WO2023131690A1 - Substituted heterocycles as hset inhibitors - Google Patents

Substituted heterocycles as hset inhibitors Download PDF

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WO2023131690A1
WO2023131690A1 PCT/EP2023/050255 EP2023050255W WO2023131690A1 WO 2023131690 A1 WO2023131690 A1 WO 2023131690A1 EP 2023050255 W EP2023050255 W EP 2023050255W WO 2023131690 A1 WO2023131690 A1 WO 2023131690A1
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mmol
methyl
amino
oxadiazol
hplc
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French (fr)
Inventor
Hans-Peter Buchstaller
Daniel Kuhn
Ian Collins
Thomas Matthews
Jan LANZ
John Caldwell
Giampiero COLOMBANO
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Merck Patent GmbH
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Merck Patent GmbH
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Priority to CN202380026269.4A priority Critical patent/CN119421877A/zh
Priority to CA3247641A priority patent/CA3247641A1/en
Priority to US18/727,543 priority patent/US20250084074A1/en
Priority to IL314200A priority patent/IL314200A/en
Priority to EP23700468.4A priority patent/EP4463444A1/en
Priority to JP2024541657A priority patent/JP2025503661A/ja
Priority to AU2023205435A priority patent/AU2023205435A1/en
Publication of WO2023131690A1 publication Critical patent/WO2023131690A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • Substituted heterocycles as HSET Inhibitors The invention relates to substituted heterocycles of the general formula I, and the use of the compounds of the present invention for the treatment and/or prevention of hyperproliferative diseases and disorders such as cancer in mammals, especially humans, and pharmaceutical compositions containing such compounds.
  • Background of the invention DNA replication, followed by equal chromosome segregation, ensures the accurate transmission of the genetic information to daughter cells (Hall et al., 2003; Nigg, 2002; Zyss and Gergely, 2009). In most normal and malignant cells, centrosomes act as the dominant sites for spindle pole formation (Meunier and Vernos, 2012).
  • Centrosome duplication is also tightly controlled and occurs simultaneously with DNA replication, thereby ensuring the generation of two functional centrosomes that form the poles of the mitotic spindle (Sharp et al., 2000).
  • microtubule (MT) motor proteins play a central role (Cai et al., 2010; Ganem and Compton, 2004).
  • HSET encoded by KIFC1 in humans and Kifc5a in mice
  • a minus-end MT motor is of interest in cancer due to its impact on cell division (Cai et al., 2010; Goshima et al., 2005).
  • centrosomes and in particular HSET, for bipolar spindle formation has attracted much attention, although the precise role of HSET in this process remains a topic for debate (Mahoney et al., 2006; Tillement et al., 2009). Recent reports have linked centrosome amplification and high HSET expression to chromosome missegregation and aneuploidy, which are hallmarks of human cancer (Marx et al., 2009).
  • Centrosome amplification disrupts asymmetric cell division in neuroblastoma cells and causes tumorigenesis in a fly model (Basto et al., 2008), and supernumerary centrosomes are also found in most solid tumor types, forming markers for aggressiveness in breast, brain, prostate, cervix, kidney, and bladder cancers (Chan, 2011). Hence, it is increasingly apparent that supernumerary centrosomes are not only indicative of malignancy but may also drive malignant transformation (Ogden et al., 2013).
  • centrosome clustering prevents multipolar mitosis and cell death, it prolongs mitosis and increases the frequency of chromosome missegregation as a result of merotelic kinetochore attachments (Ganem et al., 2009; Kwon et al., 2008; Yang et al., 2008).
  • centrosome clustering may prove to be the Achilles heel of cancer cells with supernumerary centrosomes (Basto et al., 2008), and a growing body of evidence suggests that inhibition of centrosome clustering could provide a new therapeutic strategy for tumors with a high incidence of centrosome amplification (Jordan and Wilson, 2004; Ogden et al., 2012).
  • a key protein that is known to be crucial for centrosome clustering is HSET (Ncd in flies). HSET is required by tumour cells 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, which are force-generating enzymes that facilitate movement along MTs within the cell (Mountain et al., 1999) and which transport organelles, protein complexes and mRNAs along microtubules in an ATP-dependent fashion.
  • HSET is a minus-end directed motor kinesin, that cross-links and slides microtubules exerting inward forces (Walczak et al., 1997; Cai et al., 2009; Rath et al., 2012).
  • Knockdown of HSET in normal retinal pigment epithelial 1 (RPE-1) cells or the breast cancer cell line MCF- 7 does not inhibit bipolar spindle formation, and cells undergo normal division (Kleylein-Sohn et al., 2012; Kwon et al., 2008).
  • knockdown of HSET in the supernumerary centrosome-containing breast cancer and neuroblastoma cell lines MDA-MB-231 and N1E-115, respectively prevents centrosome clustering and induces cell death by multipolar anaphases (Kwon et al., 2008).
  • HSET depletion increases cell death and the frequency of multipolarity in cells with supernumerary centrosomes, but not in cells with a normal number of centrosomes.
  • HSET depletion induces spindle multi-polarity and selectively sensitizes centrosome amplified ER- breast cancer cell lines, including triple negative breast cancer (TNBC), to cell death (Patel et al., 2018).
  • TNBC triple negative breast cancer
  • HSET human sarcoma
  • NSCLC non-small cell lung carcinoma
  • tumours including centrosome amplified tumours
  • cytotoxic microtubule-targeted drugs e.g. taxol, eribulin
  • these drugs typically show severe side effects and the emergence of drug resistance leading to early relapse.
  • agents targeting kinesin motor proteins e.g. Eg5 inhibitors
  • mono-polar spindles the opposite phenotype to HSET inhibition
  • target all rapidly dividing cells including bone marrow cells. Consequently, they share dose-limiting toxicities with other antimitotic therapies.
  • HSET inhibitor is anticipated to show reduced toxicity by selectively killing cells with centrosome amplification whereas cells with the normal number of centrosomes will remain unaffected (Ganem et al., 2009; Patel et al., 2015). These data together provide support for developing agents that selectively inhibit HSET to target centrosome-amplified tumours (Myers and Collins, 2016). Examples of small molecule HSET inhibitors have been described in the literature. AZ82 is an ADP/ATP competitive inhibitor shown to be selective against a panel of nine other kinesins including Eg5 (Wu et al., 2013).
  • the aim was to find HSET inhibitors that serve as potential therapeutics for the treatment of cancer diseases.
  • Summary of the invention Surprisingly, it has been found that the compounds according to the invention are highly selective and effective inhibitors of HSET and thus the compounds of the present invention can be used for the treament of hyperproliferative diseases and disorders such as cancer.
  • the invention relates to the compounds of the general formula I, wherein W denotes R 1 denotes Hal, CN, A, COOR 7 , CON(R 7 ) 2 , COA’ or Het 1 , R 2 denotes H, Hal or A’, R 3 denotes R 4 , R 8 denote independently of one another H, unbranched or branched alkyl with 1-3 C-atoms, R 5 denotes H or one or more substituents selected from the group of Hal, A, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 and CH 2 CN, R 6 denotes benzoyl, 2-isoquinolinyl or 4-quinazolinyl, which is unsubstituted or one-, two-, or threefold substituted with Hal, A, OH, N(R 7 ) 2 , COOR 7 , CN, NO 2 and/or or Het 2 , A denotes unbranched or branched alky
  • the invention preferably relates to the compounds according to formula I, wherein W denotes 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 meanings as in Claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention more preferably relates to the compounds according to formula I, wherein W denotes 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 meanings as in Claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention particularly preferred relates to the compounds according to formula I, wherein W denotes 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 meanings as in Claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention preferably relates to the compounds according to formula I, wherein R 2 denotes H or A’ and W, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A’, Het 1 and Het2 have the meanings as in Claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention more preferably relates to the compounds according to formula I, wherein R 2 denotes H or methyl and W, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A’, Het 1 and Het2 have the meanings as in Claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention preferably relates to the compounds according to formula I, wherein R 3 denotes and W, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A’, Het 1 and Het2 have the meanings as in Claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention particularly preferred relates to the compounds according to formula I, wherein R 3 denotes and W, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A’, Het 1 and Het2 have the meanings as in Claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention particularly preferred relates to the compounds according to formula I, wherein R 6 denotes benzoyl or 2-isoquinolinyl and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , A, A’, Het 1 and Het2 have the meanings as in Claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention preferably relates to the compounds according to formula I, wherein Het 2 denotes oxadiazolyl or tetrazolyl and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A’, and Het 1 have the meanings as in Claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention particularly preferred relates to the compounds according to formula I, wherein Het 2 denotes methyl-oxadiazolyl or methyl-tetrazolyl and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A’, and Het 1 have the meanings as in Claim 1, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention preferably relates to a compound selected from the group consisting of: and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention further relates to a pharmaceutical preparation comprising one or more compounds according to the present invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios.
