concentrated under reduced pressure to give 2-[3-[[3-(N-hydroxycarbamimidoyl)-5-methoxycarbonyl-benzoyl]amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid propyl ester (63.5 mg, 97%, 0.1292 mmol). HPLC / MS m / z: 492.15, [M+H] + , Rt(P):1.35min.

[0416] Example 44.2.: In a 0.5-2 mL microwave vial under nitrogen atmosphere, acetic acid (0.004 mL, 0.0712 mmol), 2-[3-[[3-(N-hydroxycarbamimidoyl)-5-methoxycarbonyl-benzoyl]amino]propionylamino]-4-methyl-thiazole-5-carboxylic acid propyl ester (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). The solution was stirred at room temperature overnight. DIPEA (0.03 mL, 0.1709 mmol) was added. The mixture was heated at 150 ° C under microwave 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 solution (30 mL), brine (30 mL), then dried over magnesium sulfate and concentrated under reduced pressure. Purification was performed by reverse column chromatography (eluent: 25-100% MeOH in water (0.1% formic acid as buffer in both)) to give propyl 2-(3-(3-(methoxycarbonyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)-4-methylthiazole-5-carboxylate as a colorless solid. HPLC / MS m / z: 516.15, [M+H] + , Rt(S):3.09min. 1 HNMR (500MHz, DMSO-d6) δ12.56 (s, 1H), 9.11 (t, J = 5.5Hz, 1H), 8.70 (t, J = 1.7Hz, 1H), 8.63 (t, J = 1.7Hz, 1H), 8.60 (t, J = 1.7Hz, 1H), 4.15 (t, J =6.5Hz, 2H), 3.93 (s, 3H), 3.62 (q, J = 6.4Hz, 2H), 2.79 (t, J = 6.8Hz, 2H), 2.71 (s, 3H), 2.53 (s, 3H), 1.71-1.63 (m, 2H), 0.94 (t, J = 7.4Hz, 3H).

[0417] Example 45: 4-methyl-2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionylamino]thiazole-5-carboxylic acid ethyl ester

[0418]

[0419] Example 45.1.: 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) was bubbled with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium (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 (2×50 mL). The aqueous layer, containing some precipitated product, was re-extracted with dichloromethane (2×50 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 give 0.314 g (83%) of 1-hydroxyisoquinoline-7-carbonitrile. HPLC / MS m / z:171.05[M+H] + , Rt(R):0.84min. 1 H NMR (500MHz, DMSO-d6) δ11.64 (s, 1H), 8.53-8.47 (m, 1H), 8.03 (dd, J=8.3, 1. 8Hz, 1H), 7.84 (d, J=8.3Hz, 1H), 7.38 (d, J=7.1Hz, 1H), 6.65 (d, J=7.2Hz, 1H).

[0420] 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 give 0.235 g (92%) of N′,1-dihydroxyisoquinoline-7-carboximidamide. HPLC / MS m / z: 204.07 [M+H] + , Rt(R):0.36min.

[0421] Example 45.3.: N',1-dihydroxyisoquinoline-7-carboximidamide (0.235 g, 1.16 mmol) and acetic anhydride (0.13 mL, 1.39 mmol) in acetonitrile (4.6 mL) were heated at 180°C for 10 min by microwave irradiation. Water (25 mL) was added and the resulting precipitate was filtered, washed with water (25 mL), diethyl ether (2 x 10 mL), and dried to give 0.180 g (68%) of 7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-ol. HPLC / MS m / z: 228.08 [M+H] +, Rt(R):1.07min.

[0422] 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 give 0.054 g (100%) of 3-(1-chloro-7-isoquinolinyl)-5-methyl-1,2,4-oxadiazole. HPLC / MS m / z: 246 / 248 Cl split [M+H] + , Rt(R):1.32min.

[0423] Example 45.5.: 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole (70 mg, 0.28 mmol) and 3-aminopropionitrile (0.42 mL, 5.69 mmol) in NMP (1.10 mL) were heated at 160° C. for 1 h. Ethyl acetate (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 = 20-100% gradient) to give 0.020 g (25%) of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propionitrile. HPLC / MS m / z: 280.12 [M+H] + , Rt(R):0.79min.

[0424] Example 45.6.: 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionitrile (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 give 0.020 g (100%) of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoic acid. HPLC / MS m / z: 299.11 [M+H] + , Rt(R):0.93min.

[0425] Example 45.7.: Under nitrogen, 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-isoquinolinyl]amino]propionic acid (20 mg, 0.068 mmol), ethyl 2-amino-4-methylthiazole-5-carboxylate (15 mg, 0.082 mmol), and HOBt (18 mg, 0.014 mmol) in DMF (0.68 mL). The mixture was heated at 60° C. for 17 h. The solution was cooled, injected directly onto the column, and purified by reverse-phase column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 10-100% gradient) to give 0.012 g (38%) of the product as an off-white solid. HPLC / MS m / z:467.15[M+H] + , Rt(P):1.34min. 1 H NMR (500MHz, DMSO-d6) δ12.56 (s, 1H), 8.87 (s, 1H), 8.15 (dd, J=8.5, 1.6Hz, 1H), 8.02 (t, J=5.5Hz, 1H), 7.96 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 6.97 (d, J=5.9Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.81 (q, J=6.5Hz, 2H) , 2.89 (t, J=6.8Hz, 2H), 2.70 (s, 3H), 2.53 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

[0426] The following examples were prepared similarly:

[0427] Example 46: 4-methyl-2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionylamino]thiazole-5-carboxylic acid methyl ester

[0428]

[0429] 3 mg (6%) colorless amorphous solid [formate salt]. HPLC / MS m / z: 453.13 [M+H] + , Rt(P):1.29min. 1H NMR (500MHz, MeOD-d4) δ8.87 (s, 1H), 8.33-8.15 (m, 2H), 7.91 (d, J = 6.1Hz, 1H), 7.85 (d, J = 8.4Hz, 1H), 7. 05 (d, J=6.1Hz, 1H), 3.96 (t, J=6.6Hz, 2H), 3.84 (s, 3H), 2.98 (t, J=6.6Hz, 2H), 2.69 (s, 3H), 2.57 (s, 3H).

[0430] Example 47: Formic acid N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[[6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl]amino]propanamide

[0431]

[0432] Example 47.1.: 4-Hydroxyquinazoline-6-carbonitrile (500 mg, 2.92 mmol) and triethylamine (0.41 mL, 2.92 mmol) in [bmim]OAc (2.9 mL) were heated at 80°C and hydroxylamine hydrochloride (406 mg, 5.84 mmol) was added, after which some foaming was observed. Stirring was continued at 80°C for 30 min. The reaction mixture was cooled to room temperature and water (50 mL) was added. The precipitate was filtered, washed with water (50 mL), and dried under reduced pressure to give 536 mg (90%) of N,4-dihydroxyquinazoline-6-carboximidamide. HPLC / MS m / z: 205.1 [M+H] + , Rt(U):0.46min.

[0433] Example 47.2.: A suspension of N,4-dihydroxyquinazoline-6-carboximidamide (480 mg, 2.35 mmol) and acetic anhydride (0.27 mL, 2.82 mmol) in anhydrous ACN (4.70 mL) under argon atmosphere was heated at 180° C. for 10 min under microwave irradiation. The reaction mixture was cooled to room temperature and cold water (50 mL) was added. The precipitate was filtered, washed with water (50 mL) and diethyl ether (10 mL), and dried under reduced pressure to give 293 mg (55%) of 6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-ol. HPLC / MS m / z: 229.0727 [M+H] + , Rt(U):1.93min.

[0434] 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) was heated at 100°C for 4 h under an argon atmosphere. The solution was cooled to room temperature 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):1.25min.

[0435] 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 room temperature for 1 h. The reaction mixture was purified by reverse-phase flash chromatography (10-100% MeOH in water) to give 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):1.41min.

[0436] 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) under argon atmosphere at room temperature and stirred for 1 h. 5-tert-Butyl-4-methyl-thiazol-2-ylamine (28 mg, 0.167 mmol) was added and the reaction was continued at 60° C. for 1 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), washed with saturated NaHCO (2 x 20 mL) and saturated NaCl (20 mL), dried over anhydrous MgSO, and concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (10-100% MeOH [0.1% FA] in water). Yield: 24 mg (64%) off-white solid. HPLC / MS m / z: 452.1861 [M+H] + , Rt(U):2.70min. 1H NMR (600MHz, DMSO-d6) δ11.86 (s, 1H), 8.93 (d, J=1.9Hz, 1H), 8.87 (t, J=5.5Hz, 1H), 8.53 (s, 1H), 8.29 (dd, J=8.7, 1.8Hz, 1H ), 8.15 (s, 1H), 7.81 (d, J=8.7Hz, 1H), 3.82 (q, J=6.4Hz, 2H), 2.81 (t, J=6.7Hz, 2H), 2.70 (s, 3H), 2.28 (s, 3H), 1.34 (s, 9H).

[0437] 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

[0438]

[0439] 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 room temperature 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 yield 142 mg (38%) of (1s,3s)-methyl 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):1.87min.

[0440] 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 yield 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):1.63min.

[0441] Example 48.3.: (1s, 3s) -3- ((6- (5- methyl -1,2,4- oxadiazole -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 under an argon atmosphere at room temperature. DIPEA (0.05 mL, 0.277 mmol) was added and the reaction mixture was stirred for 20 min. 2- amino -4- methyl- thiazole -5- carboxylic acid tert-butyl ester [0] (26 mg, 0.123 mmol) was added, and the mixture was heated at 80 ° C for 1 h under microwave irradiation. Volatiles were removed under reduced pressure and the crude reaction mixture was directly purified by reverse flash chromatography (10-40% MeOH [0.1% FA] in water). The fraction containing the product was filtered through a 1 g SCX-2 column. The compound was liberated with 2M NH3 in MeOH and the solvent was 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-carboxamido)thiazole-5-carboxylate as an off-white solid. HPLC / MS m / z: 522.1921 [M+H] + , Rt(X):2.81min. 1H NMR (600MHz, DMSO-d6) δ12.43 (s, 1H), 9.06 (d, J = 1.8Hz, 1H), 8.95 (d, J = 6.9Hz, 1H), 8.53 (s, 1H), 8.30 (dd, J = 8.7, 1.8Hz, 1H), 7.81 ( d, J=8.7Hz, 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).

[0442] 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

[0443]

[0444] Under an argon atmosphere, 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) and cooled in an ice-water bath. A 60% dispersion of sodium hydride 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 uL, 0.042 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirring was continued 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-carboxamido)thiazole-5-carboxylate formate as a colorless powder. HPLC / MS m / z: 536.2084 [M+H] + , Rt(X):2.86min.

[0445] Example 50: N-(5-tert-Butyl-4-methyl-thiazol-2-yl)-3-[(7-cyano-1-isoquinolinyl)amino]acrylamide

[0446]

[0447] Example 50.1.: Isoquinoline-7-carbonitrile (1.00 g, 6.49 mmol) was suspended in anhydrous chloroform (20 mL) under argon atmosphere and cooled in an ice-water bath. 3-Chloroperoxybenzoic acid (1.74 g, 7.78 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The off-white precipitate was filtered, washed with chloroform, and dried under reduced pressure to yield 1.10 g (100%) of 2-oxoisoquinolin-2-ium-7-carbonitrile as an off-white powder. HPLC / MS m / z: 171.0559 [M+H] + , Rt(U):1.11min.

[0448] Example 50.2.: 2-Oxoisoquinolin-2-ium-7-carbonitrile (300 mg, 1.76 mmol), tert-butyl β-alaninate hydrochloride (400 mg, 2.2037 mmol), and DIPEA (1.46 mL, 8.37 mmol) were combined 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 yield 271 mg (52%) of tert-butyl 3-[(7-cyano-1-isoquinolinyl)amino]propanoate as an off-white solid. HPLC / MS m / z: 298.2 [M+H] + , Rt(P):1.15min.

[0449] Example 50.3.: To a solution of tert-butyl 3-[(7-cyano-1-isoquinolinyl)amino]propanoate (271 mg, 0.911 mmol) in DCM (1.82 mL) was added TFA (0.70 mL, 9.11 mmol) under argon atmosphere. The resulting solution was stirred at room temperature overnight. The volatiles were removed under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (5-40% MeOH in water [0.1% FA]) to yield 119 mg (54%) of 3-[(7-cyano-1-isoquinolinyl)amino]propanoic acid as an off-white solid. HPLC / MS m / z: 242.1 [M+H] + , Rt(Q):0.39min.

[0450] Example 50.4.: Prepared as described in Example 47.5 using 3-[(7-cyano-1-isoquinolinyl)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 gave N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[(7-cyano-1-isoquinolinyl)amino]propanamide (57 mg, 58%) as an off-white crystalline solid. HPLC / MS m / z: 394.1698 [M+H] + , Rt(U):2.58min. 1 H NMR (600MHz, DMSO-d6) δ11.82 (s, 1H), 8.82 (s, 1H), 8.05 (d, J=5.7Hz, 1H), 7.89 (dd, J=8.5, 1.5Hz, 1H), 7.8 7-7.84 (m, 2H), 6.98 (d, J=5.8Hz, 1H), 3.80-3.75 (m, 2H), 2.78 (t, J=6.8Hz, 2H), 2.29 (s, 3H), 1.35 (s, 9H).

[0451] Example 51: 3-[(7-cyano-1-isoquinolinyl)amino]-N-[4-methyl-5-[1-(trifluoro-methyl)cyclopropyl]thiazol-2-yl]acrylamide

[0452]

[0453] 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-water bath. Tert-butyl hydroperoxide (70% solution in water, 0.84 mL, 4.25 mmol) was added and the mixture was stirred for 5 min at 0 ° C and then heated at 90 ° C for 3 h. The reaction mixture was cooled to room temperature and mixed with saturated NaHCO (30 mL) and extracted with EtOAc (3x20 mL). The combined organic phases were washed with saturated NaHCO (20 mL) and saturated NaCl (2x20 mL), dried over anhydrous MgSO and concentrated under reduced pressure. The crude reaction mixture was directly purified by reverse flash chromatography (10-80% MeOH [0.1% FA] in water). The product-containing fractions were filtered through a 1 g SCX-2 column. The compound was released with 7 M NH 3 in MeOH, and the solvent was 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):1.65min.

[0454] 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 gave 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):2.56min. 1 HNMR (600MHz, DMSO-d6) δ12.18 (s, 1H), 8.82 (s, 1H), 8.04 (d, J=5.7Hz, 1H), 7.91-7.84 (m, 3H), 6.98 (d, J= 5.7Hz, 1H), 3.81-3.76 (m, 2H), 2.82 (t, J=6.8Hz, 2H), 2.26 (s, 3H), 1.47-1.44 (m, 2H), 1.18-1.15 (m, 2H).

[0455] Example 52: 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-N-[4-methyl-5-[1-(trifluoromethyl)cyclopropyl]thiazol-2-yl]acrylamide

[0456]

[0457] Prepared as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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 gave 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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):2.70min. 1 H NMR (600MHz, DMSO-d6) δ12.19 (s, 1H), 8.87 (s, 1H), 8.14 (dd, J=8.5, 1.5Hz, 1H), 8.00 (t, J=5.5Hz, 1H), 7.97 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 6.97 (d, J=5.7Hz, 1H), 3.79 (q, J=6.5Hz, 2H), 2.84 (t, J=6.8Hz, 2H), 2.70 (s, 3H), 2.25 (s, 3H), 1.47-1.43 (m, 2H), 1.18-1.15 (m, 2H).

[0458] Example 53: N-(5-tert-Butyl-4-methyl-thiazol-2-yl)-3-[(7-cyano-5-fluoro-1-isoquinolinyl)amino]acrylamide

[0459]

[0460] 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) was stirred at reflux overnight under argon. The 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 a quantitative yield (14.7 g, 100%) of (tert-butoxycarbonylamino)-2,2-dimethylpropanoate 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):2.64min.

[0461] 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 room temperature under argon and stirred for 3 h. The white crystalline precipitate was filtered, washed with diethyl ether, and dried under reduced pressure to yield 7.0 g (40%) of 2,2-dimethylpropionyloxyammonium trifluoromethanesulfonate. 1 H NMR (500MHz, DMSO-d6) δ10.68 (s, 3H), 1.22 (s, 9H).

[0462] 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-water 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-dimethylpropionyloxy ammonium trifluoromethanesulfonate (1.94 g, 7.27 mmol) was then added, and the reaction mixture was allowed to warm to room temperature and continued to stir overnight. The precipitate was filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure and purified by flash chromatography (0-40% EtOAc in cyclohexane) to produce 1.17 g (73%) of [(3-cyano-5-fluoro-benzoyl)amino] 2,2-dimethylpropanoate as a colorless oil. HPLC / MS m / z:287.0810[M+Na] + , Rt(U):2.55min.

[0463] Example 53.4.: [(3-Cyano-5-fluoro-benzoyl)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 room temperature under 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, 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):0.97min.

[0464] 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 argon atmosphere. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure to give a quantitative yield of crude 1-chloro-5-fluoro-isoquinoline-7-carbonitrile as an off-white solid, which was used in the next step without further purification. HPLC / MS m / z: 207.0 [M+H] + , Rt(U):1.19min.

[0465] 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 argon atmosphere and stirred at 60° C. overnight. The reaction mixture was purified by reverse-phase flash chromatography (5-30% MeOH [0.1% FA] in water) to yield 107 mg (38%) of 3-[(7-cyano-5-fluoro-1-isoquinolinyl)amino]propanoic acid as an off-white solid. HPLC / MS m / z: 260.0840 [M+H] + , Rt(U):1.33min.

[0466] Example 53.7.: Prepared as described in Example 47.5 using 3-[(7-cyano-5-fluoro-1-isoquinolinyl)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 gave N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[(7-cyano-5-fluoro-1-isoquinolinyl)amino]propanamide (61 mg, 77%) as an off-white crystalline solid. HPLC / MS m / z: 412.1602 [M+H] + , Rt(Q):2.93min. 1 HNMR (500MHz, DMSO-d6) δ11.84 (s, 1H), 8.70 (d, J = 1.2Hz, 1H), 8.15 (d, J = 5.8Hz, 1H), 8.02 (t, J = 5.4Hz, 1H), 7.93 (dd, J=10.1, 1.3Hz, 1H), 7.00 (dd, J=5.8, 0.9Hz, 1H), 3.81–3.75 (m, 2H), 2.78 (t, J=6.8Hz, 2H), 2.29 (s, 3H), 1.35 (s, 9H).