  • the invention also relates to a pharmaceutical preparation according to the invention of this type, comprising further excipients and/or adjuvants.
  • the invention relates to an above pharmaceutical preparation according to the invention, comprising at least one further medicament active compound.
  • Pharmaceutically or physiologically acceptable derivatives are taken to mean, for example, salts of the compounds of the present invention, and also so-called pro- drug compounds.
  • Prodrug compounds are taken to mean derivatives of the compounds of the present invention which have been modified by means of, for example, alkyl or acyl groups (see also amino- and hydroxyl-protecting groups below), sugars or oligopeptides and which are rapidly cleaved or liberated in the organism to form the effective molecules.
  • biodegradable polymer derivatives of the compound of the present invention can be used in its final non-salt form.
  • the present invention also encompasses the use of the compound of the present invention in the form of its pharmaceutically acceptable salts, which can be derived from various organic and inorganic bases by procedures known in the art.
  • Pharmaceutically acceptable salt forms of the compound of the present invention are for the most part prepared by conventional methods. If the compound of the present invention contains a carboxyl group, one of its suitable salts can be formed by reacting the compound of the present invention ith a suitable base to give the corresponding base-addition salt.
  • Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline-earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, for example potassium ethoxide and sodium pro- poxide; and various organic bases, such as piperidine, diethanolamine and N-methylglutamine.
  • 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 for example potassium ethoxide and sodium pro- poxide
  • organic bases such as piperidine, diethanolamine and N-methylglutamine.
  • the aluminium salts of the compound of the present invetion are likewise included.
  • the base salts of the compounds of the present invention include aluminium, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, man- ganese(III), manganese(II), potassium, sodium and zinc salts, but this is not intended to represent a restriction.
  • Salts of the compounds of the present invention which are derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion exchanger resins, for example arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylen- ediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethyl- aminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins
  • the pharmaceutically acceptable base-addition salts of the compound of the present invention are formed with metals or amines, such as alkali metals and alkaline-earth metals or organic amines.
  • metals are sodium, potassium, magnesium and calcium.
  • Preferred organic amines are N,N’- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylene- diamine, N-methyl-D-glucamine and procaine.
  • the base-addition salts of the compounds of the present invention are prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conventional manner.
  • the free acid can be regenerated by bringing the salt form into contact with an acid and isolating the free acid in a conventional manner.
  • the free acid forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts otherwise correspond to the respective free acid forms thereof.
  • the term “pharmaceutically acceptable salt” in the present connection is taken to mean an active compound which comprises the compound of the present invention in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active compound compared with the free form of the active compound or any other salt form of the active compound used earlier.
  • the pharmaceutically acceptable salt form of the active compound can also provide this active compound for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active compound with respect to its therapeutic efficacy in the body.
  • Solvates of the compound of the present invention are taken to mean adductions of inert solvent molecules of the compound of the present invention which form owing to their mutual attractive force.
  • Solvates are, for example, hydrates, such as monohydrates or dihydrates, or alcoholates, i.e. addition compounds with alcohols, such as, for example, with methanol or ethanol.
  • All physiologically acceptable salts, derivatives, solvates and stereoisomers of these compounds, including mixtures thereof in all ratios, are also in accordance with the invention.
  • Compounds of the present invention may contain one or more centres of chirality, so that all stereoisomers, enentiomers, diastereomers, etc., of the compounds of the present inventionare also claimed in the present invention.
  • the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and hydrates and solvates of these compounds.
  • Compounds of the present invention according to the invention may be chiral owing to their molecular structure and may accordingly occur in various enantiomeric forms.
  • racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers.
  • the end product, but also even the intermediates, may be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or already employed as such in the synthesis.
  • Pharmaceutically or physiologically acceptable derivatives are taken to mean, for example, salts of the compounds according to the invention and also so-called prodrug compounds.
  • Prodrug compounds are taken to mean compounds of the present invention which have been modified with, for example, alkyl or acyl groups (see also amino- and hydroxyl-protecting groups below), sugars or oligopeptides and which are rapidly cleaved or liberated in the organism to form the effective compounds according to the invention.
  • These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm.115 (1995), 61-67.
  • Suitable acid-addition salts are inorganic or organic salts of all physiologically or pharmacologically acceptable acids, for example halides, in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methylsulfonates or p- toluenesulfonates.
  • halides in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methylsulfonates or p- toluenesulfonates.
  • Solvates of the compounds of the present invention are taken to mean adductions of inert solvent molecules onto the compounds of the present invention which form owing to their mutual attractive force.
  • Solvates are, for example, hydrates, such as monohydrates or dihydrates, or alcoholates, i.e. addition compounds with alcohols, such as, for example, with methanol or ethanol. It is furthermore intended that a compound of the present invention includes iso- tope-labelled forms thereof.
  • An isotope-labelled form of a compound of the present invention is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally.
  • isotopes which are readily commercially available, and which can be incorporated into a compound of the present inventionby 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.
  • a compound of the present invention, a prodrug thereof or a pharmaceutically acceptable salt of either which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention.
  • An isotope-labelled compound of the present invention can be used in a number of beneficial ways.
  • an isotope-labelled compound of the present inventioninto which, for example, a radioisotope, such as 3 H or 14 C, has been incorporated is suitable for medicament and/or substrate tissue distribution assays.
  • radioisotopes i.e. tritium ( 3 H) and carbon-14 ( 14 C)
  • 3 H tritium
  • 14 C carbon-14
  • Incorporation of heavier isotopes, for example deuterium ( 2 H) into a compound of the present invention has therapeutic advantages owing to the higher metabolic stability of this isotope-labelled com- pound. Higher metabolic stability translates directly into an increased in-vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention.
  • An isotope-labelled compound of the present invention can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant with a readily available isotope-labelled reactant.
  • deuterium ( 2 H) can also be incorporated into a com- pound of the present invention.
  • the primary kinetic isotope effect is a change in the rate of a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange.
  • Half-life determinations enable favourable and accurate determination of the extent to which the improve- ment in resistance to oxidative metabolism has improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type.
  • the replacement of hydrogen by deuterium in a compound of the present invention can also be used to achieve a favourable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites.
  • the invention also relates to mixtures of the compounds of the present invention according to the invention, for example mixtures of two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. These are particularly preferably mixtures of two stereoisomeric compounds. However, preference is also given to mixtures of two or more compounds of the present invention.
  • the invention relates to a process for the preparation of the compounds of the present invention, characterized in that a) the base of a compound of the present invention is converted into one of its salts by treatment with an acid, or b) an acid of a compound of the present invention is converted into one of its salts by treatment with a base. It is also possible to carry out the reactions stepwise in each case and to modify the sequence of the linking reactions of the building blocks with adaptation of the protecting-group concept.
  • the starting materials or starting compounds are generally known. If they are novel, they can be prepared by methods known per se. If desired, the starting materials can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the present invention.
  • the compounds of the present invention are preferably obtained by liberating them from their functional derivatives by solvolysis, in particular by hydrolysis, or by hydrogenolysis.
  • Preferred starting materials for the solvolysis or hydrogenolysis are those which contain correspondingly protected amino, carboxyl and/or hydroxyl groups instead of one or more free amino, carboxyl and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom which is connected to an N atom.
  • Preference is furthermore given to starting materials which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group.
  • Preference is also given to starting materials which carry a protected carboxyl group instead of a free carboxyl group.
  • amino-protecting group is generally known and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule.
  • Typical of such groups are, in particular, unsubstituted or substituted acyl groups, furthermore unsubstituted or substituted aryl (for example 2,4-dinitophenyl) or aralkyl groups (for example benzyl, 4- nitrobenzyl, triphenylmethyl).
  • aryl for example 2,4-dinitophenyl
  • aralkyl groups for example benzyl, 4- nitrobenzyl, triphenylmethyl
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxy- carbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl, such as acteyl, propionyl, buturyl, aralkanoyl, such as phenylacetyl, aroyl, such as benzoyl or toluyl, aryoxyaklkanoyl, such as phenoxyacetyl, alkyoxycarbonyyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, BOC, 2-iodoethoxycaronyl, aralkoxycarbonyl, such as CBZ, 4-methoxybenzyloxycarbonyl or FMOC.
  • alkanoyl such as acteyl, propionyl, buturyl
  • aralkanoyl such as phenylacetyl, aroyl, such as benzoyl or toluyl
  • aryoxyaklkanoyl such as phenoxyacetyl
  • Preferred acyl groups are CBZ, FMOC, benzyl and acetyl.
  • the term “acid-protecting group” or “carboxyl-protecting group” is likewise generally known and relates to groups which are suitable for protecting a ⁇ COOH group against chemical reactions, but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule.
  • esters instead of the free acids, for example of substituted and unsubstituted alkyl esters (such as methyl, ethyl, tert-butyl and substituted derivatives thereof), of substituted and unsubstituted benzyl esters or silyl esters, is typical.
  • the type and size of the acid-protecting groups is not crucial, but preference is given to those having 1-20, in particular 1-10, C atoms.
  • the term “hydroxyl-protecting group” is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above- mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.
  • Their type and size of the hydroxyl-protecting groups is not crucial, but preference is given to those having 1-20, in particular 1-10, C atoms.
  • hyrdoxyl-protecting groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, where benzyl and acetyl are preferred.
  • amino-, acid- and hydroxyl-protecting groups are found, for example, in “Greene’s Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2007.
  • the functional derivatives of the compounds of the present invention to be used as starting materials can be prepared by known methods of amino-acid and peptide synthesis, as described, for example, in the said standard works and patent applications.
  • the compounds of the present invention are liberated from their functional deriva- tives, depending on the protecting group used, for example, with the aid of strong acids, advantageously using trifluoroacetic acid or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic acids, such as trichloroacetic acid, or sulfonic acids, such as benzoyl- or p- toluenesulfonic acid.
  • strong acids advantageously using trifluoroacetic acid or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic acids, such as trichloroacetic acid, or sulfonic acids, such as benzoyl- or p- toluenesulfonic acid.
  • strong acids advantageously using trifluoroacetic acid or perchloric acid
  • other strong inorganic acids such as hydrochloric acid or sulfuric acid
  • strong organic acids such as
  • Suitable inert solvents are, for example, heptane, hexane, petroleum ether, DMSO, benzene, toluene, xylene, trichloroethylene-, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether (preferably for substitution on the indole nitrogen), tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidon
  • the amount of solvent is not crucial; 10 g to 500 g of solvent can preferably be added per g of the compound of the present invention to be reacted. It may be advantageous to add an acid-binding agent, for example an alkali metal or alkaline-earth metal hydroxide, carbonate or bicarbonate or other alkali or alkaline-earth metal salts of weak acids, preferably a potassium, sodium or calcium salt, or to add an organic base, such as, for example, triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine component.
  • an acid-binding agent for example an alkali metal or alkaline-earth metal hydroxide, carbonate or bicarbonate or other alkali or alkaline-earth metal salts of weak acids, preferably a potassium, sodium or calcium salt
  • organic base such as, for example, triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine component.
  • the resultant compounds according to the invention can be separated from the corresponding solution in which they are prepared (for example by centrifugation and washing) and can be stored in another composition after separation, or they can remain directly in the preparation solution.
  • the resultant compounds according to the invention can also be taken up in desired solvents for the particular use.
  • the reaction duration depends on the reaction conditions selected. In general, the reaction duration is 0.5 hour to 10 days, preferably 1 to 24 hours. On use of a microwave, the reaction time can be reduced to values of 1 to 60 minutes.
  • the compounds of the present invention and also the starting materials for their preparation are, in addition, prepared by known methods, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), for example under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants known per se, which are not described here in greater detail.
  • Conventional work-up steps such as, for example, addition of water to the reaction mixture and extraction, enable the compounds to be obtained after removal of the solvent. It may be advantageous, for further purification of the product, to follow this with a distillation or crystallisation or to carry out a chromatographic purification.
  • An acid of the present invention can be converted into the associated addition salt using a base, for example by reaction of equivalent amounts of the acid and base in an inert solvent, such as ethanol, and inclusive evaporation.
  • Suitable bases for this reaction are, in particular, those which give physiologically acceptable salts.
  • the acid of the present invention can be converted into the corresponding metal salt, in particular alkali or alkaline-earth metal salt, using a base (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) or into the corresponding ammonium salt.
  • Organic bases which give physiologically acceptable salts, such as, for example, ethanolamine, are also suitable for this reaction.
  • a base of the present invention can be converted into the asso- ciated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and acid in an inert solvent, such as ethanol, with subsequent evaporation.
  • Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts.
  • inorganic acids for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxysulfonic acid, benzenesulfonic acid, p-tol
  • Salts with physiologically unacceptable acids can be used for the isolation and/or purification of the compounds of the present invention. It has been found that the compounds of the present invention are well tolerated and have valuable pharmacological properties.
  • the invention therefore furthermore relates to the use of compounds according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of diseases which are caused, promoted and/or propagated by HSET.
  • the invention thus also relates, in particular, to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states.
  • physiological and/or pathophysiological states which are connected to HSET.
  • Physiological and/or pathophysiological states are taken to mean physiological and/or pathophysiological states which are medically relevant, such as, for example, diseases or illnesses and medical disorders, complaints, symptoms or complications and the like, in particular diseases.
  • the invention furthermore relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states selected from the group consisting of hyperproliferative diseases and disorders.
  • the invention further relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states selected from the group consisting of hyperproliferative and infectious diseases and disorders, wherein the hyperproliferative disease or disorder is cancer.
  • the invention thus 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 granulocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, breast cancer, cervical hyperplasia, cervical cancer, chorio cancer, chronic granulocytic leukemia, chronic lymphocytic leukemia, colon cancer, endometrial ccancer, esophageal cancer, essential thrombocytosis, genitourinary carcinoma, glioma, glioblastoma, hairy cell leukemia, head and neck carcinoma, Hodgkin's disease, Kaposi's sarcoma, lung carcinoma, lymphoma, malignant carcinoid carcinoma, malignant hypercalcemia, malignant melanoma, mal
  • the invention further preferably relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states selected from the group consisting of hyperproliferative and infectious diseases and disorders, wherein the hyperproliferative disease or disorder is selected from the group consisting of age-related macular degeneration, Crohn's disease, cirrhosis, chronic inflammatory-related disorders, proliferative diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, granulomatosis, immune hyperproliferation associated with organ or tissue transplantation and an immunoproliferative disease or disorder selected from the group comnsisting of inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus
  • the medicaments disclosed above include a corresponding use of the compounds according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of the above physiological and/or pathophysiological states. It is additionally intended that the medicaments disclosed above include a corresponding method for the treatment and/or prophylaxis of the above physiological and/or pathophysiological states in which at least one compound according to the invention is administered to a patient in need of such a treatment.
  • the compounds according to the invention preferably exhibit an advantageous biological activity which can easily be demonstrated in enzyme assays and animal experiments, as described in the examples.
  • the compounds according to the invention preferably exhibit and cause an inhibiting effect, which is usually documented by IC 50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.
  • 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 in the therapeutic treatment of the human or animal body and in the combating of the above-mentioned diseases. They can furthermore be used as diagnostic agents or as reagents.
  • compounds according to the invention can be used for the isolation and investigation of the activity or expression of HSET. In addition, they are particularly suitable for use in diagnostic methods for diseases in connection with disturbed HSET activity.