[0467] Example 54: Propyl 4-methyl-2-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propionylamino)thiazole-5-carboxylate

[0468]

[0469] 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, then 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole [Example 45] (118.00 mg, 0.4803 mmol) was added under a nitrogen atmosphere. Stir 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) ​​gave 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoic acid (123 mg, 86%, 0.4123 mmol) as a colorless powder. HPLC / MS m / z: 299.1, [M+H] + , Rt(P):0.98min.

[0470] Example 54.2.: To a mixture of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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 2-amino-4-methyl-thiazole-5-carboxylic acid propyl ester [Example 63.1] (30.21 mg, 0.1509 mmol) was added DMF (0.40 mL) under nitrogen. The resulting solution was stirred at 70° C. overnight. LCMS showed complete conversion. Purification by reverse phase column chromatography (eluent: 10-100% MeOH (+0.1% formic acid) in water) followed by ion exchange SCX-II column chromatography, washing with MeOH and then eluting with 2M NH3 in MeOH, gave propyl 4-methyl-2-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propionylamino)thiazole-5-carboxylate (32 mg, 66%, 0.0666 mmol) as a colorless solid. HPLC / MS m / z: 481.2, [M+H] + , Rt(Q):2.65min. 1 H NMR (600MHz, DMSO-d6) δ12.56 (s, 1H), 8.88 (d, J=1.5Hz, 1H), 8.15 (dd, J=8.5, 1. 5Hz, 1H), 8.02 (t, J=5.4Hz, 1H), 7.97 (d, J=5.7Hz, 1H), 7.86 (d, J=8.5Hz, 1H), 6.9 8(d, J=5.7Hz, 1H), 4.16 (t, J=6.5Hz, 2H), 3.82 (q, J=6.4Hz, 2H), 2.90 (t, J=6.8Hz , 2H), 2.70 (s, 3H), 2.54 (s, 3H), 1.68 (sext, J=7.1Hz, 2H), 0.95 (t, J=7.4Hz, 3H).

[0471] The following examples were prepared by similar procedures:

[0472] Example 55: N-(5-cyanothiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)acrylamide

[0473]

[0474] 38 mg (54%) colorless solid. HPLC / MS m / z: 406.11, [M+H] + , Rt(U):2.11min.1 HNMR (600MHz, DMSO-d6) δ13.00 (s, 1H), 8.87 (s, 1H), 8.35 (s, 1H), 8.15 (dd, J=8.5, 1.5Hz, 1H), 8.05 (t, J=5.5Hz, 1H), 7.95 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 6.97 (d, J=5.7Hz, 1H), 3.83 (q, J=6.3Hz, 2H), 2.94 (t, J=6.7Hz, 2H), 2.70 (s, 3H).

[0475] 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)acrylamide

[0476]

[0477] 14 mg (47%) colorless solid. HPLC / MS m / z: 446.16, [M+H] + , Rt(U):2.39min. 1 HNMR (600MHz, DMSO-d6) δ10.77 (s, 1H), 8.88 (s, 1H), 8.14 (dd, J=8.5, 1.5Hz, 1H), 7.98 (d, J=5.7Hz, 1H), 7.96 (t, J=6.5Hz, 1H), 7 .85 (d, J=8.5Hz, 1H), 7.00 (s, 1H), 6.96 (d, J=5.7Hz, 1H), 3.85 (s, 3H), 3.77 (q, J=6.8Hz, 2H), 2.75 (t, J=7.0Hz, 2H), 2.70 (s, 3H).

[0478] 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

[0479]

[0480] Example 57.1.: To a solution of diisopropylamine (0.33 mL, 2.3603 mmol) in THF (1.9 mL) was added 1.6 M nBuLi (1.48 mL, 2.3603 mmol) at -78 ° C. The solution was stirred at 0 ° C for 15 min. The solution was then recooled to -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 room temperature and stirred for 2 h. The reaction was quenched with a saturated solution of Na2S2O3 (10 mL) and NH4Cl (25 mL). The residue was extracted with EtOAc (2 x 15 mL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel column chromatography (eluent: 0-40% EtOAc in cyclohexane) gave 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).

[0481] 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) / TEA (3.00 mL). The resulting solution was heated at 90° C. for 30 min under microwave irradiation. The volatiles were removed under reduced pressure. Purification by silica gel column chromatography (eluent: 0-8% EtOAc in cyclohexane) gave 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):1.43min.

[0482] 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 H2 atmosphere and the solution was stirred at room temperature 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, washing with MeOH, then eluting with 2M NH3 in 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):0.95min.

[0483] Example 57.4.: Analogous to the procedure of 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, 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(1-methyl-5-pentyl-1H-pyrazol-3-yl)propanamide was obtained as a colorless solid (10.2 mg, 34%, 0.0228 mmol). HPLC / MS m / z: 448.25, [M+H] + , Rt(U):2.62min. 1 H NMR (600MHz, DMSO-d6) δ10.29 (s, 1H), 8.88 (s, 1H), 8.14 (dd, J=8.5, 1.6Hz, 1H), 7.9 8(d, J=5.7Hz, 1H), 7.93 (t, J=5.4Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 6.95 (d, J=5.7Hz, 1H ), 6.30 (s, 1H), 3.74 (td, J = 7.1, 5.2Hz, 2H), 3.59 (s, 3H), 2.69 (d, J = 8.1Hz, 5H), 2.5 4 (t, J=7.6Hz, 2H), 1.55 (quint, J=7.3Hz, 2H), 1.37-1.26 (m, 4H), 0.91-0.83 (m, 3H).

[0484] Example 58: N-(5-(tert-Butyl)-4-methylthiazol-2-yl)-3-((7-(5-methyl-2H-tetrazol-2-yl)isoquinolin-1-yl)amino)acrylamide

[0485]

[0486] Example 58.1.: 7-Aminoisoquinoline (720.85 mg, 5 mmol) was dissolved in a mixture of 50% aqueous fluoroboric 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. The mixture was stirred at room temperature for 1 h, and diethyl ether (10 mL) was added to precipitate the diazonium compound, which was filtered and washed with diethyl ether (3 x 5 mL). Drying gave isoquinoline-7-tetrafluoroborate diazonium salt (1.02 g, 84%, 4.1857 mmol) as a dark red powder. 1 HNMR (500MHz, DMSO-d6) δ9.77 (d, J=0.9Hz, 1H), 9.75 (d, J=2.1Hz, 1H), 8.97 (d, J= 5.7Hz, 1H), 8.65 (dd, J=9.0, 2.1Hz, 1H), 8.50 (d, J=9.1Hz, 1H), 8.22-8.17 (m, 1H).

[0487] 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-tetrafluoroborate diazonium salt (400.00 mg, 1.6463 mmol) portionwise. After stirring at room temperature for 1.5 h, potassium iodide (409.93 mg, 2.4694 mmol) and iodine (501.41 mg, 1.9756 mmol) were added. After stirring at room temperature for 1.5 h, a solution of brine and sodium thiosulfate was added to the mixture. 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) gave 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):0.96min.

[0488] 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-water bath. 3-Chloro-peroxybenzoic acid (0.15 g, 0.6818 mmol) was added. The reaction was stirred at room temperature for 2 h. K₂CO₃ (0.31 g, 2.2725 mmol) was added, stirred for 0.5 h, and then filtered. 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 afford 7-(5-methyltetrazol-2-yl)-2-oxo-isoquinolin-2-ium (122 mg, 95%, 0.5369 mmol) as a yellow powder. HPLC / MS m / z: 228.1, [M+H] + , Rt(P):1.04min.

[0489] Example 58.4.: 7-(5-Methyltetrazol-2-yl)-2-oxoisoquinolin-2-ium (120.00 mg, 0.5281 mmol) and tert-butyl β-alaninate 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 room temperature 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) gave tert-butyl 3-[[7-(5-methyltetrazol-2-yl)-1-isoquinolinyl]amino]propanoate (95 mg, 51%, 0.2681 mmol) as an orange powder. HPLC / MS m / z: 355.2, [M+H] + , Rt(T):1.13min.

[0490] Example 58.5.: Tert-butyl 3-[[7-(5-methyltetrazol-2-yl)-1-isoquinolinyl]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 / H 2 O + 0.1% formic acid) gave 3-[[7-(5-methyltetrazol-2-yl)-1-isoquinolinyl]amino]propanoic acid (60 mg, 84%, 0.2011 mmol) as a colorless powder. HPLC / MS m / z: 299.1, [M+H] + , Rt(P):0.98min.

[0491] Example 58.6: 3-[[7-(5-Methyltetrazol-2-yl)-1-isoquinolinyl]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 uL, 1.0057 mmol) was added, and the reaction mixture was stirred at 50° C. for 21 h. Purification was performed by reverse phase column chromatography (eluent: 30-100% MeOH / H 2 O + 0.1% formic acid) followed by ion exchange SCX-II column chromatography, washing with MeOH and then eluting with 2M NH 3 in MeOH. Trituration with MeOH gave 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):2.69min. 1 H NMR (600MHz, DMSO-d6) δ11.84 (s, 1H), 8.96 (d, J=2.1Hz, 1H), 8.28 (dd, J=8.8, 2.1Hz, 1H), 8.06-7.90 (m, 3H ), 7.02 (d, J=5.8Hz, 1H), 3.81-3.74 (m, 2H), 2.80 (t, J=6.8Hz, 2H), 2.62 (s, 3H), 2.28 (s, 3H), 1.35 (s, 9H).

[0492] Example 59: N-(3-((5-(tert-Butyl)-4-methylthiazol-2-yl)amino)-3-oxopropyl)-3-(5-methyl-2H-tetrazol-2-yl)benzamide

[0493]

[0494] Example 59.1.: Ethyl 3-aminobenzoate (0.81 mL, 5 mmol) was dissolved in a mixture of water (1.00 mL) and 50% aqueous fluoroboric 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 Et2O and dried to give 3-(ethoxycarbonyl)benzenediazonium tetrafluoroborate (1.19 g, 90%, 4.489 mmol). 1 H NMR (600MHz, DMSO-d6) δ9.26 (t, J=1.9Hz, 1H), 8.88 (ddd, J=8.3, 2.1, 1.1Hz, 1H), 8.70 (d t, J=8.0, 1.4Hz, 1H), 8.12 (t, J=8.1Hz, 1H), 4.42 (q, J=7.1Hz, 2H), 1.37 (t, J=7.1Hz, 3H).

[0495] 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) portionwise. After stirring at room temperature 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 room temperature for 1.5 h, and then 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: 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):1.46min.

[0496]

[0146] 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 stirred at 50 °C for 2 h. The mixture was cooled to room temperature, 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):1.23min.

[0497] 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 uL, 1.3442 mmol) was added and the reaction mixture was stirred at 50° C. for 2 h. The mixture was cooled to room temperature and diluted with a mixture of water and EtOAc. The product was extracted with EtOAc, washed with water, dried over MgSO 4 , and concentrated in vacuo. Purification by reverse phase column chromatography (eluent: 30-100% MeOH / H2O + 0.1% formic acid) gave 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):2.98min. 1 H NMR (500MHz, DMSO-d6) δ11.86 (s, 1H), 8.92 (t, J=5.6Hz, 1H), 8.52 (t, J=1.9Hz, 1H), 8.21 (ddd, J=8.1, 2.2, 1.0Hz, 1H), 8.03 (ddd, J =7.8, 1.6, 1.0Hz, 1H), 7.75 (t, J = 8.0Hz, 1H), 3.58 (q, J = 6.7Hz, 2H), 2.69 (t, J = 6.9Hz, 2H), 2.61 (s, 3H), 2.29 (s, 3H), 1.35 (s, 9H).

[0498] 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

[0499]

[0500] Example 60.1.: Ethyl 3-aminobenzoate (0.81 mL, 5 mmol) was dissolved in a mixture of water (1.00 mL) and 50% aqueous fluoroboric 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 Et2O. The solid was transferred to a flask and dried under vacuum for 30 min to give 3-ethoxycarbonylbenzenediazonium; tetrafluoroboron compound (1.1 g, 83%, 4.167 mmol) as a light pink powder. HPLC / MS m / z: 177.07, [M+H] + , Rt(T):0.31min.

[0501] 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) were added portionwise 3-ethoxycarbonylbenzenediazonium and tetrafluoroboron (1.10 g, 4.167 mmol). After stirring for 1.5 h at room temperature, potassium iodide (1.04 g, 6.2505 mmol) and iodine (1.27 g, 5.0004 mmol) were added, and the mixture was stirred for 1.5 h at room temperature. 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) gave 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):1.36min.

[0502]

[0114] 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 were added to help dissolve the LiOH and the mixture was stirred for 1 hour and 15 minutes. The mixture was cooled to room temperature, 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):1.13min.

[0503] 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 room temperature for 3 days. EtOAc and NaHCO3 solution were added. The product was extracted with EtOAc, washed with water, and dried over MgSO4. Purification by silica gel column chromatography (eluent: 10-50% EtOAc in cyclohexane) gave 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):1.50min.

[0504] Example 60.5.: A procedure analogous to that of Examples 152.6 to 152.8 was used using (3S)-tert-butyl 6-[tert-butoxycarbonyl(methyl)amino]-3-[[3-(5-methyltetrazol-2-yl)benzoyl]amino]hexanoate to afford (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 as a colorless powder (36 mg, 56%, 0.0722 mmol). HPLC / MS m / z: 499.3, [M+H] + , Rt(U):2.66min. 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: 2xNH was not observed).

[0505] Example 61: Ethyl 2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0506]

[0507] To a solution of ethyl 2-aminothiazole-5-carboxylate (37.11 mg, 0.2155 mmol), 3-[[3-(5-methyl-1,2,4-oxadiazole-3-yl)benzoyl]amino]propionic 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 distributed between water (50 mL) and EtOAc (40 mL). The organic phase was washed with water (40 mL), 1N HCl (20 mL), saturated aqueous bicarbonate solution (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by reverse phase chromatography (eluent: 30-100% MeOH in water (both + 0.1% formic acid modifier)) to give ethyl 2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate (10 mg, 13%, 0.0233 mmol) as a colorless fluffy powder. HPLC / MS m / z: 430.1 [M+H] + , Rt(Q):2.75min. 1 HNMR (500MHz, DMSO-d6) δ12.66 (s, 1H), 8.89 (t, J = 5.5Hz, 1H), 8.47 (t, J = 1.7Hz, 1H), 8.17-8.11 (m, 2H), 8.07-8.01 (m, 1H), 7 .66 (t, J=7.8Hz, 1H), 4.28 (q, J=7.1Hz, 2H), 3.62 (q, J=6.5Hz, 2H), 2.82 (t, J=6.8Hz, 2H), 2.69 (s, 3H), 1.29 (t, J=7.1Hz, 3H).

[0508] Example 62: Methyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0509]

[0510] Under nitrogen, 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionic acid [Example 63.3] (99.00 mg, 0.3597 mmol), 2-amino-4-methyl-thiazole-5-carboxylic acid methyl ester (73.49 mg, 0.4267 mmol) and HOBt (97.19 mg, 0.7193 mmol) in DMF (1.80 mL) were 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 phase was retained and the aqueous phase was re-extracted with fresh EtOAc. The organic phases were combined, washed with saturated aqueous bicarbonate solution (30 mL) and brine (30 mL) and dried over MgSO 4 . Concentrated in vacuo to give a yellow crude product (approximately 150 mg). This was purified by reverse column chromatography (eluent: 30-100% MeOH in water (both + 0.1% formic acid modifier)) to give methyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate (40 mg, 26%, 0.0931 mmol) as a colorless powder. HPLC / MS m / z: 430.1 [M+H] + , Rt(Q):3.08min. 1 H NMR (500MHz, DMSO-d6) δ12.66 (s, 1H), 8.89 (t, J = 5.5Hz, 1H), 8.47 (t, J = 1.7Hz, 1H), 8.17-8.11 (m, 2H), 8.07-8.01 (m, 1H), 7. 66 (t, J=7.8Hz, 1H), 4.28 (q, J=7.1Hz, 2H), 3.62 (q, J=6.5Hz, 2H), 2.82 (t, J=6.8Hz, 2H), 2.69 (s, 3H), 1.29 (t, J=7.1Hz, 3H).

[0511] Example 63: Propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0512]

[0513] 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. The mixture was partitioned between EtOAc and water. The organic phase was washed with saturated aqueous bicarbonate solution and brine, then dried over MgSO4. Purification by silica gel column chromatography (eluent: 25-60% EtOAc in cyclohexane) gave 2-amino-4-methyl-thiazole-5-carboxylic acid propyl ester (115 mg, 45%, 0.5743 mmol) as an off-white powder. HPLC / MS m / z:201.1[M+H] + , Rt(R):1.00min.

[0514] 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). The mixture was stirred at room temperature 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 organic phases were combined and washed with saturated aqueous bicarbonate solution (150 mL) and brine (200 mL), then dried 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):1.02min.

[0515] 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 hour and 20 minutes, the THF was removed in vacuo. The solution was acidified to pH 3 with 1M citric acid solution and extracted with EtOAc (2x100 mL). The organic phases were combined, washed with brine (150 mL) and dried over MgSO4. This gave 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionic acid (917.3 mg, 86%, 3.3325 mmol) as a colorless solid. HPLC / MS m / z:276.1[M+H] + , Rt(R):0.93min.

[0516] Example 63.4.: 2-Amino-4-methyl-thiazole-5-carboxylic acid propyl ester (24.00 mg, 0.1198 mmol), 1-hydroxybenzotriazole (32.39 mg, 0.2397 mmol), 3-(ethyliminomethylene-amino)-N,N-dimethyl-propan-1-amine, HCl (37.21 mg, 0.2397 mmol) and 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionic acid (42.88 mg, 0.1558 mmol) were dissolved in dry DMF (0.60 mL) at room temperature for 60 h. The reaction mixture was diluted with EtOAc and washed with NaHCO (2x8 mL) and water (8 mL), dried over MgSO and concentrated under reduced pressure. Purification by reverse phase column chromatography (eluent: 30-100% MeOH / H2O + 0.1% formic acid) gave propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate (30 mg, 55%, 0.0656 mmol) as an off-white solid. HPLC / MS m / z: 458.1 [M+H] + , Rt(S):2.93min. 1H NMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.86 (t, J=5.5Hz, 1H), 8.46 (t, J=1.7Hz, 1H), 8.12 (dt, J=7.7, 1.4Hz, 1H), 8.05-8.01 (m, 1H), 7.65 (t, J=7. 8Hz, 1H), 4.15 (t, J=6.5Hz, 2H), 3.60 (q, J=6.6Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.68 (s, 3H), 2.53 (s, 3H), 1.72-1.62 (m, 2H), 0.93 (t, J=7.4Hz, 3H).