  • the invention therefore furthermore relates to the use of the compounds according to the invention for the isolation and investigation of the activity or expression of HSET or as binders and inhibitors of HSET.
  • the compounds according to the invention can, for example, be radioactively labelled. Examples of radioactive labels are 3 H, 14 C, 231 I and 125 I.
  • a preferred labelling method is the iodogen method (Fraker et al., 1978).
  • the compounds according to the invention can be labelled by enzymes, fluorophores and chemophores.
  • the present invention further relates to pharmaceutical compositions containing the compounds of the present invention and their use for the treatment and/or prophylaxis of diseases and disorders where the partial or total inactivation of HSET could be beneficial.
  • the compounds of the present invention can be used for the preparation of pharmaceutical preparations, in particular by non-chemical methods.
  • the invention therefore furthermore relates to pharmaceutical preparations comprising at least one compound of the present invention and/or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
  • the invention also relates to phar- maceutical preparations which comprise further excipients and/or adjuvants, and also to pharmaceutical preparations which comprise at least one further medicament active compound.
  • the invention also relates to a process for the preparation of a pharmaceutical preparation, characterised in that a compound of the present inventionand/or one of its physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, is brought into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant and optionally with a further medicament active compound.
  • the pharmaceutical preparations according to the invention can be used as medicaments in human or veterinary medicine.
  • the patient or host can belong to any mammal species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cattle, dogs, cats, etc.
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils (such as sunflower oil or cod-liver oil), benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc, lanolin or vaseline. Owing to his expert knowledge, the person skilled in the art is familiar which adjuvants are suitable for the desired medicament formulation.
  • solvents for example water, physiological saline solution or alcohols, such as, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose or mannitol solutions, or a mixture of the said solvents, gel formers, tablet assistants and other active- ingredient carriers
  • lubricants for example water, physiological saline solution or alcohols, such as, for example, ethanol, propanol or glycerol
  • sugar solutions such as glucose or mannitol solutions
  • gel formers such as glucose or mannitol solutions
  • preparations or medicaments according to the invention may comprise one or more further active compounds, for example one or more vitamins. If desired, preparations or medicaments according to the invention may comprise one or more further active compounds and/or one or more action enhancers (adjuvants).
  • pharmaceutical formulation and “pharmaceutical preparation” are used as synonyms for the purposes of the present invention.
  • pharmaceutically tolerated relates to medicaments, precipitation reagents, excipients, adjuvants, stabilisers, solvents and other agents which facilitate the administration of the pharmaceutical preparations obtained therefrom to a mammal without undesired physiological side effects, such as, for example, nausea, dizziness, digestion problems or the like.
  • the compounds according to the invention preferably have the advantage that direct use is possible and further purification steps for the removal of toxicologically unacceptable agents, such as, for example, high concentrations of organic solvents or other toxicologically unacceptable adjuvants, are thus unnecessary before use of the compounds according to the invention in pharmaceutical formulations.
  • the invention particularly preferably also relates to pharmaceutical preparations comprising at least one compound according to the invention in precipitated non- crystalline, precipitated crystalline or in dissolved or suspended form, and optionally excipients and/or adjuvants and/or further pharmaceutical active compounds.
  • the compounds according to the invention preferably enable the preparation of highly concentrated formulations without unfavourable, undesired aggregation of the compounds according to the invention occurring.
  • ready-to-use solutions having a high active-ingredient content can be prepared with the aid of compounds according to the invention with aqueous solvents or in aqueous media.
  • the compounds and/or physiologically acceptable salts and solvates thereof can also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations.
  • Aqueous preparations can be prepared by dissolving or suspending compounds according to the invention in an aqueous solution and optionally adding adjuvants.
  • defined volumes of stock solutions comprising the said further adjuvants in defined concentration are advantageously added to a solution or suspension having a defined concentration of compounds according to the invention, and the mixture is optionally diluted with water to the pre-calculated concentration.
  • the adjuvants can be added in solid form. The amounts of stock solutions and/or water which are necessary in each case can subsequently be added to the aqueous solution or suspension obtained.
  • Compounds according to the invention can also advantageously be dissolved or suspended directly in a solution comprising all further adjuvants.
  • the solutions or suspensions comprising compounds according to the invention and having a pH of 4 to 10, preferably having a pH of 5 to 9, and an osmolality of 250 to 350 mosmol/kg can advantageously be prepared.
  • the pharmaceutical preparation can thus be administered directly substantially without pain intravenously, intra- arterially, intraarticularly, subcutaneously or percutaneously.
  • the preparation may also be added to infusion solutions, such as, for example, glucose solution, isotonic saline solution or Ringer‘s solution, which may also contain further active compounds, thus also enabling relatively large amounts of active compound to be administered.
  • Pharmaceutical preparations according to the invention may also comprise mixtures of a plurality of compounds according to the invention.
  • the preparations according to the invention are physiologically well tolerated, easy to prepare, can be dispensed precisely and are preferably stable with respect to assay, decomposition products and aggregates throughout storage and transport and during multiple freezing and thawing processes. They can preferably be stored in a stable manner over a period of at least three months to two years at refrigerator temperature (2-8°C) and at rt (23-27 °C) and 60% relative atmospheric humidity (R.H.).
  • the compounds according to the invention can be stored in a stable manner by drying and when necessary converted into a ready-to-use pharmaceutical preparation by dissolution or suspension.
  • drying methods are, for example, without being restricted to these examples, nitrogen-gas drying, vacuum-oven drying, lyophilisation, washing with organic solvents and subsequent air drying, liquid-bed drying, fluidised-bed drying, spray drying, roller drying, layer drying, air drying at rt and further methods.
  • effective amount denotes the amount of a medicament or of a pharmaceutical active compound which causes in a tissue, system, animal or human a biological or medical response which is sought or desired, for example, by a researcher or physician.
  • the term “therapeutically effective amount” denotes an amount which, compared with a corresponding subject who has not received this amount, has the following consequence: improved treatment, healing, prevention or elimination of a disease, syndrome, disease state, complaint, disorder or prevention of side effects or also a reduction in the progress of a disease, complaint or disorder.
  • the term “therapeutically effective amount” also encompasses the amounts which are effective for increasing normal physiological function.
  • the compounds according to the invention and/or physiologically acceptable salts and solvates thereof are generally used analogously to known, commercially available preparations or preparations, preferably in dosages of between 0.1 and 500 mg, in particular 5 and 300 mg, per use unit.
  • the daily dose is preferably between 0.001 and 250 mg/kg, in particular 0.01 and 100 mg/kg, of body weight.
  • the preparation can be administered one or more times per day, for example two, three or four times per day.
  • the individual dose for a patient depends on a large number of individual factors, such as, for example, on the efficacy of the particular compound used, on the age, body weight, general state of health, sex, nutrition, on the time and method of administration, on the excretion rate, on the combination with other medicaments and on the severity and duration of the particular disease.
  • a measure of the uptake of a medicament active compound in an organism is its bioavailability.
  • the medicament active compound is delivered to the organism intravenously in the form of an injection solution, its absolute bioavailability, i.e. the proportion of the pharmaceutical which reaches the systemic blood, i.e. the major circulation, in unchanged form, is 100%.
  • the active compound is generally in the form of a solid in the formulation and must therefore first be dissolved in order that it is able to overcome the entry barriers, for example the gastrointestinal tract, the oral mucous membrane, nasal membranes or the skin, in particular the stratum corneum, or can be absorbed by the body.
  • Data on the pharmacokinetics, i.e. on the bioavailability can be obtained analogously to the method of J. Shaffer et al., J.
  • medicaments of this type can be prepared by means of one of the processes generally known in the pharmaceutical art.
  • Medicaments can be adapted for administration via any desired suitable route, for example by the oral (including buccal or sublingual), rectal, pulmonary, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and in particular intra- articular) routes.
  • Medicaments of this type can be prepared by means of all processes known in the pharmaceutical art by, for example, combining the active compound with the excipient(s) or adjuvant(s).
  • Parenteral administration is preferably suitable for administration of the medicaments according to the invention.
  • intra-articular administration is particularly preferred.
  • the compounds according to the invention are also suitable for the preparation of medicaments to be administered parenterally having slow, sustained and/or controlled release of active compound. They are thus also suitable for the preparation of delayed-release formulations, which are advantageous for the patient since administration is only necessary at relatively large time intervals.
  • the medicaments adapted to parenteral administration include aqueous and non- aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood or synovial fluid of the recipient to be treated; as well as aqueous and non-aqueous sterile suspensions, which can comprise suspension media and thickeners.
  • the formulations can be delivered in single-dose or multi-dose containers, for example sealed ampoules and vials, and stored in the freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary.
  • Injection solutions and suspensions prepared in accordance with the formulation can be prepared from sterile powders, granules and tablets.
  • the compounds according to the invention can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.
  • the compounds according to the invention can also be coupled to soluble polymers as targeted medicament excipients.
  • Such polymers can encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine, substituted by palmitoyl radicals.
  • the compounds according to the invention can furthermore be coupled to a class of biodegradable polymers which are suitable for achieving slow release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, poly- cyanoacrylates, polylactic-co-glycolic acid, polymers, such as conjugates between dextran and methacrylates, polyphosphoesters, various polysaccharides and poly- amines and poly- ⁇ -caprolactone, albumin, chitosan, collagen or modified gelatine and crosslinked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers which are suitable for achieving slow release of a medicament
  • biodegradable polymers which are suitable for achieving slow release of a medicament
  • a medicament for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters
  • Suitable for enteral administration are, in particular, tablets, dragees, capsules, syrups, juices, drops or suppositories
  • suitable for topical use are ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example solutions in alcohols, such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol or mixtures thereof with one another and/or with water) or powders.
  • liposomal preparations are particularly suitable for topical uses.
  • the active compound in the case of formulation to give an ointment, can be employed either with a paraffinic or a water-miscible cream base. Alternatively, the active compound can be formulated to a cream with an oil-in-water cream base or a water-in-oil base. Medicaments adapted to transdermal administration can be delivered as independent plasters for extended, close contact with the epidermis of the recipient. Thus, for example, the active compound can be supplied from the plaster by means of iontophoresis, as described in general terms in Pharmaceutical Research, 3 (6), 318 (1986). It goes without saying that, besides the constituents particularly mentioned above, the medicaments according to the invention may also comprise other agents usual in the art with respect to the particular type of pharmaceutical formulation.
  • the invention also relates to a set (kit) consisting of separate packs of a) an effective amount of a compound of the present invention and/or physiologi- cally acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and b) an effective amount of a further medicament active compound.
  • 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 present inventionand/or pharmaceutically acceptable salts, derivatives, solvates, prodrugs and stereoisom- ers thereof, including mixtures thereof in all ratios, and an effective amount of a further medicament active compound in dissolved or lyophilised form.
  • the medicaments according to the invention can be used in order to provide additive or synergistic effects in certain known therapies and/or can be used in order to restore the efficacy of certain existing therapies.
  • the pharmaceutical preparations according to the invention may also comprise further medicament active compounds, for example for use in the treatment of cancer, other anti-tumor medicaments.
  • the pharmaceutical preparations according to the invention may also, besides the compounds according to the invention, comprise further medicament active compounds which are known to the person skilled in the art in the treatment thereof.
  • methods are provided for enhancing an immune response in a host in need thereof.
  • the immune response can be enhanced by reducing T cell tolerance, including by increasing IFN- ⁇ release, by decreasing regulatory T cell production or activation, or by increasing antigen-specific memory T cell production in a host.
  • the method comprises administering a compound of the present invention to a host in combination or alternation with an antibody.
  • the antibody is a therapeutic antibody.
  • a method of enhancing efficacy of passive antibody therapy comprising administering a compound of the present invention in combination or alternation with one or more passive antibodies.
  • This method can enhance the efficacy of antibody therapy for treatment of abnormal cell proliferative disorders such as cancer or can enhance the efficacy of therapy in the treatment or prevention of infectious diseases.
  • the compound of the present invention can be administered in combination or alternation with antibodies such as rituximab, herceptin or erbitux, for example.
  • a method of treating or preventing abnormal cell proliferation comprising administering a compound of the present invention to a host in need thereof substantially in the absence of another anti- cancer agent.
  • a method of treating or preventing abnormal cell proliferation in a host in need thereof comprising administering a first compound of the present invention substantially in combination with a first anti- cancer agent to the host and subsequently administering a second compound of the present invention receptor antagonist.
  • the second antagonist is administered substantially in the absence of another anti-cancer agent.
  • a method of treating or preventing abnormal cell proliferation in a host in need thereof comprising administering a compound of the present invention substantially in combination with a first anti-cancer agent to the host and subsequently administering a second anti- cancer agent in the absence of the antagonist.
  • Chemotherapy of this type can include the use of one or more active compounds of the following categories of antitumour active compounds: (i) antiproliferative/antineoplastic/DNA-damaging active compounds and combi- nations thereof, as used in medical oncology, such as alkylating active compounds (for example cis-platin, parboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines, such as adriamycin, bleomycin,
  • the medicaments from table 1 can preferably, but not exclusively, be combined with the compounds of the present invention. 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 scope. The preferred embodiments should therefore merely be regarded as descriptive disclosure which is absolutely not limiting in any way. The following examples are thus intended to explain the invention without limiting it. Unless indicated otherwise, per cent data denote per cent by weight. All temperatures are indicated in degrees Celsius.
  • “Conventional work-up” water is added if necessary, the pH is adjusted, if necessary, to values between 2 and 10, depending on the constitution 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 crystallisation.
  • Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), sext (sextet), hept (heptet), m (multiplet), br (broad).
  • HPLC/MS spectra of the products were recorded on an Agilent 1100 HPLC system (1100 high pressure gradient pump, 1100 diode array detector, wavelength: 220 nm) interfaced to an Agilent 1100 mass spectrometer detector (positive mode).
  • LC-MS analyses were performed on a SHIMADZU LC-MS machine consisting of an UFLC 20-AD system and LCMS 2020 MS detector.
  • the mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing formic acid at 0.1%.
  • Gradient elution was as follows: 10:90 (A/B) to 90:10 (A/B) over 2.5 min, 90:10 (A/B) for 1 min, and then reversion back to 10:90 (A/B) over 0.3 min, finally 10:90 (A/B) for 0.2 min.
  • Example 1 Ethyl 4-methyl-2-(3-(3-methylbenzamido)propanamido)thiazole-5- carboxylate
  • 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, under nitrogen atmosphere at rt, were added EDC (4.05 g, 21.14 mmol) and ethyl 2-amino-4- methylthiazole-5-carboxylate (2.165 g, 11.63 mmol) sequentially. The mixture was stirred at 50 °C overnight. The mixture was concentrated in vacuo.
  • Example 1.2 4M HCl in dioxane (26.86 mL, 107.43 mmol) was added dropwise to a solution of ethyl 2-[3-(tert-butoxycarbonylamino)propanoylamino]-4-methyl- thiazole-5-carboxylate (1.28 g, 3.5811 mmol) in EtOH (35.81 mL). The reaction mixture was stirred at rt for 2 h before concentrating in vacuo.
  • Example 1.3 To 3-methylbenzoic acid (38.1 mg, 0.280 mmol), ethyl 2-(3- aminopropanoylamino)-4-methyl-thiazole-5-carboxylate (80 mg, 0.311 mmol) and DIPEA (163 ⁇ l, 0.933 mmol) in DMF (3109 ⁇ l) was added HATU (110 mg, 0.466 mmol) and the reaction mixture stirred overnight at rt. The mixture was concentrated in vacuo. The crude was dissolved in EtOAc and washed with 1N HCl, aqueous saturated bicarbonate, and brine.
  • Example 2 Ethyl 4-methyl-2-(3-(3-(pyrrolidin-1-yl)benzamido)propan- amido)thiazole-5-carboxylate 14 mg (26%, 0.0325 mmol) yellow solid.
  • Example 3 Ethyl 2-(3-(3-(1H-pyrazol-1-yl)benzamido)propanamido)-4- methylthiazole-5-carboxylate 27 mg (51%, 0.0632 mmol) colorless solid. HPLC/MS m/z: 428.1 [M+H] + , Rt (S): 2.70 min.
  • Example 4 Ethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate 47 mg(68%, 0.1060 mmol) off-white solid.