[0517] The following examples were prepared in a similar manner:

[0518] Example 64: N-(3-((5-butyl-4-methylthiazol-2-yl)amino)-3-oxopropyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide

[0519]

[0520] 31 mg (27%). HPLC / MS m / z: 428.18[M+H] + , Rt(R):1.44min. 1 H NMR (500MHz, DMSO-d6) δ11.90 (s, 1H), 8.85 (t, J=5.5Hz, 1H), 8.47 (t, J=1.7H z, 1H), 8.12 (dt, J=7.7, 1.4Hz, 1H), 8.03 (dt, J=7.9, 1.4Hz, 1H), 7.65 (t, J=7 .8Hz, 1H), 3.57 (q, J=6.7Hz, 2H), 2.69 (d, J=9.5Hz, 5H), 2.63 (t, J=7.4Hz, 2H ), 2.14 (s, 3H), 1.57-1.42 (m, 2H), 1.39-1.24 (m, 2H), 0.88 (t, J=7.4Hz, 3H).

[0521] Example 65: Ethyl 4-methyl-2-(3-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)butyrylamino)thiazole-5-carboxylate

[0522]

[0523] 3-Amino-3-methyl-butyric acid ethyl ester hydrochloride was used to prepare 4-methyl-2-(3-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)butyrylamino)thiazole-5-carboxylic acid ethyl ester (40 mg, 33%, 0.0848 mmol) as a colorless solid. HPLC / MS m / z: 472.17, [M+H] + , Rt(S):2.98min. 1 H NMR (500MHz, DMSO-d6) δ12.46 (s, 1H), 8.38 (t, J=1.7Hz, 1H), 8.22 (s, 1H), 8.11 (dt, J=7.8, 1.4Hz, 1H), 7.97 (dt, J=7.9, 1.4Hz , 1H), 7.64 (t, J=7.8Hz, 1H), 4.21 (q, J=7.1Hz, 2H), 3.07 (s, 2H), 2.68 (s, 3H), 2.52 (s, 3H), 1.48 (s, 6H), 1.26 (t, J=7.1Hz, 3H).

[0524] Example 66: Isopropyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0525]

[0526] Example 66.1.: Prepared similarly to the procedure of Example 63 using 2-amino-4-methyl-thiazole-5-carboxylic acid to give 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylic acid as a brown powder (84 mg, 62%, 0.2022 mmol). HPLC / MS m / z: 416.1 [M+H] + , Rt(R):1.13min.

[0527] Example 66.2.: 4-Methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylic acid (40.00 mg, 0.0963 mmol) was dissolved in dry DCM (1.50 mL). The mixture was stirred at room temperature for 6 h, and then 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 give isopropyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoylamino)propionylamino)thiazole-5-carboxylate (22 mg, 50%, 0.0481 mmol) as a colorless powder. HPLC / MS m / z:458.2[M+H] + , Rt(S):2.90min. 1 H NMR (500MHz, DMSO-d6) δ12.52 (s, 1H), 8.86 (t, J=5.5Hz, 1H), 8.47-8.44 (m, 1H), 8.13 (ddd, J=7.7, 1.7, 1.2Hz, 1H), 8.02 (ddd, J=7.8, 1.9, 1.2Hz, 1H ), 7.65 (td, J=7.7, 0.5Hz, 1H), 5.05 (hept, J=6.3Hz, 1H), 3.63-3.57 (m, 2H ), 2.78 (t, J=6.8Hz, 2H), 2.68 (s, 3H), 2.53 (s, 3H), 1.28 (d, J=6.2Hz, 6H).

[0528] The following examples were prepared similarly.

[0529] Example 67: 2-methoxyethyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0530]

[0531] 23 mg (50%) colorless amorphous solid. HPLC / MS m / z: 474.1 [M+H] + , Rt(S):2.59min. 1H NMR (500MHz, DMSO-d6) δ12.55 (s, 1H), 8.86 (t, J=5.5Hz, 1H), 8.46 (td, J=1.8, 0.5Hz, 1H), 8.13 (ddd, J=7.7, 1.8, 1.2Hz, 1H), 8.02 (ddd, J=7.9, 1 .9, 1.2Hz, 1H), 7.65 (td, J=7.7, 0.6Hz, 1H), 4.34-4.28 (m, 2H), 3.63-3. 55 (m, 4H), 3.29 (s, 3H), 2.79 (t, J=6.8Hz, 2H), 2.68 (s, 3H), 2.54 (s, 3H).

[0532] Example 68: Isobutyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0533]

[0534] 18 mg (40%) colorless powder. HPLC / MS m / z: 472.2 [M+H] + , Rt(S):3.06min. 1 HNMR (500MHz, DMSO-d6) δ12.55 (s, 1H), 8.87 (t, J = 5.5Hz, 1H), 8.46 (t, J = 1.7Hz, 1H), 8.13 (dt, J = 7.7, 1.4Hz, 1H), 8.03 (dt, J = 7.9, 1.4Hz, 1H), 7.65 ( t, J=7.8Hz, 1H), 4.00 (d, J=6.4Hz, 2H), 3.66-3.55 (m, 2H), 2.78 (t, J=6.8H z, 2H), 2.68 (s, 3H), 2.54 (s, 3H), 2.02-1.91 (m, 1H), 0.94 (d, J=6.7Hz, 6H).

[0535] Example 69: 4-methoxybutyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0536]

[0537] 30 mg (62%) colorless powder. HPLC / MS m / z: 502.2 [M+H] + , Rt(S):2.83min. 1HNMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.86 (t, J=5.5Hz, 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. 4Hz, 2H), 3.63-3.56 (m, 2H), 3.35 (t, J=6.3Hz, 2H), 3.22 (s, 3H), 2.78 (t, J= 6.8Hz, 2H), 2.68(s, 3H), 2.53(s, 3H), 1.73-1.65(m, 2H), 1.62-1.55(m, 2H).

[0538] Example 70: 4-methyl-2-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)thiazole-5-carboxylic acid propyl ester

[0539]

[0540] Example 70.1.: In a 0.5-2 mL microwave vial, 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) was heated at 160° C. under microwave irradiation for 1 h. The volatiles were removed under reduced pressure. The residue was taken up in saturated bicarbonate solution (15 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined, 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) gave N'-[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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):0.23min.

[0541] 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 room temperature for 3 h. LCMS indicated 50% conversion. The solution was stirred at room temperature over the weekend. LCMS indicated 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) and 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 column chromatography (eluent: 10-100% MeOH in water (both + 0.1% formic acid)). Purification was performed by ion exchange SCX-II column chromatography, washed with MeOH, and then eluted with 2M NH3 in MeOH to give 4-methyl-2-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)thiazole-5-carboxylic acid propyl ester (29 mg, 38%, 0.0603 mmol) as a colorless solid. HPLC / MS m / z: 481.16, [M+H] + , Rt(S):2.61min. 1 H NMR (600MHz, DMSO-d6) δ9.37 (t, J=5.5Hz, 1H), 8.89-8.87 (m, 1H), 8.15 (dd, J= 8.5, 1.5Hz, 1H), 8.03 (t, J=5.5Hz, 1H), 7.99 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5H z, 1H), 7.00-6.96 (m, 1H), 4.22 (t, J=6.5Hz, 2H), 3.72 (q, J=5.6Hz, 2H), 3.59 ( q, J=5.7Hz, 2H), 2.71-2.68 (m, 6H), 1.73-1.65 (m, 2H), 0.94 (t, J=7.4Hz, 3H).

[0542] Example 71: 1-Methyl-3-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)-1H-pyrazole-5-carboxylic acid ethyl ester

[0543]

[0544] To a stirred solution of 5-ethyl 1-methyl-1H-pyrazole-3,5-dicarboxylate (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 was added N'-[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]ethane-1,2-diamine [Example 70] (97.16 mg, 0.3608 mmol). The resulting solution was stirred at room temperature overnight. Purification was performed 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 and then eluting with a mixture of 7M DCM / NH3 (1 / 1) in MeOH to give 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):2.12min. 1 H NMR (600MHz, DMSO-d6) δ8.90-8.86 (m, 1H), 8.78 (t, J=5.7Hz, 1H), 8.15 (dd, J= 8.5, 1.5Hz, 1H), 8.00 (t, J=5.5Hz, 1H), 7.96 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5H z, 1H), 7.37 (s, 1H), 6.99-6.96 (m, 1H), 4.27 (q, J=7.1Hz, 2H), 4.13 (s, 3H), 3. 68 (q, J=6.1Hz, 2H), 3.54 (q, J=6.1Hz, 2H), 2.70 (s, 3H), 1.28 (t, J=7.1Hz, 3H).

[0545] Example 72: 1-methyl-3-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)-1H-pyrazole-5-carboxylic acid propyl ester

[0546]

[0547] 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) at room temperature, and water (0.75 mL) and lithium hydroxide hydrate (24.27 mg, 0.5785 mmol) were added. The resulting solution was heated at 70°C for 4 h. The solution was cooled to room temperature and the volatiles were removed under reduced pressure. Water (2 mL) was added, and the solution was then acidified by adding a few drops of HCl 37% until a pH of around 1 was reached. A solid precipitated in solution, was filtered, washed with water (5 mL) and dried under high vacuum to give 2-methyl-5-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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):1.11min.

[0548] Example 72.2.: 2-Methyl-5-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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 room temperature. 1 M DCC (0.06 mL, 0.0570 mmol) and propan-1-ol (0.04 mL, 0.4746 mmol) were added sequentially, and the reaction mixture was stirred at room temperature 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 and then eluting with 2M NH in MeOH to give (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):2.29min. 1H NMR (600MHz, DMSO-d6) δ8.91-8.87 (m, 1H), 8.79 (t, J=5.7Hz, 1H), 8.15 (dd, J=8.5, 1 .5Hz, 1H), 8.01 (t, J=5.6Hz, 1H), 7.96 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 7.37 ( s, 1H), 6.99-6.94 (m, 1H), 4.18 (t, J=6.6Hz, 2H), 4.13 (s, 3H), 3.69 (q, J=6.1Hz, 2H), 3.54 (q, J=6.1Hz, 2H), 2.70 (s, 3H), 1.68 (sext, J=7.1Hz, 2H), 0.93 (t, J=7.4Hz, 3H).

[0549] Example 73: 1-methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propionylamino)-N-propyl-1H-pyrazole-5-carboxamide

[0550]

[0551] A solution of 2-methyl-5-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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 room temperature for 16 h. 2 equivalents of EDC.HCl, 2 equivalents of HOBt and 5 equivalents of propylamine were added and the resulting solution was stirred at 40° C. for 4 h. Cooled to room temperature and purified by reverse phase column chromatography (eluent: 20-80% MeOH (+0.1% formic acid) in water followed by ion exchange SCX-II column chromatography, washing with MeOH and then eluting with 2M NH3 in MeOH to give 1-methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propionylamino)-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):2.11min. 1H NMR (600MHz, DMSO-d6) δ10.57 (s, 1H), 8.90-8.87 (m, 1H), 8.52 (t, J=5.7Hz, 1H), 8.15 (dd, J= 8.5, 1.6Hz, 1H), 7.99 (d, J=5.7Hz, 1H), 7.94 (t, J=5.4Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 7.16 (s , 1H), 6.97 (d, J=5.7Hz, 1H), 3.95 (s, 3H), 3.78 (td, J=7.1, 5.3Hz, 2H), 3.15 (dt, J=7.3, 6.0H z, 2H), 2.74 (t, J=7.1Hz, 2H), 2.71 (s, 3H), 1.51 (sext, J=7.3Hz, 2H), 0.87 (t, J=7.4Hz, 3H).

[0552] Example 74: 4-methyl-2-(methyl(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)thiazole-5-carboxylic acid propyl ester

[0553]

[0554] Example 74.1.: In a 0.5-2 mL microwave vial, a solution of 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole [Example 45] (50.00 mg, 0.2035 mmol) and tert-butyl N-(2-aminoethyl)-N-methylcarbamate (0.73 mL, 4.0707 mmol) in NMP (0.81 mL) was heated at 160° C. under microwave irradiation for 1 h. The residue was added to water (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, 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)) gave tert-butyl N-methyl-N-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]ethyl]carbamate (60 mg, 77%, 0.1565 mmol) as a pale yellow oil. HPLC / MS m / z: 384.20, [M+H] + , Rt(P):1.25min.

[0555] Example 74.2.: tert-Butyl N-methyl-N-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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 while stirring at room temperature. The mixture was stirred at room temperature for 5.5 h. Purification by ion exchange SCX-II column chromatography, washing with MeOH, then eluting with 2 M NH3 in MeOH, afforded N-methyl-N'-[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]ethane-1,2-diamine (30 mg, 74%, 0.1059 mmol) as a colorless powder. HPLC / MS m / z: 284.15, [M+H] + , Rt(P):0.31min.

[0556] 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 room temperature, water (75 mL) was added, 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% (cyclohexane / EtOAc-9 / 1) in cyclohexane) gave 2-bromo-4-methyl-thiazole-5-carboxylic acid propyl ester (410 mg, 65%, 1.5522 mmol) as a colorless solid. HPLC / MS m / z: 265.97, [M+H] + , Rt(P):1.55min.

[0557] Example 74.4.: A solution of isopropylmagnesium chloride-lithium chloride complex (1.53 mL, 1.9933 mmol) was added to a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid propyl ester (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 (2x15 mL). The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: 0-40% mixture (cyclohexane / EtOAc - 9 / 1) in cyclohexane) gave 2-formyl-4-methyl-thiazole-5-carboxylic acid propyl ester (186 mg, 57%, 0.8722 mmol) as a colorless oil. HPLC / MS m / z: 214.05, [M+H] + , Rt(T):1.35min.

[0558] Example 74.5.: t-BuOH (2.85 mL) was added to a solution of 2-formyl-4-methyl-thiazole-5-carboxylic acid propyl ester (80.00 mg, 0.3751 mmol) and 2-methyl-2-butane (1.19 mL, 11.254 mmol) in THF (3.01 mL). The resulting solution was stirred at room temperature for 10 min. Freshly prepared aqueous sodium chlorite (111.96 mg, 1.238 mmol) and sodium dihydrogen phosphate hydrate (155.30 mg, 1.1254 mmol) in water (0.56 mL) were added and the solution was stirred at room temperature for 15 min. The solution was quenched with saturated Na2S2O3 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 give 4-methyl-5-propyloxycarbonyl-thiazole-2-carboxylic acid (44 mg, 51%, 0.1919 mmol) as a colorless oil, which was used in the next step without further purification. HPLC / MS m / z: 230.05, [M+H] + , Rt(T):1.14min.

[0559] Example 74.6.: To a stirred solution of 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-isoquinolinyl]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 room temperature for 4.5 h. The solution was added to water (15 mL) and the residue was extracted with EtOAc (3 x 10 mL). Purification was performed 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, then eluting with 7M DCM / NH3 in MeOH (1 / 1) gave 4-methyl-2-(methyl(2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)thiazole-5-carboxylic acid propyl ester (24.2 mg, 46%, 0.0489 mmol) as a colorless solid. HPLC / MS m / z: 495.18, [M+H] + , Rt(P):2.55min. 1 H NMR (600MHz, DMSO-d6) δ8.57 (s, 1H), 8.05 (dd, J=8.4, 1.5Hz, 1H), 7.89 (t, J= 5.7Hz, 1H), 7.84 (d, J=5.7Hz, 1H), 7.69 (d, J=8.5Hz, 1H), 6.82 (d, J=5.7Hz, 1H ), 4.36-4.31 (m, 2H), 3.94 (t, J=6.6Hz, 2H), 3.61 (q, J=5.2Hz, 2H), 3.13 (s, 3H ), 2.71 (s, 3H), 2.25 (s, 3H), 1.50 (hept, J=6.8Hz, 2H), 0.82 (t, J=7.4Hz, 3H).

[0560] Example 75: N-(5-(tert-Butyl)-4-methylthiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)acrylamide

[0561]

[0562] 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 at 100°C under a nitrogen atmosphere overnight. After cooling to room temperature, water (6 mL) was added. The resulting solution was purified directly by reverse phase column chromatography (eluent: 20-70% MeOH in water (both + 0.1% formic acid modifier)) to give 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoic acid (503 mg, 94%, 1.6862 mmol) as a light brown powder. HPLC / MS m / z: 299.11, [M+H] + , Rt(R):0.78min.

[0563] Example 75.2.: To 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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 room temperature overnight. Water (2 mL) was added and the residue was extracted with DCM (3 x 1 mL) using a small phase separator column. The organic layers were combined and concentrated under reduced pressure. Purification was performed 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). Ion exchange SCX-II column chromatography, washing the column with MeOH and then eluting with 2M NH3 in MeOH, afforded 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):2.69min. 1HNMR (500MHz, DMSO-d6) δ11.87 (s, 1H), 8.93-8.85 (m, 1H), 8.15 (dd, J=8.5, 1.6Hz, 1H), 8.03-7.95 (m, 2H), 7.86 (d, J=8. 4Hz, 1H), 6.98 (dd, J=5.9, 0.9Hz, 1H), 3.83-3.75 (m, 2H), 2.81 (t, J=6.9Hz, 2H), 2.71 (s, 3H), 2.30 (s, 3H), 1.36 (s, 9H).

[0564] The following examples were synthesized by similar procedures:

[0565] 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)acrylamide

[0566]

[0567] 7 mg (30%) pale yellow solid. HPLC / MS m / z: 406.20, [M+H] + , Rt(S):2.04min. 1 HNMR (600MHz, DMSO-d6) δ10.28 (s, 1H), 8.90-8.87 (m, 1H), 8.14 (dd, J=8.5, 1.5Hz, 1H), 7.98 (d, J=5.7Hz, 1H), 7.93 (t, J=5.4Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 6.95 (d, J=5.7Hz, 1H), 6.32 (s, 1H), 3.74 (td, J=7.1, 5.3Hz, 2H), 3.59 ( s, 3H), 2.69 (d, J=8.3Hz, 5H), 2.56 (q, J=7.5Hz, 2H), 1.16 (t, J=7.5Hz, 3H).