  • Example 5 Ethyl 4-methyl-2-(3-(5,6,7,8-tetrahydronaphthalene-2- carboxamido)propanamido)thiazole-5-carboxylate 24 mg (37%, 0.0578 mmol) colorless solid.
  • Example 6 Ethyl 4-methyl-2-(3-(3-(oxazol-5-yl)benzamido)propanamido)thiazole-5- carboxylate 40 mg (60%, 0.0934 mmol) yellow solid. HPLC/MS m/z: 429.1 [M+H] + , Rt (S): 2.67 min.
  • Example 7 Ethyl 4-methyl-2-(3-(3-morpholinobenzamido)propanamido)thiazole-5- carboxylate 22 mg (32%, 0.0493 mmol) off-white solid.
  • Example 8 Ethyl (S)-2-(2-hydroxy-3-(3-methylbenzamido)propanamido)-4- methylthiazole-5-carboxylate Using (S)-3-((tert-butoxycarbonyl)amino)-2-hydroxypropanoic acid to afford 16 mg (12%, 0.041 mmol) of ethyl (S)-2-(2-hydroxy-3-(3-methylbenzamido)propanamido)- 4-methylthiazole-5-carboxylate as a colorless solid.
  • the reaction mixture was then diluted with EtOAc (40 mL) and washed with water (40 mL). The aqueous layer was re-extracted with EtOAc (40 mL). The organic layers were combined and washed with aqueous saturated sodium bicarbonate solution (50 mL) and brine (50 mL). The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. The crude was purified using reverse phase column chromatography with a 12 g C18 Biotage ULTRA column.
  • Example 10 Ethyl 2-[3-[(3-fluoro-5-methoxycarbonyl- benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate 43 mg (51%) colorless, fluffy solid. HPLC/MS m/z: 438.11 [M+H] + , Rt (R): 1.35 min.
  • Example 11 Ethyl 2-[3-[(2-fluoro-3-methoxycarbonyl- benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate 26 mg (31%) colorless, fluffy solid. HPLC/MS m/z: 438.11 [M+H] + , Rt (R): 1.23 min.
  • Example 12 Ethyl 2-[3-[(2-chloro-5-methoxycarbonyl- benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate 41 mg (46%) fine, colorless powder.
  • Example 13 Ethyl 2-[3-[(3-chloro-5-methoxycarbonyl- benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate 37 mg (42%) colorless, granular solid. HPLC/MS m/z: 454.08 [M+H] + , Rt (R): 1.41 min.
  • Example 14 Ethyl 2-[3-[(3-methoxycarbonyl-4-methyl- benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate 56 mg (66%) colorless solid. HPLC/MS m/z: 434.14 [M+H] + , Rt (R): 1.33 min.
  • Example 15 Ethyl 2-[3-[(3-methoxycarbonyl-5-methyl- benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate 56 mg (67%) colorless solid. HPLC/MS m/z: 434.14 [M+H] + , Rt (R): 1.35 min.
  • Example 16 Ethyl 2-[3-[(3-methoxy-5-methoxycarbonyl- benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate 35 mg (40%) colorless solid. HPLC/MS m/z: 450.13 [M+H] + , Rt (R): 1.33 min.
  • Example 17 Ethyl 2-[3-[(3-cyano-5-methoxycarbonyl- benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate 32 mg (37%) colorless, amorphous solid. HPLC/MS m/z: 445.12 [M+H] + , Rt (R): 1.30 min.
  • Example 18 Ethyl 2-[3-[(3-bromo-5-methoxycarbonyl- benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate 163 mg (47%) amorphous, colorless solid. HPLC/MS m/z: 498.03 [M+H] + , Rt (R): 1.43 min.
  • Example 19 Ethyl 2-[3-[(3-ethyl-5-methoxycarbonyl-benzoyl)amino]- propanoylamino]-4-methyl-thiazole-5-carboxylate 3 mg (7%) colorless, amorphous solid. HPLC/MS m/z: 448.15 [M+H] + , Rt (R): 1.40 min.
  • Example 20 Ethyl 2-[3-[(3-hydroxy-5-methoxycarbonyl-benzoyl)amino]- propanoylamino]-4-methyl-thiazole-5-carboxylate 20 mg (12%) colorless, amorphous solid. HPLC/MS m/z: 436.12 [M+H] + , Rt (R): 1.26 min.
  • Example 21 Ethyl 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]- propylamino]thiazole-5-carboxylate 50 mg (51%) colorless, amorphous solid. HPLC/MS m/z: 430.15 [M+H] + , Rt (R): 1.31 min.
  • Example 22 Ethyl 2-[3-[[3-methoxycarbonyl-5-[(E)-styryl]benzoyl]amino]- propanoylamino]-4-methyl-thiazole-5-carboxylate 15 mg (24%) colorless, amorphous solid. HPLC/MS m/z: 522.17 [M+H] + , Rt (R): 1.56 min.
  • Example 23 Ethyl 2-(3-(3-(1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4- methylthiazole-5-carboxylate 51 mg (75%). HPLC/MS m/z: 430.1 [M+H] + , Rt (U): 2.77 min.
  • Example 24 Ethyl 2-(3-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)- propanamido)-4-methylthiazole-5-carboxylate
  • Example 24.1 Methyl 3-chloro-5-cyano-benzoate (250.00 mg, 1.2781 mmol) was dissolved in MeOH (12.78 mL). Hydroxylamine (50 % in water) (0.20 mL, 6.3906 mmol) was added, and the solution was stirred at rt for overnight.
  • Example 24.2. Acetic acid (0.06 mL, 1.0852 mmol), methyl 3-chloro-5-[(Z)-N'- hydroxycarbamimidoyl]benzoate (175.00 mg, 0.7654 mmol) and EDC.HCl (207.37 mg, 1.0818 mmol) were dissolved in THF (4.53 mL) and MeCN (4.53 mL) in a microwave vial under N 2 . The reaction mixture was stirred overnight at rt. DIPEA (0.38 mL, 2.1652 mmol) was added and the solution was heated under microwave irradiation for 30 min at 150 °C. Solvents were evaporated and EtOAc was added.
  • Example 24.3 To methyl 3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate (50.00 mg, 0.1979 mmol) in THF (0.99 mL) was added water (0.99 mL) followed by LiOH hydrate (24.91 mg, 0.5937 mmol). After stirring for at rt volatile were removed in vacuo and the crude partitioned between EtOAc (15 mL) and 1M HCl (15 mL). The organic was retained and the aqueous extracted with further EtOAc (10 mL).
  • Example 24.4 An analogous procedure to the preparation of 0 using 3-chloro-5-(5- methyl-1,2,4-oxadiazol-3-yl)benzoic acid and ethyl 2-(3-aminopropanoylamino)-4- methyl-thiazole-5-carboxylate afforded 26 mg (52%, 0.0544 mmol) of ethyl 2-(3-(3- chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4-methylthiazole- 5-carboxylate as a colorless solid.
  • Example 25 Propyl 2-(3-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate 31 mg (60%) colorless solid. HPLC/MS m/z: 492.11, [M+H] + , Rt (S): 3.20 min.
  • Example 26 Propyl 4-methyl-2-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate Prepared in analogous procedure from methyl 3-cyano-5-methyl-benzoate to afford 58 mg (73%) of propyl 4-methyl-2-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate as a colorless solid.
  • Example 27 Propyl 1-methyl-3-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)-1H-pyrazole-5-carboxylate
  • Propyl 1-methyl-3-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)- propanamido)-1H-pyrazole-5-carboxylate (20 mg, 21%, 0.0440 mmol) was prepared in analogous procedure from methyl 3-cyano-5-methyl-benzoate and propyl 5-amino-2-methyl-pyrazole-3-carboxylate as a colorless solid.
  • Example 28 Propyl 2-(3-(3-cyano-5-(trifluoromethyl)benzamido)propanamido)-4- methylthiazole-5-carboxylate 40.5 mg (53%) yellow solid.
  • Example 29 Propyl 2-(3-(3-(tert-butyl)-5- (methoxycarbonyl)benzamido)propanamido)-4-methylthiazole-5-carboxylate 23 mg (36%) colorless solid.
  • Example 30 Propyl 2-(3-(3-cyano-5-(methoxycarbonyl)benzamido)propanamido)-4- methylthiazole-5-carboxylate 15 mg (10%) colorless solid. HPLC/MS m/z: 459.13, [M+H] + , Rt (S): 2.94 min.
  • 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
  • Example 31.1 Using 3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid [0] in an analogous procedure to 0 afforded 3-[[3-chloro-5-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoic acid.
  • Example 32 Propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-5- (trifluoromethyl)benzamido)propanamido)thiazole-5-carboxylate
  • Example 32.1. Propyl 2-[3-[[3-cyano-5-(trifluoromethyl)benzoyl]amino]propanoyl- amino]-4-methyl-thiazole-5-carboxylate [0] (105.00 mg, 0.2241 mmol) and TEA (0.03 mL, 0.2241 mmol) were heated at 80 °C in [bmim]OAc (0.22 mL) and hydroxylamine hydrochloride (31.15 mg, 0.4483 mmol) was added.
  • Example 32.2 To a solution of propyl 2-[3-[[3-(N-hydroxycarbamimidoyl)-5- (trifluoromethyl)benzoyl]amino]propanoylamino]-4-methyl-thiazole-5-carboxylate (20.00 mg, 0.0368 mmol) in DMSO (0.40 mL) was added potassium hydroxide (2.06 mg, 0.0368 mmol). The solution was stirred at rt for 1 h. Water (15mL) was added, and the residue was extracted with EtOAc (3 x 15 mL). Organic layers were combined, washed with brine (15 mL), dried over MgSO 4 and concentrated in vacuo.
  • Example 33 Propyl 2-[3-[(3-methoxycarbonyl-5-nitro- benzoyl)amino]propanoylamino]-4-methyl-thiazole-5-carboxylate 134 mg (58%) light yellow powder (134 mg, 58%, 0.28 mmol). HPLC/MS m/z: 479.12 [M+H] + , Rt (R): 1.42 min.
  • Example 34 Ethyl 4-methyl-2-(3-(3-(3-methyl-1,2,4-oxadiazol-5- yl)benzamido)propanamido)thiazole-5-carboxylate Dissolved 3-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (31.74 mg, 0.1555 mmol), ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate (40.00 mg, 0.1555 mmol) and DIPEA (81.45 uL, 0.4664 mmol) in DMF (1.55 mL).
  • Example 36 Ethyl 2-(3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4- methylthiazole-5-carboxylate
  • ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate 40.00 mg, 0.1555 mmol
  • 3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzoic acid 33.92 mg, 0.1555 mmol) in DMF (1.55 mL) was added DIPEA (81.45 uL, 0.4664 mmol) followed by HATU (54.86 mg, 0.2332 mmol).
  • Example 37 Ethyl 4-methyl-2-(3-(3-(5-methyl-1,3,4-oxadiazol-2- yl)benzamido)propanamido)thiazole-5-carboxylate
  • 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate 40.00 mg, 0.1555 mmol
  • 3-(5-methyl-1,3,4-oxadiazol-2-yl)benzoic acid 31.74 mg, 0.1555 mmol
  • DIPEA 81.45 uL, 0.4664 mmol
  • HATU 54.86 mg, 0.2332 mmol
  • Example 38 Ethyl 4-methyl-2-(3-(3-(2-methyl-2H-tetrazol-5- yl)benzamido)propanamido)thiazole-5-carboxylate
  • 2-(3-aminopropanoylamino)-4-methyl-thiazole-5-carboxylate 40.00 mg, 0.1555 mmol
  • 3-(2-methyltetrazol-5-yl)benzoic acid 31.74 mg, 0.1555 mmol
  • DMF 1.55 mL
  • DIPEA 108.60 uL, 0.6218 mmol
  • HATU 54.86 mg, 0.2332 mmol
  • Example 39 tert-Butyl 4-methyl-2-[3-[[3-(2-methyltetrazol-5- yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate
  • Example 39.1. To methyl 3-aminopropanoate hydrochloride (100.00 mg, 0.7164 mmol), 3-(2-Methyl-2H-tetrazol-5-yl)-benzoic acid (146.29 mg, 0.7164 mmol) in DMF (4.21 mL) was added DIPEA (0.50 mL, 2.8657 mmol) followed by HATU (252.83 mg, 1.0747 mmol). The obtained yellow solution was stirred overnight at rt.
  • Example 39.3. To a solution of HOBt (29.45 mg, 0.2180 mmol), 3-[[3-(2- methyltetrazol-5-yl)benzoyl]amino]propanoic acid (30.00 mg, 0.1090 mmol) in DMF (0.54 mL) was added EDC (33.84 mg, 0.2180 mmol) and tert-butyl 2-amino-4- methyl-thiazole-5-carboxylate (27.79 mg, 0.1297 mmol). The mixture was stirred for 18 h at 70 °C.
  • Example 40 Isopropyl 4-methyl-2-[3-[[3-(2-methyltetrazol-5- yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate 27 mg (54%) colorless, amorphous solid.
  • Example 41 N-[3-[(5-tert-butyl-4-methyl-thiazol-2-yl)amino]-3-oxo-propyl]-3-(2- methyltetrazol-5-yl)benzamide 7 mg (24%) colorless solid.
  • Example 42 Ethyl 2-(3-(3-(ethoxycarbonyl)benzamido)propanamido)-4- methylthiazole-5-carboxylate
  • 3-ethoxycarbonylbenzoic acid 37.73 mg, 0.1943 mmol
  • ethyl 2-(3- aminopropanoylamino)-4-methyl-thiazole-5-carboxylate 50.00 mg, 0.1943 mmol
  • DMF 0.97 mL
  • DIPEA 1, 35.75 uL, 0.7773 mmol
  • HATU 68.57 mg, 0.2915 mmol
  • Example 43 Ethyl 4-methyl-2-(3-(3-methyl-5-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate
  • Example 43.1. Methyl 3-cyano-5-methyl-benzoate (268.00 mg, 1.5299 mmol) was dissolved in MeOH (15.30 mL). Hydroxylamine (50 % in water) (0.47 mL, 3.8246 mmol) was added, and the solution was stirred at rt overnight.
  • Example 43.2 Acetic acid (0.06 mL, 1.0827 mmol), methyl 3-[(Z)-N'- hydroxycarbamimidoyl]-5-methyl-benzoate (159.00 mg, 0.7637 mmol) and EDC.HCl (206.89 mg, 1.0793 mmol) were dissolved in THF (3.00 mL) and MeCN (3.00 mL) in a microwave vial under nitrogen atmosphere. The reaction mixture was stirred overnight at rt. DIPEA (0.38 mL, 2.1601 mmol) was added and the solution was heated under microwave irradiation for 1 hr at 150 °C.
  • DIPEA 0.38 mL, 2.1601 mmol
  • Example 43.4 To 3-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (17.00 mg, 0.0779 mmol), ethyl 2-(3-aminopropanoylamino)-4-methyl-thiazole-5- carboxylate (20.05 mg, 0.0779 mmol) in DMF (0.73 mL) was added HATU (29.62 mg, 0.0779 mmol) and DIPEA (54.43 uL, 0.3116 mmol). After stirring at rt for 1.5 h the volatiles were removed in vacuo.
  • Example 44 Propyl 2-(3-(3-(methoxycarbonyl)-5-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate
  • Example 44.1 propyl 2-[3-[(3-cyano-5-methoxycarbonyl-benzoyl)amino]propanoyl- amino]-4-methyl-thiazole-5-carboxylate [0] (61.00 mg, 0.1330 mmol) and TEA (0.02 mL, 0.1330 mmol) in [bmim]OAc (0.13 mL) were heated at 80 °C and hydroxylamine hydrochloride (18.49 mg, 0.2661 mmol) was added.
  • Example 44.2 Acetic acid (0.004 mL, 0.0712 mmol), propyl 2-[3-[[3-(N- hydroxycarbamimidoyl)-5-methoxycarbonyl-benzoyl]amino]propanoylamino]-4- methyl-thiazole-5-carboxylate (35.00 mg, 0.0712 mmol) and EDC.HCl (14.33 mg, 0.0748 mmol) were dissolved MeCN (0.43 mL) and THF (0.43 mL) in a 0.5-2 mL microwave vial under nitrogen atmosphere. The solution was stirred overnight at rt.