[0568] Example 77: N-(5-(tert-butyl)isoxazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)acrylamide

[0569]

[0570] 10 mg (41%) colorless solid. HPLC / MS m / z: 421.20, [M+H] + , Rt(S):2.41min. 1HNMR (600MHz, DMSO-d6) δ10.98 (s, 1H), 8.92-8.83 (m, 1H), 8.14 (dd, J=8.5, 1.5Hz, 1H), 7.97 (d, J=5.7Hz, 1H), 7.95 (t, J=5.4Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 7.00-6.92 (m, 1H), 6.61 (s, 1H), 3.80-3.74 (m, 2H), 2.77 (t, J=6.9Hz, 2H), 2.70 (s, 3H), 1.28 (s, 9H).

[0571] Example 78: N-(5-cyclopropylisoxazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)acrylamide

[0572]

[0573] 9 mg (41%) colorless solid. HPLC / MS m / z: 405.17, [M+H] + , Rt(P):1.21min. 1 HNMR (600MHz, DMSO-d6) δ10.92 (s, 1H), 8.90-8.84 (m, 1H), 8.14 (dd, J=8.5, 1.5H z, 1H), 7.97 (d, J = 5.8Hz, 1H), 7.95 (d, J = 5.4Hz, 1H), 7.84 (d, J = 8.5Hz, 1H), 6.96 ( d, J=5.7Hz, 1H), 6.58 (s, 1H), 3.76 (td, J=6.9, 5.2Hz, 2H), 2.77 (t, J=6.9Hz, 2H) , 2.70 (s, 3H), 2.10 (tt, J=8.5, 5.0Hz, 1H), 1.07-0.99 (m, 2H), 0.90-0.82 (m, 2H).

[0574] Example 79: N-(5-ethylisoxazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide

[0575]

[0576] 1 mg (4%) of colorless oil. HPLC / MS m / z: 393.17, [M+H]+, Rt(S): 2.10 min. 1HNMR (600MHz, DMSO-d6) δ11.56 (s, 1H), 8.90-8.86 (m, 1H), 8.15 (dd, J=8.5, 1.5Hz, 1H), 7.99 (d, J=5.4Hz, 1H), 7.97 (d, J=5.8Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 6.97 (d, J=5.7Hz, 1H), 6.17 (s, 1H), 3.78 (q, J=6.6Hz, 2H), 2.80 (t , J=6.8Hz, 2H), 2.70 (s, 3H), 2.56 (q, J=7.6Hz, 2H), 1.16 (t, J=7.6Hz, 3H).

[0577] Example 80: N-(5-(tert-Butyl)thiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide

[0578]

[0579] 8mg (27%). HPLC / MS m / z: 437.17, [M+H] + , Rt(Q):2.62min. 1 H NMR (600MHz, DMSO-d6) δ11.94 (s, 1H), 8.91-8.84 (m, 1H), 8.14 (dd, J=8.5, 1.6Hz, 1H), 7.99 (t, J=5.4Hz, 1H), 7.98 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 7.12 (s, 1H), 6.97 (dd, J=5.9, 0.8Hz, 1H), 3.79 (td, J=6.8, 5.2Hz, 2H), 2.83 (t, J=6.8Hz, 2H), 2.70 (s, 3H), 1.32 (s, 9H).

[0580] 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

[0581]

[0582] 9.5 mg (30%) colorless solid. HPLC / MS m / z: 465.21, [M+H] + , Rt(U):2.92min. 1HNMR (600MHz, DMSO-d6) δ11.88 (s, 1H), 8.91-8.85 (m, 1H), 8.14 (dd, J=8.4, 1.5Hz, 1H), 8.02-7.93 (m, 2H), 7.85 (d, J=8.5Hz, 1H), 7.00- 6.93 (m, 1H), 3.78 (td, J=6.9, 5.4Hz, 2H), 2.80 (t, J=6.9Hz, 2H), 2.70 (s, 3H), 2.64 (q, J=7.4Hz, 2H), 1.36 (s, 9H), 1.15 (t, J=7.4Hz, 3H).

[0583] 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

[0584]

[0585] 13 mg (45%) colorless solid. HPLC / MS m / z: 434.23, [M+H] + , Rt(U):2.41min. 1 HNMR (600MHz, DMSO-d6) δ10.29 (s, 1H), 8.89 (s, 1H), 8.14 (dd, J=8.5, 1.5Hz, 1H), 7.98 (d, J=5.7Hz, 1H), 7.94 (s, 1H) , 7.84 (d, J=8.5Hz, 1H), 6.96 (d, J=5.8Hz, 1H), 6.33 (s, 1H), 3.79-3.71 (m, 5H), 2.69 (d, J=11.8Hz, 5H), 1.31 (s, 9H).

[0586] Example 83: N-[5-(3-methoxyoxetan-3-yl)-4-methyl-thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide

[0587]

[0588] 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 in MeOH and evaporated to dryness. Purification was performed by silica gel column chromatography (eluent: 0-30% EtOAc in cyclohexane) to give 2-(2,5-dimethylpyrrol-1-yl)-4-methyl-thiazole (565.7 mg, 67%, 2.9421 mmol) as a light yellow oil. HPLC / MS m / z: 193.08, [M+H] + , Rt(T):1.35min.

[0589] Example 83.2.: 1.6M 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 was slightly warmed 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 gradually warmed to room temperature (overnight). 1.65 mL of saturated NH4Cl aqueous solution was added dropwise and the volatiles were evaporated to near completion. The crude product 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 4 , filtered and evaporated to dryness. Purification by silica gel column chromatography (eluent: 20-80% EtOAc in cyclohexane) gave 3-[2-(2,5-dimethylpyrrol-1-yl)-4-methyl-thiazol-5-yl]oxetan-3-ol (220 mg, 80%, 0.8323 mmol) as a light yellow thin layer. HPLC / MS m / z: 265.10, [M+H] + , Rt(T):1.22min.

[0590] 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 room temperature and stirred 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 afford 2-(2,5-dimethylpyrrol-1-yl)-5-(3-methoxyoxetan-3-yl)-4-methylthiazole (230.5 mg, 99%, 0.8280 mmol) as a light brown solid. This compound was used without further purification. HPLC / MS m / z: 279.12, [M+H] + , Rt(T):1.35min.

[0591] 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-methyl-thiazole (79.00 mg, 0.2838 mmol) and MeOH (0.69 mL) in a vial. The vial was capped and irradiated at 90 ° C for 15 min. The volatiles were carefully evaporated to dryness. The crude product obtained was purified by SCX-II column (2 g, 15 mL). The base fractions were evaporated to dryness. Purification by silica gel column chromatography (eluent: 5% MeOH in DCM) gave 5-(3-methoxyoxetan-3-yl)-4-methyl-thiazole-2-amine (11.2 mg, 20%, 0.056 mmol). HPLC / MS m / z: 171.06, [M+H] + , Rt(T):0.44min.

[0592] Example 83.5.: Using 5-(3-methoxyoxetan-3-yl)-4-methyl-thiazol-2-amine and the procedure of 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-isoquinolinyl]amino]propanamide was obtained as a colorless amorphous solid (1.2 mg, 3%). HPLC / MS m / z: 481.16 [M+H] + , Rt(T):1.04min. 1H NMR (500MHz, DMSO-d6) δ11.90 (brs, 1H), 8.91-8.86 (m, 1H), 8.15 (dd, J=8.5, 1.6Hz, 1H), 8.02 (d, J=5.3Hz, 1H), 7.97 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 6.69 (d, J=6.2Hz, 1H), 4.78 (s, 4H), 3.80 (q, J=6.5Hz, 2H), 3.05 (s, 3H), 2.85 (t, J=6.8Hz, 2H), 2.70 (s, 3H), 2.13 (s, 3H).

[0593] Example 84: 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-N-[4-methyl-5-(3-propoxyoxetan-3-yl)thiazol-2-yl]acrylamide

[0594]

[0595] Example 84.1.: 2-(2,5-Dimethylpyrrol-1-yl)-4-methyl-5-(3-propoxyoxetan-3-yl)thiazole was prepared using iodopropane according to the procedure of Example 83. 2-(2,5-Dimethylpyrrol-1-yl)-4-methyl-5-(3-propoxyoxetan-3-yl)thiazole (162.5 mg, 99%, 0.5303 mmol) was obtained as a light brown gum. HPLC / MS m / z: 307.15, [M+H] + , Rt(T):1.52min.

[0596] 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 hours and 5 minutes. The reaction mixture was evaporated to dryness and then purified by an SCX-II column (2 g, 15 mL) using MeOH and 2M NH3 in MeOH. Purification by silica gel column chromatography (eluent: 0-15% MeOH in DCM) gave 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):0.73min.

[0597] Example 84.3.: Using 4-methyl-5-(3-propoxyoxetan-3-yl)thiazol-2-amine and the procedure of Example 45.7, 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-N-[4-methyl-5-(3-propoxyoxetan-3-yl)thiazol-2-yl]propanamide was obtained as a light brown solid (17 mg, 71%). HPLC / MS m / z: 509.20 [M+H] + , Rt(P):1.34min. 1 H NMR (600MHz, DMSO-d6) δ12.16 (s, 1H), 8.95-8.81 (m, 1H), 8.15 (dd, J=8.5, 1.6Hz, 1 H), 8.00 (t, J=5.5Hz, 1H), 7.97 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 7.01-6.92 (m, 1H), 4.78 (s, 4H), 3.80 (q, J=6.7Hz, 2H), 3.12 (t, J=6.5Hz, 2H), 2.85 (t, J=6.8H z, 2H), 2.70 (s, 3H), 2.14 (s, 3H), 1.48 (sext, J=7.1Hz, 2H), 0.83 (t, J=7.4Hz, 3H).

[0598] Example 85: N,4-dimethyl-2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionylamino]-N-propyl-thiazole-5-carboxamide

[0599]

[0600] Example 85.1.: Under nitrogen, 2-amino-4-methyl-thiazole-5-carboxylic acid (100.00 mg, 0.6322 mmol), DIPEA (0.44 mL, 2.5288 mmol), and HATU (223.09 mg, 0.9483 mmol) were suspended in dry DMF (3.61 mL), followed by the addition of N-methylpropan-1-amine (0.10 mL, 0.9483 mmol). The mixture was stirred at room temperature for 22 h. The reaction mixture was partitioned between EtOAc (50 mL) and water (40 mL). The organic phase was retained and washed with saturated aqueous bicarbonate solution (50 mL) and brine (50 mL), dried over MgSO₄, and concentrated in vacuo to dryness to afford 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):0.63min.

[0601] Example 85.2. Using 2-amino-N,4-dimethyl-N-propyl-thiazole-5-carboxamide and the procedure of Example 45.7, N,4-dimethyl-2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionylamino]-N-propyl-thiazole-5-carboxamide (24.6 mg, 50%, 0.0498 mmol) was obtained as a clear thin layer. HPLC / MS m / z: 494.20 [M+H] + , Rt(T):1.07min. 1 H NMR (600MHz, MeOD-d4) δ8.87-8.77 (m, 1H), 8.20 (dd, J=8.5, 1.6Hz, 1H), 7.95 (dd, J=6.0, 1.7Hz, 1H), 7.86-7.76 (m, 1H), 6.99 (dt, J=5.9, 1.4Hz, 1H ), 3.96 (t, J=6.7Hz, 2H), 3.50-3.41 (m, 2H), 3.06 (s, 3H), 2.96 (t, J=6.7H z, 2H), 2.69 (s, 3H), 2.28 (s, 3H), 1.66 (brd, J=8.5Hz, 2H), 0.90 (brs, 3H).

[0602] Example 86: N-[5-(Cyclohexen-1-yl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]acrylamide

[0603]

[0604] 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) was added 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionic acid (20.00 mg, 0.0670 mmol) in DMF (0.34 mL) under nitrogen atmosphere, 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)) gave N-[5-(cyclohexen-1-yl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide (8.2 mg, 27%, 0.0178 mmol) as a colorless solid. HPLC / MS m / z: 461.18 [M+H] + , Rt(T):1.36min. 1 H NMR (600MHz, DMSO-d6) δ12.08 (s, 1H), 8.88 (d, J=1.6Hz, 1H), 8.14 (dd, J=8.5, 1.5Hz, 1H), 8.0 1(t, J=5.4Hz, 1H), 7.97 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 7.30 (s, 1H), 6.97 (d, J=5.7H z, 1H), 5.97 (tt, J=4.0, 1.6Hz, 1H), 3.79 (q, J=6.4Hz, 2H), 2.85 (t, J=6.8Hz, 2H), 2.70 (s, 3H) , 2.33 (ddt, J=6.4, 4.4, 2.0Hz, 2H), 2.21-2.11 (m, 2H), 1.72-1.65 (m, 2H), 1.62-1.54 (m, 2H).

[0605] Example 87: N-[5-(1-methoxycyclohexyl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]acrylamide

[0606]

[0607] To 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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 uL, 0.2414 mmol). The resulting solution was stirred at room temperature for 19 h. Purification 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, washing with MeOH and then eluting with 2M NH3 in MeOH, gave a mixture of N-[5-(1-hydroxycyclohexyl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide and N-[5-(1-methoxycyclohexyl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide. Using 5% Preparative TLC (500 μm) using MeOH as the eluent gave N-[5-(1-methoxycyclohexyl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide (3 mg, 8%) as a colorless amorphous solid. HPLC / MS m / z: 493.21 [M+H] + , Rt(P):1.34min. 1 H NMR (600MHz, DMSO-d6) δ12.07 (s, 1H), 8.89 (d, J=1.6Hz, 1H), 8.15 (dd, J=8.5, 1.5Hz, 1 H), 8.01 (t, J=5.4Hz, 1H), 7.97 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 7.29 (s, 1H), 6. 97 (d, J=5.7Hz, 1H), 3.80 (q, J=6.4Hz, 2H), 2.93 (s, 3H), 2.85 (t, J=6.8Hz, 2H), 2.70 (s , 3H), 1.96 (d, J=13.4Hz, 2H), 1.82-1.68 (m, 2H), 1.61-1.42 (m, 3H), 1.30-1.21 (m, 3H).

[0608] Example 88: 4-Isopropyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylic acid ethyl ester

[0609]

[0610] To a stirred solution of 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionic 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 room temperature, 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 column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 20-100% gradient) to give 0.031 g (57%) as an off-white solid. HPLC / MS m / z:472.16[M+H] + , Rt(R):1.42min. 1 H NMR (500MHz, DMSO-d6) δ12.59 (s, 1H), 8.85 (t, J = 5.5Hz, 1H), 8.46 (t, J = 1.7Hz, 1H), 8.13 (dt, J=7.8, 1.3Hz, 1H), 8.02 (dt, J=7.9, 1.3Hz, 1H), 7.65 (t, J=7.8Hz, 1H), 4.24 (q, J=7.1Hz, 2H), 3.89 (quint, J=6.9Hz, 1H), 3.60 (q, J=6.6Hz, 2H), 2 .78 (t, J=6.8Hz, 2H), 2.68 (s, 3H), 1.27 (t, J=7.1Hz, 3H), 1.18 (d, J=6.8Hz, 6H).

[0611] The following examples were prepared in a similar manner:

[0612] Example 89: tert-Butyl 4-methyl-2-(3-(3-(1-methyl-1H-pyrazol-4-yl)benzamido)propionamido)thiazole-5-carboxylate

[0613]

[0614] Using 3-(1-methylpyrazol-4-yl)benzoic acid and the procedure from Example 63.3, 3-[[3-(1-methylpyrazol-4-yl)benzoyl]amino]propanoic acid was obtained, which was used in the above procedure to give 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 light yellow powder. HPLC / MS m / z: 470.2, [M+H] + , Rt(Z):2.72min. 1 H NMR (600MHz, DMSO-d6) δ12.43 (s, 1H), 8.62 (t, J = 5.6Hz, 1H), 8.16 (d, J = 0.8Hz, 1H), 7.99 (t, J = 1.8Hz, 1H), 7.88 (d, J = 0.9Hz, 1H), 7.69 (ddd, J = 7.7, 1 .8, 1.1Hz, 1H), 7.62 (dt, J=7.8, 1.3Hz, 1H), 7.43 (t, J=7.7Hz, 1H), 3.87 (s , 3H), 3.63-3.55 (m, 2H), 2.77 (t, J=6.8Hz, 2H), 2.50 (s, 3H), 1.50 (s, 9H).

[0615] Example 90: 4-ethyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylic acid methyl ester

[0616]

[0617] To a stirred solution of 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionic acid [Example 63.3] (35 mg, 0.13 mmol), 2-amino-4-ethyl-thiazole-5-carboxylic acid methyl ester (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 room temperature, and the resulting mixture was stirred for 17 h. The reaction mixture was diluted with saturated 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 column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 20-100% gradient) to give 0.035 g (64%) as an off-white solid. HPLC / MS m / z:444.13[M+H] + , Rt(R):1.30min.1 H NMR (500MHz, DMSO-d6) δ12.58 (s, 1H), 8.86 (t, J = 5.5Hz, 1H), 8.46 (t, J = 1.7Hz, 1H), 8.13 (dd, J = 7.8, 1.7Hz, 1H), 8.02 (dd, J = 7.8, 1.7Hz, 1H) ), 7.65 (t, J=7.8Hz, 1H), 3.77 (s, 3H), 3.64-3.56 (m, 2H), 2.98 (q, J=7.5Hz, 2H), 2.78 (t, J=6.8Hz, 2H), 2.68 (s, 3H), 1.17 (t, J=7.5Hz, 3H).

[0618] Example 91: Ethyl 2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]-4-(trifluoromethyl)thiazole-5-carboxylate

[0619]

[0620] To a stirred solution of 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionic 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 room temperature, and the resulting mixture was stirred for 17 h. The reaction mixture was diluted with saturated 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 column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 20-100% gradient) to give 0.014 g (24%) as an off-white solid. HPLC / MS m / z:498.11[M+H] + , Rt(R):1.37min. 1H NMR (500MHz, DMSO-d6) δ13.10 (s, 1H), 8.86 (t, J=5.6Hz, 1H), 8.45 (t, J=1.7Hz, 1H), 8.13 (dt, J=7.7, 1.4Hz, 1H), 8.02 (dt, J=7.9, 1.4H z, 1H), 7.65 (t, J=7.8Hz, 1H), 4.31 (q, J=7.1Hz, 2H), 3.62 (q, J=6.5Hz, 2H), 2.82 (t, J=6.8Hz, 2H), 2.68 (s, 3H), 1.29 (t, J=7.1Hz, 3H).

[0621] Example 92: 4-ethyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylic acid ethyl ester

[0622]

[0623] At room temperature, to a stirred solution of 3-[[3-(5-methyl-1,2,4-oxadiazole-3-yl)benzoyl]amino]propionic acid [0] (35 mg, 0.13 mmol), 2-amino-4-ethyl-thiazole-5-carboxylic acid ethyl ester (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), and the resulting mixture was stirred for 23 h. The reaction mixture was diluted with saturated 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 column chromatography (eluent: methanol / water, 0.1% formic acid modifier = 40-100% gradient) to obtain 0.023 g (43%) of an off-white solid. HPLC / MS m / z:458.15[M+H] + , Rt(R):1.36min. 1H NMR (500MHz, DMSO-d6) δ12.57 (s, 1H), 8.86 (t, J = 5.5Hz, 1H), 8.46 (t, J = 1.7Hz , 1H), 8.13 (dt, J=7.7, 1.4Hz, 1H), 8.02 (dt, J=7.9, 1.3Hz, 1H), 7.65 (t, J=7.8H z, 1H), 4.23 (q, J=7.1Hz, 2H), 3.60 (q, J=6.5Hz, 2H), 2.98 (q, J=7.5Hz, 2H), 2. 78 (t, J=6.8Hz, 2H), 2.68 (s, 3H), 1.27 (t, J=7.1Hz, 3H), 1.17 (t, J=7.5Hz, 3H).

[0624] Example 93: N-[3-[[5-[(E)-2-Cyclopentylvinyl]-4-methyl-thiazol-2-yl]amino]-3-oxo-propyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide

[0625]

[0626] 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 room temperature, and the resulting mixture was stirred for 20 h. The reaction mixture was diluted with saturated 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 give 0.506 g (52%) of N-[3-[(5-bromo-4-methyl-thiazol-2-yl)amino]-3-oxo-propyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide. HPLC / MS m / z: 450 / 452 Br split [M+H] + , Rt(R):1.35min. 1H NMR (500MHz, DMSO-d6) δ12.36 (s, 1H), 8.87 (t, J=5.5Hz, 1H), 8.46 (t, J=1.7Hz, 1H), 8.12 (dt, J=7.7, 1.4Hz, 1H), 8.02 (dt, J=8.0, 1.4Hz, 1H), 7.65 (t, J=7.8Hz, 1H), 3.58 (q, J=6.5Hz, 2H), 2.75 (t, J=6.8Hz, 2H), 2.69 (s, 3H), 2.21 (s, 3H).

[0627] Example 93.2.: Nitrogen was passed 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 2M aqueous sodium carbonate solution (0.22 mL, 0.44 mmol) for 5 min. Tetrakis(triphenylphosphine)palladium (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 give 0.023 g (44%) as an off-white solid. HPLC / MS m / z: 466.19 [M+H] + , Rt(P):1.67min. 1 H NMR (500MHz, DMSO-d6) δ12.05 (s, 1H), 8.85 (t, J = 5.5Hz, 1H), 8.46 (t, J = 1.7Hz, 1H), 8.13 (dt , J=7.7, 1.4Hz, 1H), 8.03 (dt, J=7.9, 1.3Hz, 1H), 7.65 (t, J=7.8Hz, 1H), 6.48 (dd, J=15.6, 1.1 Hz, 1H), 5.75 (dd, J=15.6, 7.9Hz, 1H), 3.58 (q, J=6.6Hz, 2H), 2.73 (t, J=6.9Hz, 2H), 2.68 (s, 3 H), 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).

[0628] 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

[0629]

[0630] Nitrogen was passed 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) [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 2M aqueous sodium carbonate (0.22 mL, 0.44 mmol) for 5 min. Tetrakis(triphenylphosphine)palladium (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, 0.1% formic acid modifier = 20-100% gradient), and column chromatography (eluent: methanol / dichloromethane = 0-8% gradient) to give 0.011 g (22%) of the product as a light yellow gum. HPLC / MS m / z: 442.15 [M+H] + , Rt(R):1.29min. 1 H NMR (500MHz, MeOD-d4) δ8.49 (td, J=1.7, 0.5Hz, 1H), 8.18 (ddd, J=7.7, 1.7, 1.2H z, 1H), 7.96 (ddd, J=7.8, 1.8, 1.2Hz, 1H), 7.61 (td, J=7.8, 0.6Hz, 1H), 6.74 (dt, J =15.7, 1.4Hz, 1H), 5.89 (dt, J = 15.7, 6.1Hz, 1H), 4.05 (dd, J = 6.1, 1.4Hz, 2H), 3.7 6 (t, J=6.7Hz, 2H), 3.36 (s, 3H), 2.83 (t, J=6.7Hz, 2H), 2.66 (s, 3H), 2.27 (s, 3H).

[0631] 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

[0632]

[0633] Nitrogen was passed 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) [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 2M aqueous sodium carbonate (0.22 mL, 0.44 mmol) for 5 min. Tetrakis(triphenylphosphine)palladium (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 give 0.018 g (34%) of a light yellow gum. HPLC / MS m / z: 474.16 [M+H] + , Rt(R):1.48min. 1 H NMR (500MHz, MeOD-d4) δ8.49 (td, J=1.8, 0.6Hz, 1H), 8.18 (ddd, J=7.7, 1.7, 1.1Hz, 1H), 7.96 (ddd, J=7.8, 1.9, 1.2Hz, 1H), 7.60 (td, J=7.8, 0.6H z, 1H), 7.37-7.29 (m, 5H), 5.64 (d, J=1.1Hz, 1H), 5.37 (d, J=1.2Hz, 1H), 3.76 (t, J=6.7Hz, 2H), 2.84 (t, J=6.7Hz, 2H), 2.65 (s, 3H), 2.02 (s, 3H).

[0634] Example 96: 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]-N-[5-(1,1,2,2,2-pentafluoroethyl)thiazol-2-yl]cyclobutanecarboxamide

[0635]

[0636] 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 stirred at 80°C for 1.5 h. The reaction mixture was cooled to room temperature and mixed thoroughly with EtOAc (250 mL). The emulsion was then mixed with water (750 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with saturated NaCl (3 x 100 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to yield 3.70 g (76%) of N'-hydroxyisoquinoline-7-carboximidamide as an off-white solid. HPLC / MS m / z: 188.0829 [M+H] + , Rt(S):0.37min.

[0637] Example 96.2.: Four separate 20 mL microwave vials were each charged with one-quarter of the following: N'-hydroxyisoquinoline-7-carboximidamide (3.67 g, 19.6 mmol) was mixed with acetonitrile (40 mL) and acetic anhydride (2.2 mL, 23.5 mmol) under an argon atmosphere. Each portion of the reaction mixture was heated at 180°C for 10 min under microwave irradiation. The combined reaction mixture was evaporated onto silica gel and purified by flash chromatography (20-80% EtOAc in cyclohexane) to yield 3.59 g (87%) of 3-(7-isoquinolinyl)-5-methyl-1,2,4-oxadiazole as an off-white solid. HPLC / MS m / z: 212.1 [M+H] + , Rt(R):0.88min.

[0638] Example 96.3.: Under an argon atmosphere, 3-(7-isoquinolinyl)-5-methyl-1,2,4-oxadiazole (3.59 g, 17.0 mmol) was suspended in anhydrous chloroform (57 mL) and cooled in an ice-water bath. 3-Chloroperoxybenzoic acid (4.57 g, 20.4 mmol) was added. The stirred reaction mixture was allowed to warm to ambient temperature and stirring continued overnight. Potassium carbonate (9.40 g, 68.0 mmol) was added. The mixture was stirred at room temperature for 4 h and then filtered through a pad of anhydrous MgSO4. The filtrate was concentrated under reduced pressure to yield 5-methyl-3-(2-oxoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole (3.12 g, 81%) as an off-white powder. HPLC / MS m / z: 228.0713 [M+H] + , Rt(X):1.73min.

[0639] Example 96.4.: 5-Methyl-3-(2-oxoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] (900.00 mg, 3.9609 mmol) and cis-3-amino-cyclobutanecarboxylic acid methyl ester hydrochloride (820.01 mg, 4.9511 mmol) were mixed in DCM (7.92 mL) at room temperature under argon atmosphere. DIPEA (3.28 mL, 18.814 mmol) and PyBrop (2400.46 mg, 5.1492 mmol) were added, and the reaction mixture was stirred at room temperature for 3 days. The volatiles were removed in vacuo and the crude product 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-isoquinolinyl]amino]cyclobutane-carboxylate (1090.6 mg, 81%, 3.2232 mmol) as an off-white solid. HPLC / MS m / z: 339.15, [M+H] + , Rt(T):1.05min.

[0640] Example 96.5.: Methyl 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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 performed by reverse-phase column chromatography (eluent: 5-30% MeOH in water). The fractions were combined and concentrated in vacuo to afford 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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):0.97min.

[0641] Example 96.6.: Methyl 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarboxylate (40.00 mg, 0.1080 mmol) and bis(tetramethylene)fluoroformamidine (68.30 mg, 0.2160 mmol) were mixed in DCM (0.43 mL) at room temperature under a nitrogen atmosphere 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 under microwave for 1 h. The volatiles were removed in vacuo, and the crude reaction mixture was directly purified by flash chromatography (5-70% MeOH [0.1% FA] in water). The product-containing fractions were filtered through a 2 g SCX-2 cartridge. The compound was liberated with 2 M NH3 in MeOH and the solvent removed in vacuo to afford the desired product, 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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):3.05min. 1 H NMR (600MHz, DMSO-d6) δ12.79 (s, 1H), 8.74-9.27 (m, 1H), 8.15 (dd, J=1.6, 8.5Hz, 1H), 8.07-8.12 (m, 2H), 7.96 (d, J=5.7Hz, 1H), 7.85 (d, J=8.5Hz, 1H) , 6.94-7.00 (m, 1H), 4.72 (ddt, J=7.4, 9.3, 16.7Hz, 1H), 3.17 (d, J=5.3Hz, 2H), 2.71 (s, 3H), 2.63 (qd, J=2.6, 7.8Hz, 2H), 2.45 (qd, J=2.6, 9.3Hz, 2H).

[0642] Example 97: N-(5-Bromo-4-methyl-thiazol-2-yl)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarboxamide

[0643]

[0644] At room temperature under nitrogen atmosphere, 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl] amino] cyclobutanecarboxylic acid [Example 96] (265.00 mg, 0.8171 mmol) and bis(tetramethylene)fluoroformamidine (335.86 mg, 1.0622 mmol) were mixed in DCM (3.27 mL) 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-thiazole-2-amine (205.07 mg, 1.0622 mmol) was added. The vial was capped and the reaction was heated at 80 ° C for 2 h in 4% HCl. The volatiles were removed in vacuo and the crude reaction mixture was purified directly by flash chromatography (5-70% MeOH [0.1% FA] in water). The fraction containing the product was filtered through a 2 g SCX-2 column. The compound was liberated with 2N NH3 in MeOH and the solvent was removed in vacuo to give the desired product N-(5-bromo-4-methyl-thiazol-2-yl)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarboxamide (227.2 mg, 55%, 0.4486 mmol) as a light brown solid. HPLC / MS m / z 531.1241 [M+H] + , Rt(U):2.37min. 1 H NMR (600MHz, DMSO-d6) δ12.25 (s, 1H), 8.92-9.11 (m, 1H), 8.14 (dd, J=1.6, 8 .5Hz, 1H), 8.08 (d, J=7.1Hz, 1H), 7.95 (d, J=5.7Hz, 1H), 7.83 (d, J=8.5Hz, 1H ), 6.92-6.99 (m, 1H), 4.70 (tq, J=7.4, 9.3Hz, 1H), 3.07 (tt, J=7.8, 9.8Hz, 1H ), 2.54-2.62 (m, 2H), 2.71 (s, 3H), 2.41 (qd, J=2.6, 9.3Hz, 2H), 2.23 (s, 3H).

[0645] 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

[0646]

[0647] Example 98.1.: 5-Methyl-3-(2-oxoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] (900 mg, 3.96 mmol) and cis-3-amino-cyclobutanecarboxylic acid methyl ester hydrochloride (820 mg, 4.95 mmol) were mixed in anhydrous DCM (7.9 mL) under argon atmosphere at room temperature, DIPEA (3.3 mL, 18.81 mmol) and PyBroP (2.40 g, 5.15 mmol) were added and the reaction mixture was stirred at room temperature 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 (1s,3s)-methyl 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):1.05min.

[0648] 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 [0.1% FA] in water) to yield 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):0.97min.

[0649] Example 98.3. Prepared as described in 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). Purified 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):2.84min. 1H NMR (600MHz, DMSO-d6) δ11.76 (s, 1H), 9.01 (s, 1H), 8.14 (dd, J=8.5, 1.5Hz, 1H), 8.08 (d, J=6.9Hz, 1H), 7.95 (d, J=5.7Hz, 1H), 7.83 (d, J=8.5Hz, 1H), 6.96 (d, J=5.7Hz, 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).

[0650] The following examples were synthesized similarly:

[0651] Example 99: 4-methyl-2-((1s,3s)-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutane-1-carboxamido)thiazole-5-carboxylic acid propyl ester

[0652]

[0653] Prepared as described for Example 47.5 to give 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):2.84min. 1 H NMR (600MHz, DMSO-d6) δ12.48 (s, 1H), 9.01 (s, 1H), 8.15 (dd, J=8.4, 1.5Hz, 1H), 8.12-8.08 (m, 1 H), 7.95 (d, J=5.7Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 6.97 (d, J=5.7Hz, 1H), 4.69 (ddt, J=16.8, 9.2, 7 .3Hz, 1H), 4.16 (t, J=6.5Hz, 2H), 3.11 (ddd, J=17.5, 9.8, 7.8Hz, 1H), 2.71 (s, 3H), 2.64-2.57 (m , 2H), 2.55 (s, 3H), 2.42 (qd, J=9.4, 2.5Hz, 2H), 1.68 (sext, J=7.1Hz, 2H), 0.95 (t, J=7.4Hz, 3H).

[0654] 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

[0655]

[0656] Prepared as described in Example 48 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarboxylic acid [Example 96] (30 mg, 0.093 mmol) and 3-amino-5-tert-butylisoxazole (26 mg, 0.185 mmol). Purified by reverse-phase flash chromatography followed by SCX-2 filtration. Yield: 22 mg (53%) of a colorless amorphous solid. HPLC / MS m / z: 447.2133 [M+H] + , Rt(U):2.62min. 1 H NMR (600MHz, DMSO-d6) δ10.88 (s, 1H), 9.02 (d, J=1.6Hz, 1H), 8.14 (dd, J=8.5, 1.5Hz, 1H), 8.08 (d, J=6.9Hz, 1H), 7.95 (d, J=5.7Hz, 1H), 7.83 (d, J=8. 5Hz, 1H), 6.96 (d, J=5.7Hz, 1H), 6.63 (s, 1H), 4.68-4.58 (m, 1H), 3.04-2.9 6(m, 1H), 2.71(s, 3H), 2.58-2.52(m, 2H), 2.40-2.34(m, 2H), 1.29(s, 9H).

[0657] 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

[0658]

[0659] Prepared as described in Example 48 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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). Purified by reverse-phase flash chromatography followed by SCX-2 filtration. Yield: 23 mg (51%) of off-white amorphous solid. HPLC / MS m / z: 474.2615 [M+H] +, Rt(Q):2.72min. 1 H NMR (600MHz, DMSO-d6) δ10.18 (s, 1H), 9.03 (s, 1H), 8.14 (dd, J=8.5, 1.5Hz, 1H), 8.08 (d, J= 6.9Hz, 1H), 7.95 (d, J=5.7Hz, 1H), 7.83 (d, J=8.5Hz, 1H), 6.95 (d, J=5.7Hz, 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=7.7Hz, 2H), 2.5 2-2.47 (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).

[0660] 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

[0661]

[0662] Prepared as described in Example 96 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarboxylic acid and 5-isobutyl-4-methyl-phenylthio-2-amine. Purified by reverse-phase flash chromatography. Yield: 41 mg (35%). HPLC / MS m / z: 476.21, [M+H] + , Rt(U):2.99min. 1HNMR (500MHz, DMSO-d6) δ10.82 (s, 1H), 9.03 (d, J=1.5Hz, 1H), 8.16 (s, 1H), 8.14 (dd, J=8.5, 1.6Hz , 1H), 8.10 (d, J=7.1Hz, 1H), 7.95 (d, J=5.7Hz, 1H), 7.83 (d, J=8.5Hz, 1H), 6.96 (dd, J=5.9, 0.9Hz, 1 H), 6.36 (s, 1H), 4.68 (sext, J=8.2Hz, 1H), 2.95-2.83 (m, 1H), 2.71 (s, 3H), 2.58-2.50 (m, 2H), 2.46 (d, J=7.1Hz, 2H), 2.43-2.32 (m, 2H), 2.01 (s, 3H), 1.74 (hept, J=6.7Hz, 1H), 0.89 (d, J=6.6Hz, 6H).

[0663] 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

[0664]

[0665] Prepared as described in Example 48 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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):2.90min. 1 H NMR (600MHz, DMSO-d6) δ12.61 (s, 1H), 9.02-8.99 (m, 1H), 8.14 (dd, J=8.5, 1.6Hz , 1H), 8.09 (d, J=7.1Hz, 1H), 7.95 (d, J=5.7Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 6.97 ( dd, J=5.9, 0.8Hz, 1H), 4.71 (ddt, J=16.7, 9.2, 7.3Hz, 1H), 3.12 (tt, J=9.8, 7.8H z, 1H), 2.71 (s, 3H), 2.64-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.40 (q, J=1.8Hz, 3H).

[0666] 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

[0667]

[0668] 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). Concentrate in vacuo to give 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):1.64min.

[0669] 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 room temperature for 1 h. The volatiles were removed in vacuo. Purification by ion exchange SCX-II column chromatography, washing with MeOH and then eluting with 2M NH3 in MeOH, gave 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):1.20min.

[0670] 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 room temperature under argon. DIPEA (0.06 mL, 0.3306 mmol) was added and the reaction mixture was stirred for 30 min. 2-[(3-aminocyclobutanecarbonyl)amino]-4-methyl-thiazole-5-carboxylic acid tert-butyl ester (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) gave 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):1.57min. 1 HNMR(600MHz, DMSO-d6)δ12.36(br s, 1H), 9.00 (d, J=7.5Hz, 1H), 8.52-8.49 (m, 1H), 8.16-8.12 (m, 1H), 8.09-8.06 (m, 1H), 7.66 (t, J=7.8Hz, 1 H), 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).

[0671] The following examples were prepared similarly:

[0672] Example 105: tert-Butyl 2-((1s,3s)-3-(3-(1,2,4-oxadiazol-3-yl)benzamido)cyclobutane-1-carboxamido)-4-methylthiazole-5-carboxylate

[0673]

[0674] 14mg (39%). HPLC / MS m / z: 484.16, [M+H] + , Rt(U):3.22min. 1H NMR (600MHz, DMSO-d6) δ12.40 (s, 1H), 9.78 (d, J=2.3Hz, 1H), 9.02 (dd, J=7.4, 2.2Hz, 1H), 8.55 (d, J=2.1Hz, 1H), 8.24-8.16 (m, 1H), 8.12-8.06 ( m, 1H), 7.69 (td, J=7.8, 2.2Hz, 1H), 4.46 (dt, J=9.4, 7.4Hz, 1H), 3.13-3 .04 (m, 1H), 2.57-2.49 (m, 5H), 2.40-2.28 (m, 2H), 1.52 (d, J=2.4Hz, 9H).

[0675] 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

[0676]

[0677] 20 mg (55%) colorless amorphous solid. HPLC / MS m / z: 498.18, [M+H] + , Rt(U):3.13min. 1 HNMR (600MHz, DMSO-d6) δ12.41 (s, 1H), 9.02 (d, J=7.5Hz, 1H), 8.48 (t, J=1.8Hz, 1H), 8.11 (ddt, J=12.0, 7.8, 1.4Hz, 2H), 7.70 (t, J=7.8Hz, 1H ), 4.46 (ddt, J=17.0, 9.3, 7.6Hz, 1H), 3.08 (tt, J=9.8, 7.8Hz, 1H), 2.62 (s, 3H), 2.56-2.47 (m, 5H), 2.37 (qd, J=9.4, 2.6Hz, 2H), 1.52 (s, 9H).

[0678] Example 107: tert-Butyl 4-methyl-2-((1s,3s)-3-(3-(2-methyl-2H-tetrazol-5-yl)benzamido)cyclobutane-1-carboxamido)thiazole-5-carboxylate

[0679]

[0680] 20mg(50%). HPLC / MS m / z: 498.19, [M+H] + , Rt(U):3.20min. 1H NMR (600MHz, DMSO-d6) δ12.39 (s, 1H), 9.00 (d, J = 7.5Hz, 1H), 8.58 (t, J = 1.8Hz, 1H), 8.20 (dt, J = 7.7, 1.4Hz, 1H), 8.04 (dt, J = 7.9, 1.5 Hz, 1H), 7.66 (t, J=7.8Hz, 1H), 4.46 (s, 4H), 3.08 (tt, J=9.8, 7.8Hz, 1H), 2.57-2.45 (m, 5H), 2.37 (qd, J=9.4, 2.6Hz, 2H), 1.52 (s, 9H).

[0681] Example 108: tert-Butyl 2-((1s,3s)-3-((7-chloroisoquinolin-1-yl)amino)cyclobutane-1-carboxamido)-4-methylthiazole-5-carboxylate

[0682]

[0683] Example 108.1: 7-Chloroisoquinoline (0.15 g, 0.9169 mmol) was dissolved in CHCl (2.86 mL) and cooled in an ice-water bath. mCPBA (0.24 g, 1.0885 mmol) was added. The reaction was stirred in an ice-water bath for 2 h. Warmed to room temperature and additional CHCl (1 mL) was added. KCO (0.51 g, 3.6675 mmol) was added and the mixture was stirred at room temperature for 3 h, then filtered through a pad of anhydrous MgSO. The filtrate was concentrated in vacuo to yield 7-chloro-2-oxo-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):0.93min.

[0684] Example 108.2.: 7-Chloro-2-oxo-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 by the rapid addition of 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 room temperature overnight. Purification was performed by silica gel column chromatography (eluent: 20-70% EtOAc in cyclohexane) followed by ion exchange SCX-II column chromatography, washing with MeOH and then eluting with 2M NH3 in MeOH to give 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 yellow powder. HPLC / MS m / z: 473.14, [M+H] + , Rt(U):3.03min. 1 H NMR (600MHz, chloroform-d) δ 10.74 (s, 1H), 8.35 (d, J = 5.9Hz, 1H), 7.76 (d, J = 2.0Hz, 1H), 7.64 (d, J = 8.7Hz, 1H), 7.55 (dd, J = 8.7, 1.9Hz, 1H), 6.99 (d, J = 5.9Hz, 1H), 5.64 (d, J=7.5Hz, 1H), 4.64 (q, J=8.2Hz, 1H), 3.05 (t, J=8.6Hz, 1H), 2.82 (ddt, J=12.1, 6.8, 3.1Hz, 4H), 2.64 (s, 3H), 1.57 (s, 9H).

[0685] The following examples were prepared similarly:

[0686] Example 109: tert-Butyl 4-methyl-2-((1s,3s)-3-((7-(trifluoromethyl)isoquinolin-1-yl)amino)cyclobutane-1-carboxamido)thiazole-5-carboxylate

[0687]

[0688] 16 mg (22%) yellow powder. HPLC / MS m / z: 507.17, [M+H] + , Rt(U):3.17min. 1HNMR (600MHz, chloroform-d) δ10.57 (s, 1H), 8.46 (d, J=5.9Hz, 1H), 8.07-8.01 (m, 1H), 7.83-7.71 (m, 2H), 7.05 (dd, J=5.9, 0.9Hz, 1H), 5. 87 (d, J=7.4Hz, 1H), 4.74-4.59 (m, 1H), 3.07 (quint, J=8.6Hz, 1H), 2.85 (ddd, J=12.0, 6.4, 3.1Hz, 4H), 2.64 (s, 3H), 1.57 (s, 9H).

[0689] Example 110: tert-Butyl 4-methyl-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate

[0690]

[0691] Example 110.1: Under argon atmosphere, 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). 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 (3×75 mL). The combined organic layers were washed with saturated NaCl (3×50 mL), dried over MgSO 4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (20-60% EtOAc in cyclohexane) to yield 2.10 g (52%) of 2-amino-4-methyl-thiazole-5-carboxylic acid tert-butyl ester as an off-white crystalline solid. HPLC / MS m / z: 215.0866 [M+H] + , Rt(X):2.21min.

[0692] Example 110.2.: Prepared as described in Example 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarboxylic acid [0] (30 mg, 0.093 mmol) and tert-butyl 2-amino-4-methylthiazole-5-carboxylate (50 mg, 0.234 mmol). Purification was by reverse-phase flash chromatography followed by SCX-2 filtration. Yield: 33 mg (53%) of a colorless amorphous solid. HPLC / MS m / z: 521.1965 [M+H] + , Rt(U):2.92min.1 H NMR (600MHz, DMSO-d6) δ12.40 (s, 1H), 9.01 (s, 1H), 8.14 (dd, J=8.5, 1.6Hz, 1H), 8.09 (d, J=7.0Hz, 1H), 7.95 (d, J=5.7Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 6.97 (d, J=5.7Hz, 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).

[0693] Example 111: tert-Butyl 4-methyl-2-[methyl-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate

[0694]

[0695] Example 111.1: tert-Butyl acetoacetate (0.50 mL, 3.02 mmol) and pyridine (0.24 mL, 3.02 mmol) were dissolved in anhydrous EtOH (6.0 mL) and heated at 70 ° C for 15 min. The mixture was then cooled to room temperature followed by addition of iodine (765 mg, 3.015 mmol) and N-methylthiourea (544 mg, 6.03 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then heated at 50 ° C overnight. The reaction mixture was cooled to room temperature 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 (2x20 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 yield 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):1.24min. 1H 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):1.08min. 1 HNMR (600MHz, DMSO-d6) δ7.40 (q, J=4.8Hz, 1H), 6.32 (s, 1H), 3.38 (d, J=0.9Hz, 2H), 2.76 (d, J=4.8Hz, 3H), 1.40 (s, 9H).

[0696] Example 111.2: Prepared as described in Example 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarboxylic acid [0] (34 mg, 0.104 mmol) and tert-butyl 4-methyl-2-(methylamino)thiazole-5-carboxylate (30 mg, 0.104 mmol). Purified by reverse-phase flash chromatography. Yield: 7.3 mg (13%) colorless solid. HPLC / MS m / z: 535.2119 [M+H] + , Rt(U):3.01min. 1 H NMR (600MHz, DMSO-d6) δ9.03 (s, 1H), 8.22-8.14 (m, 1H), 8.08 (br s, 1H), 7.94 (d, J=5.8Hz, 1H), 7.87 (d, J=8.4Hz, 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).

[0697] Example 112: tert-Butyl 4-chloro-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate

[0698]

[0699] Example 112.1: At room temperature under argon atmosphere, tert-butyl (5-carboxyl-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). 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 sequentially. The reaction mixture was heated at 60 ° C. Due to the formation of two by-products, the reaction stopped after 3 h. The reaction mixture was cooled to room temperature, mixed with 0.5M HCl (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with saturated NaCl (3x20 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 yield 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):3.47min.

[0700] 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 room temperature under an argon atmosphere. 4M HCl in dioxane (2.2 mL, 8.96 mmol) was added and the reaction mixture was rapidly cooled in an ice-water bath and then allowed to slowly warm to room temperature. 4M HCl in dioxane was further added and the mixture was continued to stir at ambient temperature. The reaction was stopped after 2 days [Note: some starting material was still present, but cleavage of the ester became a problem]. 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):1.37min.

[0701] Example 112.3.: Prepared as described in Example 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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). Purified by reverse-phase flash chromatography. Yield: 2.8 mg (5%) off-white solid. HPLC / MS m / z: 541.1420 [M+H] + , Rt(U):2.96min.1 H NMR (600MHz, methanol-d4) δ8.96-8.93 (m, 1H), 8.23 ​​(dd, J=8.4, 1.6Hz, 1H), 7.88 (d, J=6.0Hz, 1H), 7.81 (d, J=8.5Hz, 1H), 7.02 (dd , J=6.1, 0.9Hz, 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).

[0702] Example 113: N-tert-butyl-4-chloro-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxamide

[0703]

[0704] Example 113.1.: In a microwave vial at room temperature under an argon atmosphere, tert-butyl (5-carboxyl-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). DIPEA (1.36 mL, 7.75 mmol) was added, and the mixture was stirred for 30 min at room temperature. 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 room temperature and volatiles were removed under reduced pressure. The crude material was purified by flash chromatography (0-40% EtOAc in cyclohexane) to produce 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):3.12min.

[0705] Example 113.2.: N-[5-(tert-Butylcarbamoyl)-4-chloro-thiazol-2-yl]carbamic acid tert-butyl ester (200 mg, 0.60 mmol) was mixed with 4M HCl in dioxane (4.5 mL, 18.0 mmol) at 0°C under argon atmosphere. The reaction mixture was allowed to warm to ambient temperature and stirred for 6 h [additional 4M HCl in dioxane (1.5 mL, 6.00 mmol) was added after 4 h]. 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):2.36min.

[0706] Example 113.3.: Prepared as described in Example 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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):2.77min. 1 H NMR (600MHz, DMSO-d6) δ12.59 (s, 1H), 9.02-8.99 (m, 1H), 8.14 (dd, J=8.5, 1.6Hz, 1H), 8.09 (d, J=7.1Hz, 1H), 7.95 (d, J=5.7Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 7.42 (s, 1H), 6.97 (dd, J=5.9, 0.9Hz, 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).

[0707] Example 114: [(1R)-2,2,2-Trifluoro-1-methyl-ethyl]4-methyl-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate

[0708]

[0709] 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 room temperature under 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 3 (50 mL), saturated NaCl (2×50 mL), dried over anhydrous MgSO 4 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):2.55min.

[0710] Example 114.2.: Prepared as described in Example 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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):2.93min. 1 HNMR (600MHz, DMSO-d6) δ12.62 (s, 1H), 9.02-8.99 (m, 1H), 8.15 (dd, J=8.5, 1.6 Hz, 1H), 8.09 (d, J=7.0Hz, 1H), 7.96 (d, J=5.7Hz, 1H), 7.84 (d, J=8.5Hz, 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=6.6Hz, 3H).

[0711] Example 115: [(1S)-2,2,2-Trifluoro-1-methyl-ethyl]-4-methyl-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate

[0712]

[0713] Example 115.1.: Prepared as described in Example 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). Purified by reverse-phase flash chromatography. Yield: 69 mg (12%) of off-white solid. HPLC / MS m / z: 255.0418 [M+H] + , Rt(U):2.55min.

[0714] Example 115.2.: Prepared as described in Example 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]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):2.92min. 1 HNMR (600MHz, DMSO-d6) δ12.62 (s, 1H), 9.02-8.99 (m, 1H), 8.14 (dd, J=8.5, 1.6Hz , 1H), 8.09 (d, J=7.0Hz, 1H), 7.96 (d, J=5.7Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 6.97 (dd , J=5.9, 0.8Hz, 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=6.6Hz, 3H).

[0715] Example 116: Ethyl 4-(difluoromethyl)-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate

[0716]

[0717] Example 116.1.: Ethyl 2-chloro-4,4-difluoroacetoacetate (200 mg, 1.00 mmol) and thiourea (151 mg, 2.00 mmol) were mixed in anhydrous EtOH (1.00 mL) in a microwave vial under argon atmosphere. The reaction mixture was heated at 100 ° C for 1 h by microwave irradiation. The reaction mixture was concentrated under reduced pressure and mixed with diethyl ether. The precipitate formed was filtered, washed with diethyl ether and dried under reduced pressure to give 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):2.04min.

[0718] Example 116.2: Prepared as described in Example 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]cyclobutanecarboxylic acid [0] (30 mg, 0.093 mmol) and ethyl 2-amino-4-(difluoromethyl)thiazole-5-carboxylate (23 mg, 0.102 mmol). Purified by reverse-phase flash chromatography. Yield: 31 mg (63%) colorless powder. HPLC / MS m / z: 529.1456 [M+H] + , Rt(X):2.86min. 1 H NMR(600MHz, DMSO-d6)δ12.93(br s, 1H), 9.02-8.99 (m, 1H), 8.15 (dd, J=8.5, 1.5Hz, 1H), 8.09 (d, J=7.0Hz, 1H ), 7.96 (d, J=5.7Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 7.42 (t, J=53.7Hz, 1H), 6.97 (d, J=5.7Hz, 1H), 4.74-4.67 (m, 1H), 4.32 (q, J=7.1Hz, 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=7.1Hz, 3H).

[0719] Example 117: N-(5-tert-Butyl-4-methyl-thiazol-2-yl)-3-[(7-methyl-1-isoquinolinyl)amino]cyclobutanecarboxamide

[0720]

[0721] 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 argon atmosphere and stirred at room temperature 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 side products. The reaction mixture was purified by reverse-phase flash chromatography (5-50% MeOH [0.1% FA] in water) to yield 98 mg (17%) of 3-[(7-methyl-1-isoquinolinyl)amino]cyclobutanecarboxylic acid as an off-white solid. HPLC / MS m / z: 257.1 [M+H] + , Rt(U):1.71min.

[0722] Example 117.2: Prepared as described in Example 117.2 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%) of a colorless amorphous solid. HPLC / MS m / z: 409.2048 [M+H] + , Rt(U):2.90min. 1 H NMR (600MHz, DMSO-d6) δ11.76 (s, 1H), 8.13 (s, 1H), 7.78 (d, J = 5.8Hz, 1H), 7.59 (d, J = 8.3Hz, 1H), 7.47-7.41 (m, 2H), 6.85 (d, J=5.8Hz, 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).

[0723] 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

[0724]

[0725] Example 118.1.: Methyl 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylate [0] (60.00 mg, 0.1397 mmol) was suspended in MeOH (1.00 mL) and water (1.00 mL), then sodium hydroxide (111.77 mg, 2.7943 mmol) was added. The reaction was heated to 55°C, but did not dissolve. THF (1.00 mL) was added and the reaction mixture became homogeneous and was stirred at 55°C for 1 hour and 20 minutes. LCMS showed nearly complete conversion and some degradation products. The mixture was cooled in an ice-water bath and acidified with 1M 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 MgSO4. Concentration in vacuo afforded 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]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):1.81min.

[0726] Example 118.2.: To 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]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 room temperature under nitrogen for 30 minutes, after which acetamide oxime (3.25 mg, 0.0438 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours, at which point LCMS indicated good conversion to [(Z)-1-aminoethylideneamino]-4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylate. A condenser was added and the reaction was heated to 100° C. under nitrogen behind a blast shield for 21 h to allow cyclization. The volatiles were removed in vacuo and the crude product was purified by reverse phase column chromatography (eluent: 20-100% MeOH in water (both + 0.1% formic acid modifier)) to give 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):1.31min. 1 H 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).

[0727] 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)acrylamide

[0728]

[0729] Example 119.1.: N-(5-cyanothiazol-2-yl)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide[0] (37.40 mg, 0.0922 mmol) and TEA (0.01 mL, 0.0922 mmol) were heated at 80° C. in [bmim]OAc (0.18 mL). 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 room temperature and partitioned between water (15 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to yield N-[5-[(Z)-N'-hydroxycarbamimidoyl]thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanamide (40 mg, 99%, 0.0912 mmol) as a colorless solid. HPLC / MS m / z: 439.14, [M+H] + , Rt(P):1.00min.

[0730] Example 119.2.: Under nitrogen, 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-isoquinolinyl]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). The resulting solution was stirred at room temperature for 17 h. The volatiles were removed under reduced pressure to give N-[(Z)-N-hydroxy-C-[2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionylamino]thiazol-5-yl]carbonimino]butanamide. HPLC / MS m / z: 509.18, [M+H] + , Rt(P):1.25min.

[0731] Example 119.3.: To a solution of N-[(Z)-N-hydroxy-C-[2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionylamino]thiazol-5-yl]carbonimido]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 room temperature for 1.5 h. Additional potassium hydroxide (4 equivalents) was added and the resulting solution was stirred at room temperature for 1.5 h. Purification by reverse phase column chromatography (eluent: 30-80% MeOH (+0.1% formic acid) in water) followed by ion exchange SCX-II column chromatography, washing with MeOH and then eluting with 2M NH3 in MeOH, gave 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):2.62min. 1 H NMR (600MHz, DMSO-d6) δ12.65 (s, 1H), 8.91-8.87 (m, 1H), 8.16 (dd, J=8.5, 1 .5Hz, 1H), 8.11(s, 1H), 8.06(t, J=5.5Hz, 1H), 7.98(d, J=5.7Hz, 1H), 7.86( d, J=8.5Hz, 1H), 7.00-6.97 (m, 1H), 3.84 (q, J=6.4Hz, 2H), 2.95 (dt, J=10.0 , 7.1Hz, 4H), 2.70 (s, 3H), 1.80 (sext, J=7.4Hz, 2H), 0.98 (t, J=7.4Hz, 3H).

[0732] Example 120: 1-methyl-3-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)-1H-pyrazole-5-carboxylic acid propyl ester

[0733]

[0734] 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionic acid [0] (49.58 mg, 0.1801 mmol), 5-amino-2-methyl-pyrazole-3-carboxylic acid propyl ester (30.00 mg, 0.1637 mmol) and HATU (87.17 mg, 0.2292 mmol) were dissolved in dry DMF (1.09 mL) at room temperature. DIPEA (0.04 mL, 0.2456 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with a solution of NH4Cl, water (2x), dried over MgSO4 and concentrated in vacuo. Purification by reverse phase column chromatography (eluent: 30-100% MeOH / H2O + 0.1% formic acid) gave 1-methyl-3-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)-1H-pyrazole-5-carboxylic acid propyl ester (54 mg, 75%, 0.1226 mmol) as a colorless powder. HPLC / MS m / z: 441.2, [M+H] + , Rt(R):1.29min. 1 HNMR (500MHz, DMSO-d6) δ10.68 (s, 1H, NH), 8.81 (t, J=5.5Hz, 1H, NH), 8.47 (t, J =1.8Hz, 1H), 8.12 (dt, J = 7.8, 1.4Hz, 1H), 8.03 (dt, J = 7.9, 1.5Hz, 1H), 7.65 (t, J =7.8Hz, 1H), 7.05 (s, 1H), 4.20 (t, J = 6.5Hz, 2H), 3.98 (s, 3H), 3.58-3.51 (m, 2H ), 2.68 (s, 3H), 2.63 (t, J=7.0Hz, 2H), 1.73-1.65 (m, 2H), 0.95 (t, J=7.4Hz, 3H).

[0735] The following examples were prepared similarly:

[0736] Example 121: 4-methyl-2-(N-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylic acid propyl ester

[0737]

[0738] 15 mg (14%), colorless powder. HPLC / MS m / z: 472.2, [M+H] + , Rt(R):1.42min. 1HNMR (500MHz, DMSO-d6) δ8.85-8.79 (m, 1H), 8.50-8.45 (m, 1H), 8.13 (dt, J=7.8, 1.5Hz, 1H), 8.04 (dt, J=7.9, 1.4Hz, 1H), 7.66 (t, J=7.8Hz, 1H), 4 .16 (t, J=6.5Hz, 2H), 3.66 (s, 3H), 3.64-3.59 (m, 2H), 3.07 (t, J=6.8Hz, 2H), 2.68 (s, 3H), 2.57 (s, 3H), 1.74-1.60 (m, 2H), 0.94 (t, J=7.4Hz, 3H).

[0739] Example 122: 4-Methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylic acid cyclopentyl ester

[0740]

[0741] 4-Methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylic acid [0] (30.00 mg, 0.0722 mmol) was dissolved in dry DCM (1.00 mL) at room temperature. Oxalyl chloride (0.06 mL, 0.7222 mmol) was added followed by a few drops of DMF. The reaction mixture was stirred at room temperature for 2 h, then the solvent was removed under reduced pressure and cyclopentanol (1.00 mL) was added. The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase column chromatography (eluent: 30-100% MeOH / H2O + 0.1% formic acid) to give cyclopentyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate (8 mg, 23%, 0.0165 mmol) as an off-white powder. HPLC / MS m / z: 484.2, [M+H] + , Rt(R):1.43min. 1H 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).

[0742] Example 123: 4-Methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylic acid hexyl ester

[0743]

[0744] Example 123.1.: 4-Methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylic acid [0] (60.00 mg, 0.1444 mmol) was dissolved in dry DMF (1.00 mL) at room temperature. Pyridine (0.07 mL, 0.1733 mmol) and (2,3,4,5,6-pentafluorophenyl) 2,2,2-trifluoroacetic acid (0.03 mL, 0.1733 mmol) were added and the mixture was stirred at room temperature for 1 h and at 60° C. overnight. The reaction mixture was diluted with EtOAc, washed with water, dried over MgSO 4 , and concentrated under reduced pressure. Purification by reverse phase column chromatography (eluent: 30-100% MeOH / H2O + 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]propionylamino]thiazole-5-carboxylate (28 mg, 33%, 0.0482 mmol) as a colorless powder. HPLC / MS m / z: 582.1, [M+H] + , Rt(Q):3.29min.

[0745] 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]propionylamino]thiazole-5-carboxylate (20.00 mg, 0.0344 mmol) at room temperature. DMF (0.50 mL) was added. The reaction mixture was stirred at room temperature 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 / H2O + 0.1% formic acid) gave 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylic acid hexyl ester (14 mg, 81%, 0.0280 mmol) as a colorless powder. HPLC / MS m / z: 500.2, [M+H] + , Rt(R):1.54min. 1 H NMR (500MHz, DMSO-d6) δ12.54 (s, 1H), 8.86 (t, J = 5.5Hz, 1H), 8.46 (t, J = 1.7Hz, 1H) , 8.13 (dt, J=7.7, 1.4Hz, 1H), 8.02 (dt, J=8.0, 1.4Hz, 1H), 7.65 (t, J=7.8Hz, 1H), 4 .19(t, J=6.5Hz, 2H), 3.65-3.56(m, 2H), 2.78(t, J=6.8Hz, 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).

[0746] The following examples were prepared similarly:

[0747] Example 124: 4-Methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylic acid cyclohexyl ester

[0748]

[0749] 11 mg (36%), colorless powder. HPLC / MS m / z: 498.2, [M+H] + , Rt(R):1.49min. 1HNMR (500MHz, DMSO-d6) δ12.52 (s, 1H), 8.86 (t, J = 5.5Hz, 1H), 8.46 (t, J = 1.8Hz, 1 H), 8.13 (dt, J=7.7, 1.4Hz, 1H), 8.02 (dt, J=7.9, 1.3Hz, 1H), 7.65 (t, J=7.8Hz, 1H) , 4.92-4.84(m, 1H), 3.64-3.56(m, 2H), 2.78(t, J=6.8Hz, 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).

[0750] Example 125: 4-aminobutyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate hydrochloride

[0751]

[0752] A similar procedure was used using tert-butyl N-(4-hydroxybutyl)carbamate, followed by deprotection using HCl in dioxane (1.04 mL, 50 equiv, 4.1762 mmol) at room temperature for 3 h. The solvent was removed under reduced pressure to give 4-aminobutyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)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):0.98min. 1 H NMR (500MHz, methanol-d4) δ8.49 (t, J=1.7Hz, 1H), 8.19 (dt, J=7.8, 1.4Hz, 1H), 7.99-7.94 (m, 1H), 7.61 (t, J=7.8Hz, 1H), 4.32 (t, J=5.8Hz, 2H), 3.77 (t, J=6.8Hz, 2H), 3.05-2.97 (m, 2H), 2.88 (t, J=6.8Hz, 2H), 2.66 (s, 3H), 2.59 (s, 3H), 1.88-1.77 (m, 4H).

[0753] Example 126: 3-(4-methoxyphenyl)propyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0754]

[0755] 20 mg (67%), colorless powder. HPLC / MS m / z: 564.2 [M+H] + , Rt(R):1.52min. 1 HNMR (500MHz, DMSO-d6) δ12.55 (s, 1H), 8.87 (t, J=5.6Hz, 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), 6.8 8-6.81 (m, 2H), 4.16 (t, J=6.4Hz, 2H), 3.71 (s, 3H), 3.60 (q, J=6.5Hz, 2H), 2.79 ( t, J=6.8Hz, 2H), 2.68 (s, 3H), 2.66-2.59 (m, 2H), 2.54 (s, 3H), 1.97-1.89 (m, 2H).

[0756] Example 127: 4-(2-methoxyethoxy)butyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0757]

[0758] 23 mg (61%), cream-colored powder. HPLC / MS m / z: 546.2, [M+H] + , Rt(R):1.35min. 1 H NMR (500MHz, methanol-d4) δ8.49-8.47 (m, 1H), 8.19-8.15 (m, 1H), 7.96 (ddd, J=7.9 , 1.9, 1.2Hz, 1H), 7.60 (td, J=7.8, 0.6Hz, 1H), 4.27 (t, J=6.4Hz, 2H), 3.77 (t , J=6.7Hz, 2H), 3.60-3.56(m, 2H), 3.55-3.51(m, 4H), 3.35(s, 3H), 2.86(t, J =6.7Hz, 2H), 2.66(s, 3H), 2.56(s, 3H), 1.84-1.77(m, 2H), 1.74-1.67(m, 2H).

[0759] Example 128: Methyl 2-methyl-5-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]pyrazole-3-carboxylate

[0760]

[0761] 42 mg (56%), colorless fluffy powder. HPLC / MS m / z: 413.16 [M+H] + , Rt(R):1.15min. 1 H NMR (500MHz, DMSO-d6) δ10.68 (s, 1H), 8.82 (t, J=5.5Hz, 1H), 8.52-8.43 (m, 1H), 8.16-8.10 (m, 1H), 8.03 (ddd, J=7.8, 1.8, 1.1H z, 1H), 7.65 (t, J=7.8Hz, 1H), 7.05 (s, 1H), 3.99 (s, 3H), 3.83 (s, 3H), 3.55 (q, J=6.8Hz, 2H), 2.69 (s, 3H), 2.63 (t, J=7.1Hz, 2H).

[0762] 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

[0763]

[0764] 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) gave 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):0.92min.

[0765] 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 a procedure similar to that of Example 0 using 4-methyl-5-(1-methylbutyl)thiazol-2-amine (12 mg, 28%, 0.0272 mmol). HPLC / MS m / z: 442.2, [M+H] + , Rt(R):1.49min. 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) (not observed for 1xNH).

[0766] Example 130: 4-Acetylaminobutyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0767]

[0768] Acetoacetic acid (6.58 uL, 0.0696 mmol) and 4-aminobutyl-4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]thiazole-5-carboxylate hydrochloride [0] (28.00 mg, 0.0535 mmol) were dissolved in dry THF (0.50 mL) at room temperature. TEA (22.39 uL, 0.1606 mmol) was added and the reaction mixture was stirred at room temperature 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 / H2O + 0.1% formic acid) to give 4-acetamidobutyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate (20 mg, 71%, 0.0378 mmol) as a colorless powder. HPLC / MS m / z: 529.2, [M+H] + , Rt(R):1.23min.1 H NMR (500MHz, DMSO-d6) δ12.50 (s, 1H), 8.86 (t, J = 5.6Hz, 1H), 8.46 (t, J = 1.8Hz, 1H), 8. 13 (dt, J=7.7, 1.4Hz, 1H), 8.02 (dt, J=8.0, 1.4Hz, 1H), 7.84 (t, J=5.6Hz, 1H), 7.65 (t, J =7.8Hz, 1H), 4.19 (t, J = 6.5Hz, 2H), 3.64-3.56 (m, 2H), 3.09-3.01 (m, 2H), 2.78 (t, J = 6. 8Hz, 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).

[0769] Example 131: 1-Methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propionylamino)-1H-pyrazole-5-carboxylic acid propyl ester formate

[0770]

[0771] 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionic acid [0] (16.05 mg, 0.0538 mmol), HOBt (14.54 mg, 0.1076 mmol), EDC.HCl (20.63 mg, 0.1076 mmol) and 5-amino-2-methyl-pyrazole-3-carboxylic acid propyl ester (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 / H2O + 0.1% formic acid) gave 1-methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propionylamino)-1H-pyrazole-5-carboxylic acid propyl ester formate (11 mg, 44%, 0.0237 mmol) as a yellow powder. HPLC / MS m / z: 464.2, [M+H] + , Rt(R):1.18min. 1HNMR (500MHz, DMSO-d6) δ10.69 (s, 1H), 8.90-8.87 (m, 1H), 8.23-8.18 (m, 1H), 8 .14 ​​(dd, J=8.5, 1.5Hz, 1H), 8.00-7.94 (m, 2H), 7.84 (d, J=8.5Hz, 1H), 7.06 (s, 1 H), 6.96 (d, J=5.7Hz, 1H), 4.20 (t, J=6.5Hz, 2H), 3.98 (s, 3H), 3.80-3.73 (m, 2H ), 2.74 (t, J=7.0Hz, 2H), 2.70 (s, 3H), 1.74-1.66 (m, 2H), 0.95 (t, J=7.4Hz, 3H).

[0772] The following examples were prepared by similar procedures:

[0773] Example 132: tert-Butyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propionamido)thiazole-5-carboxylate

[0774]

[0775] 13 mg (36%), slightly yellow powder. HPLC / MS m / z: 472.17, [M+H] + , Rt(Z):2.80min. 1 HNMR (600MHz, DMSO-d6) δ12.41 (s, 1H), 8.86 (t, J=5.5Hz, 1H), 8.47 (t, J=1.8Hz, 1H), 8.14 (dt, J=7.7, 1.4Hz, 1H), 8.04 (ddd, J=7.9 , 1.8, 1.2Hz, 1H), 7.67 (t, J=7.8Hz, 1H), 3.63-3.58 (m, 2H), 2.79 (t, J=6.8Hz, 2H), 2.70 (s, 3H), 2.51 (d, J=1.0Hz, 3H), 1.52 (s, 9H).

[0776] Example 133: Ethyl 3-methyl-5-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propionylamino]thiophene-2-carboxylate

[0777]

[0778] 6.8 mg (8%) amorphous colorless solid. HPLC / MS m / z: 443.14 [M+H] + , Rt(R):1.32min. 1H NMR (500MHz, DMSO-d6) δ 11.58 (s, 1H), 8.88 (t, J = 5.6Hz, 1H), 8.46 (d, J = 1.8Hz, 1H), 8.13 (dt, J = 7.9, 1.4Hz, 1H), 8.03 (dt, J = 7.7, 1.4Hz, 1H), 7.65 ( t, J=7.8Hz, 1H), 6.52 (s, 1H), 4.20 (q, J=7.1Hz, 2H), 3.58 (q, J=6.5Hz, 2H ), 2.71 (t, J=6.9Hz, 2H), 2.68 (s, 3H), 2.40 (s, 3H), 1.26 (t, J=7.1Hz, 3H).

[0779] Example 134: Ethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)-N-propylpropionamido)thiazole-5-carboxylate

[0780]

[0781] Example 134.1.: Sodium triacetoxyborohydride (227.61 mg, 1.0739 mmol) is added to a solution of ethyl 2-amino-4-methyl-thiazole-5-carboxylate (100.00 mg, 0.5370 mmol) and propionaldehyde (0.12 mL, 1.6109 mmol) in DCE (3.58 mL). Acetic acid (0.05 mL, 0.8055 mmol) is added and the solution is heated at 80 ° C for 30 min under microwave irradiation. The reaction mixture is quenched with saturated bicarbonate solution (20 mL) and extracted with DCM (20 mL). The organic layer is washed with brine (20 mL), dried over MgSO4 and concentrated under reduced pressure to obtain ethyl 4-methyl-2-(propylamino)thiazole-5-carboxylate (129 mg, 105%, 0.5650 mmol) as a yellow oil, which is used in the next step without further purification. HPLC / MS m / z: 229.10, [M+H] + , Rt(P):1.38min.

[0782] Example 134.2.: A procedure similar to that of Example 0 was performed using ethyl 4-methyl-2-(propylamino)thiazole-5-carboxylate to afford ethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)-N-propylpropionamido)thiazole-5-carboxylate as a colorless solid (15 mg, 11%, 0.0309 mmol). HPLC / MS m / z: 486.18, [M+H] + , Rt(S):3.16min. 1H NMR (500MHz, DMSO-d6) δ8.81 (t, J=5.4Hz, 1H), 8.47 (d, J=1.8Hz, 1H), 8.13 (dt, J=7. 7, 1.4Hz, 1H), 8.04 (dt, J=7.9, 1.5Hz, 1H), 7.66 (t, J=7.8Hz, 1H), 4.24 (q, J=7.1Hz, 2 H), 4.11 (t, J=7.9Hz, 2H), 3.64 (q, J=6.5Hz, 2H), 3.09 (t, J=6.8Hz, 2H), 2.68 (s, 3H), 2.56 (s, 3H), 1.72 (sext, J=7.5Hz, 2H), 1.28 (t, J=7.1Hz, 3H), 0.92 (t, J=7.4Hz, 3H).

[0783] Example 135: Ethyl 3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propionylamino)-1H-pyrazole-5-carboxylate

[0784]

[0785] To 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propionic acid [0] (30.00 mg, 0.1006 mmol) and PyBrop (93.77 mg, 0.2011 mmol) was added ethyl 5-amino-1h-pyrazole-3-carboxylate (18.72 mg, 0.1207 mmol) dissolved in anhydrous DMF (0.63 mL). DIPEA (70.07 uL, 0.4023 mmol) was added to the solution, and the mixture was stirred at room temperature for 3 days. Purification was performed by reverse phase column chromatography (eluent: 20-100% MeOH in water (both + 0.1% formic acid modifier)) followed by an Ion Column SCX-II, eluting with 2M NH3 in MeOH to give ethyl 3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propionylamino)-1H-pyrazole-5-carboxylate (13 mg, 30%, 0.0299 mmol). HPLC / MS m / z: 436.2 [M+H] + , Rt(U):2.12min. 1H NMR (500MHz, DMSO-d6) δ13.49 (s, 1H), 10.68 (s, 1H), 8.91-8.86 (m, 1H), 8.14 (dd, J=8.5, 1.6Hz, 1H), 7.98 (d, J=8.3Hz, 2H), 7.85 (d, J=8.5Hz, 1H) , 7.03 (s, 1H), 6.96 (d, J=5.7Hz, 1H), 4.29 (q, J=7.1Hz, 2H), 3.77 (q, J=6. 9, 6.5Hz, 2H), 2.75 (t, J=7.0Hz, 2H), 2.70 (s, 3H), 1.30 (t, J=7.1Hz, 3H).

[0786] Example 136: 6-Hydroxyhexyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzamido)propionamido)thiazole-5-carboxylate

[0787]

[0788] Example 136.1.: Nitrogen was passed 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. Tetrakis(triphenylphosphine)palladium (1347.28 mg, 1.1659 mmol) was added, purged with nitrogen for 5 min, and heated at 100° C. for 3 h. The mixture was added to brine (800 mL), extracted with diethyl ether (2×100 mL), and the combined organic layers were washed with brine (2×250 mL). The mixture was dried over magnesium sulfate. Purification by silica gel column chromatography (eluent: 0-10% EtOAc in cyclohexane) gave 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).

[0789] 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 at 80°C in [bmim]OAc (2.33 mL) 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 room temperature and water (50 mL) was added. The residue was extracted with EtOAc (3 x 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)) gave 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):0.95min.

[0790] Example 136.3.: Under nitrogen, 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). The solution was stirred at room temperature 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 room temperature for an additional 3 h. The volatiles were removed under reduced pressure to afford 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):1.32min.

[0791] 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 room temperature for 60 min. Water (1 mL) was added to allow saponification. The solution was then stirred at room temperature for an additional 1 h. LC / MS showed complete conversion to the desired carboxylic acid. Water (20 mL) was added and the aqueous layer was washed with EtOAc (20 mL). The aqueous layer was acidified by adding a few drops of fuming HCl (37%) (until the pH was approximately 1). The residue was extracted with EtOAc (3 x 20 mL). The organic layers were combined, washed with brine (25 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give 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):1.49min.

[0792] 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 that of Example 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):1.21min.

[0793] Example 136.6.: A procedure similar to that in 0 using hexane-1,6-diol gave 6-hydroxyhexyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzamido)propionamido)thiazole-5-carboxylate (43 mg, 80%, 0.0737 mmol) as a cream-colored powder. HPLC / MS m / z: 584.2, [M+H] + , Rt(R):1.46min. 1HNMR (500MHz, methanol-d4) δ8.75-8.70 (m, 1H), 8.46-8.40 (m, 1H), 8.31-8.25 (m, 1H), 4.25 (t, J=6.5Hz, 2H), 3.79 (t, J=6.6Hz, 2H), 3 .56 (t, J=6.6Hz, 2H), 2.87 (t, J=6.6Hz, 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).

[0794] 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

[0795]

[0796] 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 uL, 0.1688 mmol) in DMF (0.30 mL) was added N'-[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]ethane-1,2-diamine[0] (25.00 mg, 0.0928 mmol). The resulting solution was stirred at room temperature overnight. Purification by reverse phase column chromatography (eluent: 40-90% MeOH / H2O + 0.1% formic acid) gave 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 powder. HPLC / MS m / z: 451.2, [M+H] + , Rt(T):1.28min. 1HNMR (600MHz, methanol-d4) δ8.79 (s, 1H), 8.35-8.22 (m, 1H), 8.17 (dd, J=8.5, 1. 8Hz, 1H), 7.86 (d, J=6.1Hz, 1H), 7.76 (d, J=8.4Hz, 1H), 6.98 (d, J=6.0Hz, 1H ), 3.84-3.76 (m, 2H), 3.76-3.69 (m, 2H), 2.75 (t, J=7.5Hz, 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=7.4Hz, 3H).

[0797] Example 138: 1-Methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propionylamino)-1H-pyrazole-5-carboxylic acid cyclopentyl ester

[0798]

[0799] 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) in sequence. The resulting solution was stirred at room temperature overnight. LCMS showed complete conversion. The volatiles were removed under reduced pressure 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 C18SNAP Ultra column. The column was eluted with 20-70% MeOH (+0.1% formic acid) in water. Tubes 7-10 were passed through an SCX-II column (5 g). The column was eluted with MeOH followed by a 2 M ammonia solution in MeOH. The base fractions were concentrated under reduced pressure to give 5-amino-2-methyl-pyrazole-3-carboxylic acid cyclopentyl ester (35 mg, 47%, 0.1673 mmol) as a colorless oil. HPLC / MS m / z: 210.13, [M+H] + , Rt(T):1.22min.

[0800] Example 138.2.: 5-Amino-2-methyl-pyrazole-3-carboxylic acid cyclopentyl ester was used in a procedure similar to that of 0 to give 2-methyl-5-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]amino]propanoylamino]pyrazole-3-carboxylic acid cyclopentyl ester (8.8 mg, 27%, 0.0180 mmol) as a colorless solid. HPLC / MS m / z: 490.22, [M+H] + , Rt(U):2.67min. 1 H NMR (600MHz, DMSO-d6) δ10.67 (s, 1H), 8.91-8.85 (m, 1H), 8.15 (dd, J=8.5, 1.5Hz, 1H), 7.99 (d, J=5.7Hz, 1H), 7.96 (t, J=5.5Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 7.02 (s, 1H), 6.97 (d, J=5.7Hz, 1H) , 5.29 (dq, J=6.1, 3.0Hz, 1H), 3.97 (s, 3H), 3.77 (td, J=7.0, 5.2Hz, 2H), 2.74 (t, J=7.0Hz, 2H), 2.71 (s, 3H), 1.96-1.86 (m, 2H), 1.74 (dddd, J=20.9, 11.9, 6.5, 3.5Hz, 4H), 1.65-1.56 (m, 2H).

[0801] Example 139: 3-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido}-N-[4-methyl-5-(trifluoromethyl)-1,3-thiazol-2-yl]acrylamide

[0802]

[0803] 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 room temperature 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 yield 199 mg of a light brown solid, which was suspended in dioxane (3.0 mL), treated with HCl / (4 M, 3.2 mL) in 1,4-dioxane, and stirred at room temperature 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):1.18min.

[0804] 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 room temperature 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, filtered by suction, washed with a small amount of acetonitrile and tert-butyl methyl ether, and dried under vacuum at 60° C. overnight 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]acrylamide as a colorless solid. HPLC / MS m / z: 440.1 [M+H] + , Rt(M):1.60min. 1H NMR (500MHz, DMSO-d6): δ12.62 (s, 1H), 8.83 (t, J=5.5Hz, 1H), 8.45 (t, J=1.7Hz, 1H), 8.12 (dt, J=7.7, 1.4Hz, 1H), 8. 03-8.00 (m, 1H), 7.65 (t, J=7.8Hz, 1H), 3.61 (q, J=6.6Hz, 2H), 2.80 (t, J=6.8Hz, 2H), 2.68 (s, 3H), 2.40-2.37 (m, 3H).

[0805] Example 140: Ethyl 2-((2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzamido)ethyl)carbamoyl)-4-methylthiazole-5-carboxylate

[0806]

[0807] Example 140.1.: A solution of isopropylmagnesium chloride and lithium chloride (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 and then morpholine-4-carboxaldehyde (0.90 mL, 8.996 mmol) was added. After 25 min, the reaction mixture was quenched with NH4Cl (10 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL), dried over MgSO4 and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (eluent: 0-20% EtOAc in cyclohexane) to obtain 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):2.33min.

[0808] Example 140.2.: 2-Methylbut-2-ene (7.82 mL, 73.784 mmol) was added to a solution of ethyl 2-formyl-4-methyl-thiazole-5-carboxylate (490.00 mg, 2.4595 mmol) in THF (8.20 mL) and t-BuOH (8.20 mL) at room temperature. 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 H2O (4 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched with a saturated solution of Na2S2O3. The aqueous layer was extracted with EtOAc, then acidified to pH 1-2 with a solution of 2N HCl, and extracted again with EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give 5-ethoxycarbonyl-4-methyl-thiazole-2-carboxylic acid (382 mg, 72%, 1.7748 mmol) which was used without further purification.

[0809] 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-dimethyl-propan-1-amine, HCl (135.00 mg, 0.8696 mmol) and 1-hydroxybenzotriazole (117.00 mg, 0.8659 mmol) in dry DMF at room temperature. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (10 mL) and washed with saturated NaHCO (2x5 mL) solution and water (2x5 mL), dried over MgSO 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):2.84min.

[0810] 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 room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to afford ethyl 2-(2-aminoethylcarbamoyl)-4-methyl-thiazole-5-carboxylate as a colorless solid. No further purification was performed.

[0811] 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 room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and 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 / H2O + 0.1% formic acid) gave 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):2.96min. 1 H NMR (500MHz, DMSO-d6) δ9.17-9.09 (m, 1H), 8.85-8.78 (m, 1H), 8.45 (t, J=1.8Hz, 1H), 8.14 (dt, J=7.8, 1.4Hz, 1H), 8.02 (dt, J=8.0, 1.4Hz, 1H), 7.66 (t, J=7.7Hz, 1H), 4.30 (q, J=7.1Hz, 2H), 3.53-3.45 (m, 4H), 3.08-2.99 (m, 2H), 2.69 (s, 3H), 1.36 (t, J=7.6Hz, 3H), 1.30 (t, J=7.1Hz, 3H).

[0812] The following examples were prepared similarly:

[0813] Example 141: Ethyl 4-methyl-2-((2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)ethyl)carbamoyl)thiazole-5-carboxylate

[0814]

[0815] 48 mg (51%), colorless solid. HPLC / MS m / z: 444.1, [M+H] + , Rt(R):1.32min. 1 HNMR (500MHz, DMSO-d6) δ9.16-9.10 (m, 1H), 8.83-8.79 (m, 1H), 8.45 (t, J=1.7Hz, 1H), 8.12 (dt, J=7.8, 1.4Hz, 1H), 8.02 (dt, J=7 .9, 1.4Hz, 1H), 7.65 (t, J=7.8Hz, 1H), 4.30 (q, J=7.1Hz, 2H), 3.52-3.43 (m, 4H), 2.69 (s, 3H), 2.68 (s, 3H), 1.30 (t, J=7.1Hz, 3H).

[0816] Example 142: (R)-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)butyrylamino)thiazole-5-carboxylic acid ethyl ester

[0817]

[0818] Example 142.1.: To tert-butyl (3R)-3-aminobutyrate (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 room temperature overnight. Water (70 mL) was added and the mixture was extracted with EtOAc (2 x 60 mL). The combined organic phases were washed with saturated NaHCO 3 , brine, dried over MgSO 4 , and then concentrated in vacuo to afford 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. HPLC / MS m / z: 368.1 [M+Na] was used without further purification. + , Rt(P):1.45min.

[0819] 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. The volatiles were removed in vacuo. Toluene was added and then evaporated to help remove traces of high boiling TFA and by-products. High vacuum + 45°C water bath was used to give (3R)-3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]butanoic acid (142 mg, 102%, 0.4909 mmol) as a colorless solid. No further purification was performed. HPLC / MS m / z: 458.1 [M+H] + , Rt(P):1.51min.

[0820]

[0266] 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 air balloon were added and 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 organic phases were combined, washed with saturated NaHCO (25 mL), brine (25 mL), dried over MgSO, 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)) gave (R)-ethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)butyrylamino)thiazole-5-carboxylate (10 mg, 5%, 0.0219 mmol). HPLC / MS m / z: 458.1 [M+H] + , Rt(P):1.51min. 1HNMR (500MHz, DMSO-d6) δ12.55 (s, 1H), 8.64 (d, J = 8.0Hz, 1H), 8.44 (t, J = 1.8Hz, 1H) , 8.12 (dt, J=7.8, 1.4Hz, 1H), 8.01 (dt, J=7.9, 1.4Hz, 1H), 7.65 (t, J=7.8Hz, 1H), 4.5 7-4.44 (m, 1H), 4.22 (q, J=7.1Hz, 2H), 2.78 (dd, J=14.9, 7.2Hz, 1H), 2.72 (dd, J=14.9 , 6.8Hz, 1H), 2.69 (s, 3H), 2.53 (s, 3H), 1.26 (t, J=7.1Hz, 3H), 1.23 (d, J=6.7Hz, 3H).

[0821] The following examples were prepared in a similar manner:

[0822] Example 143: (S)-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)butyrylamino)thiazole-5-carboxylic acid ethyl ester

[0823]

[0824] 15mg(10%). HPLC / MS m / z: 458.1[M+H] + , Rt(S):2.82min. 1 H NMR (500MHz, DMSO-d6) δ12.55 (s, 1H), 8.64 (d, J = 8.0Hz, 1H), 8.44 (dt, J = 1.7, 1 .0Hz, 1H), 8.15-8.09 (m, 1H), 8.01 (ddd, J=7.8, 1.9, 1.2Hz, 1H), 7.65 (dt, J=7. 6, 0.6Hz, 1H), 4.51 (dt, J=13.9, 7.0Hz, 1H), 4.22 (q, J=7.1Hz, 2H), 2.83-2.70 ( m, 2H), 2.69 (s, 3H), 2.53 (s, 3H), 1.26 (t, J=7.1Hz, 3H), 1.23 (d, J=6.7Hz, 3H).

[0825] Example 144: Propyl 2-(2-(4-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)-1-methylpiperidin-4-yl)acetamido)-4-methylthiazole-5-carboxylate

[0826]

[0827] Tert-butyl 2-(4-amino-1-methyl-4-piperidinyl)acetate and 3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid were used to give propyl 2-(2-(4-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)-1-methylpiperidin-4-yl)acetamido)-4-methylthiazole-5...

Claims

1. Compounds of formula I and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, in W stands for R 1 Indicates Hal, CN, A, COOR 7 、CON(R 7 )2、COA' or Het 1 , R 2 Indicates H, Hal, A', R 3 express R 4 , R 8 independently of one another represent H, an unbranched or branched alkyl radical having 1 to 3 C atoms, R 5 represents H or one or more substituents selected from Hal, A, OH, OCH3, NH2, NHCH3, N(CH3)2 and CH2CN, R 6 represents benzoyl, 2-isoquinolyl or 4-quinazolinyl, which is unsubstituted or substituted with Hal, A, OH, N(R 7 2. COOR 7 , CN, NO2 and / or Het 2 Single, double or triple replacement, A denotes an unbranched or branched alkyl or cycloalkyl radical having 1 to 10 C atoms, wherein two adjacent CH- and / or CH2- groups can form a double bond and wherein one or two non-adjacent CH- and / or CH2- groups can be replaced by N, O and / or S atoms and wherein 1 to 7 H atoms can be replaced by F or Cl, A' represents an unbranched or branched alkyl group having 1 to 4 C atoms, of which 1 to 7 H atoms may be replaced by F or Cl, Het 1 represents oxadiazolyl which is unsubstituted or substituted by unbranched or branched alkyl having 1 to 4 C atoms, Het 2 represents oxadiazolyl, tetrazolyl, pyrazolyl or oxazolyl, which is unsubstituted or substituted by unbranched or branched alkyl having 1 to 4 C atoms, R 7 Indicates H or A, Hal represents F, Cl, Br or I.

2. The compound according to claim 1 and its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, wherein W stands for And R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 and Het2 have the same meanings as in claim 1.

3. The compound according to claim 1 or 2 and its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, wherein W stands for And R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 and Het2 have the same meanings as in claim 1.

4. Compounds according to one or more of the preceding claims and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, wherein W stands for And R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 and Het2 have the same meanings as in claim 1.

5. Compounds according to one or more of the preceding claims and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, 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 Het2 have the same meanings as in claim 1.

6. Compounds according to one or more of the preceding claims and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, wherein R 2 represents H or methyl, And W, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 and Het2 have the same meanings as in claim 1.

7. Compounds according to one or more of the preceding claims and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, wherein R 3 express And W, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 and Het2 have the same meanings as in claim 1.

8. Compounds according to one or more of the preceding claims and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, wherein R 3 express And W, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A', Het 1 and Het2 have the same meanings as in claim 1.

9. Compounds according to one or more of the preceding claims and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, wherein R 6 represents benzoyl or 2-isoquinolyl, and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , A, A', Het 1 and Het2 have the same meanings as in claim 1.

10. Compounds according to one or more of the preceding claims and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, wherein Het 2 represents 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 same meaning as in claim 1.

11. Compounds according to one or more of the preceding claims and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, wherein Het 2 represents 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 same meaning as in claim 1.

12. A compound selected from the group consisting of the following compounds and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios:

13. Pharmaceutical preparation comprising at least one compound according to one or more of claims 1 to 12 and / or physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

14. The pharmaceutical preparation according to claim 13, comprising further excipients and / or adjuvants.

15. Pharmaceutical preparation comprising at least one compound according to one or more of claims 1 to 12 and / or physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active compound.

16. A method for preparing a pharmaceutical preparation, characterized in that The compounds according to one or more of claims 1 to 12 and / or one of their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, together with solid, liquid or semi-liquid excipients or adjuvants are brought into suitable dosage forms.

17. Medicament comprising at least one compound according to one or more of claims 1 to 12 and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios) for the treatment and / or prevention of physiological and / or pathophysiological states.

18. A medicament comprising at least one compound according to one or more of claims 1 to 12 and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers (including mixtures thereof in all ratios) for the treatment and / or prevention of physiological and / or pathophysiological states selected from hyperproliferative diseases and disorders.

19. A medicament for use as defined in claim 18, wherein the hyperproliferative diseases and disorders are cancer.

20. A medicament for use as defined in claim 19, wherein the cancer is selected from acute and chronic lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, bladder cancer, brain cancer, breast cancer, cervical hyperplasia, cervical cancer, choriocarcinoma, chronic myeloid leukemia, colon cancer, endometrial cancer, esophageal cancer, essential thrombocythemia, genitourinary cancer, glioma, glioblastoma, hairy cell leukemia, head and neck cancer, Hodgkin's disease, Kaposi's sarcoma, lung cancer, lymphoma, malignant carcinoid, Malignant hypercalcemia, malignant melanoma, malignant pancreatic insulinoma, medullary thyroid cancer, melanoma, multiple myeloma, mycosis fungoides, myeloid and lymphocytic leukemia, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, polycythemia vera, primary brain cancer, 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. A kit consisting of the following individually packaged products: a) an effective amount of a compound according to one or more of claims 1 to 12 and / or physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and b) an effective amount of an additional pharmaceutically active compound.

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