  • Example 45 Ethyl 4-methyl-2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]propanoylamino]thiazole-5-carboxylate
  • Example 45.1 Nitrogen gas was bubbled through a mixture of 7-bromoisoquinolin- 1-ol (0.500 g, 2.23 mmol) and zinc cyanide (0.341 g, 2.90 mmol) in DMF (12.4 mL) for 15 min. Palladium tetrakis(triphenylphosphine) (0.155 g, 0.13 mmol) was added and the mixture heated at 100 °C in a sealed vial for 16 h.
  • Example 45.6 3-[[7-(5-Methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]- propanenitrile (19 mg, 0.068 mmol) in concentrated aqueous HCl (2 mL) and acetic acid (4 mL) was heated at 80 °C for 1.5 h. The mixture was concentrated to afford 0.020 g (100%) of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]- propanoic acid.
  • Example 45.7 3-(Ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (26 mg, 0.14 mmol) was added to a solution of 3-[[7-(5-methyl-1,2,4- oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid (20 mg, 0.068 mmol), ethyl 2- amino-4-methyl-thiazole-5-carboxylate (15 mg, 0.082 mmol) and HOBt (18 mg, 0.014 mmol) in DMF (0.68 mL) under nitrogen. The mixture was heated at 60 °C for 17 h.
  • Example 46 Methyl 4-methyl-2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]propanoylamino]thiazole-5-carboxylate 3 mg (6%) colorless, amorphous solid [formate salt].
  • Example 47 N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[[6-(5-methyl-1,2,4-oxadiazol-3- yl)quinazolin-4-yl]amino]propanamide formate
  • Example 47.1 4-Hydroxyquinazoline-6-carbonitrile (500 mg, 2.92 mmol) and triethylamine (0.41 mL, 2.92 mmol) were heated at 80 °C in [bmim]OAc (2.9 mL). Hydroxylamine hydrochloride (406 mg, 5.84 mmol) was added, after which some foaming was observed. The reaction mixture was continued to stir at 80 °C for 30 min.
  • Example 47.2 A suspension of N,4-dihydroxyquinazoline-6-carboxamidine (480 mg, 2.35 mmol) and acetic anhydride (0.27 mL, 2.82 mmol) in anhydrous ACN (4.70 mL) under an argon atmosphere was heated under microwave irradiation at 180 °C for 10 min. The reaction mixture was cooled to rt and cold water was added (50 mL). The precipitate was filtered off, washed with water (50 mL) and diethyl ether (10 mL), and dried under reduced pressure to yield 293 mg (55%) of 6-(5- methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-ol.
  • Example 47.4. 3-(4-chloroquinazolin-6-yl)-5-methyl-1,2,4-oxadiazole (150 mg, 0.61 mmol) and sodium 3-aminopropanoate (270 mg, 2.43 mmol) were mixed in anhydrous NMP (2.0 mL) under argon and stirred at rt for 1 h.
  • the reaction mixture was purified by reverse flash chromatography (10-100% MeOH in water) to yield 52 mg (29%) of 3-[[6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-yl]amino]propanoic acid as a colorless solid.
  • 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
  • Example 48.1 6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4-ol (250 mg, 1.10 mmol), cis-methyl 3-aminocyclobutanecarboxylate hydrochloride (200 mg, 1.21 mmol) and DIPEA (0.57 mL, 3.29 mmol) were dissolved in anhydrous DMF (11 mL) at rt under an argon atmosphere.
  • 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.
  • Example 48.3. (1s,3s)-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4- yl)amino)cyclobutane-1-carboxylic acid (20 mg, 0.062 mmol) and BTFFH (39 mg, 0.123 mmol) were mixed in anhydrous DCM (0.50 mL) in a microwave vial at rt under an argon atmosphere. DIPEA (0.05 mL, 0.277 mmol) was added and the reaction mixture was stirred for 20 min.
  • DIPEA 0.05 mL, 0.277 mmol
  • 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 tert-Butyl 4-methyl-2-((1s,3s)-3-((6-(5-methyl-1,2,4-oxadiazol-3-yl)quinazolin-4- yl)amino)cyclobutane-1-carboxamido)thiazole-5-carboxylate (20 mg, 0.038 mmol) was dissolved in anhydrous DMF (0.38 mL) under an argon atmosphere and cooled in an ice bath.
  • reaction mixture was purified by reverse 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.
  • Example 50 N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[(7-cyano-1- isoquinolyl)amino]propenamide
  • Example 50.1. Isoquinoline-7-carbonitrile (1.00 g, 6.49 mmol) was suspended in anhydrous chloroform (20 mL) under an argon atmosphere and cooled in an ice bath.3-Chloroperoxybenzoic acid (1.74 g, 7.78 mmol) was added. The reaction mixture was allowed to warm to rt and stirred overnight.
  • Example 50.3. To a solution of tert-butyl 3-[(7-cyano-1-isoquinolyl)amino]- propanoate (271 mg, 0.911 mmol) in DCM (1.82 mL) under an argon atmosphere was added TFA (0.70 mL, 9.11 mmol). The resulting solution was stirred at rt overnight. Volatiles were removed under reduced pressure and the crude was purified by reverse flash chromatography (5-40% MeOH in water [0.1% FA]) to yield 119 mg (54%) of 3-[(7-cyano-1-isoquinolyl)amino]propanoic acid as an off-white solid.
  • Example 50.4. Preparation as described for Example 47.5 using 3-[(7-cyano-1- isoquinolyl)amino]propanoic acid (60 mg, 0.249 mmol) and 5-tert-butyl-4-methyl- thiazol-2-ylamine (85 mg, 0.497 mmol). Purification by reverse flash chromatography followed by SCX-2 filtration to afford N-(5-tert-butyl-4-methyl- thiazol-2-yl)-3-[(7-cyano-1-isoquinolyl)amino]propanamide (57 mg, 58%) as an off- white, crystalline solid.
  • Example 51 3-[(7-cyano-1-isoquinolyl)amino]-N-[4-methyl-5-[1-(trifluoro- methyl)cyclopropyl]thiazol-2-yl]propenamide
  • Example 51.1 2-Amino-4-methylthiazole (97 mg, 0.850 mmol) and sodium 1- (trifluoromethyl)cyclopropanesulfinate (500 mg, 2.55 mmol) were mixed in diethyl carbonate/water (3:2, 8.50 mL) and cooled in an ice bath.
  • Example 52 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-N-[4-methyl- 5-[1-(trifluoromethyl)cyclopropyl]thiazol-2-yl]propenamide Preparation as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]propanoic acid [Example 45.6] (25 mg, 0.083 mmol) and 4- methyl-5-[1-(trifluoromethyl)cyclopropyl]thiazol-2-amine [Example 51.1] (20 mg, 0.091 mmol).
  • Example 53 N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[(7-cyano-5-fluoro-1- isoquinolyl)amino]propenamide
  • Example 53.1. A mixture of N-Boc-hydroxylamine (9.0 g, 67.6 mmol) and trimethylacetic anhydride (15.1 mL, 74.4 mmol) in anhydrous MeCN (135 mL) under an argon atmosphere was stirred at reflux overnight.
  • Example 53.2 Trifluoromethanesulfonic acid (5.9 mL, 65.8 mmol) was added to a solution of (tert-butoxycarbonylamino)-2,2-dimethylpropanoate (14.3 g, 65.8 mmol) in diethyl ether (132 mL) at rt under an argon atmosphere and stirred for 3 h. The white, crystalline precipitate was filtered off, washed with diethyl ether and dried under reduced pressure to yield 7.0 g (40%) of 2,2-dimethylpropanoyloxy- ammonium trifluoromethanesulfonate.
  • Example 53.4 [(3-cyano-5-fluoro-benzoyl)amino] 2,2-dimethylpropanoate (1.00 g, 3.784 mmol), [Cp*RhCl 2 ] 2 (58 mg, 0.095 mmol) and caesium acetate (219 mg, 1.135 mmol) were mixed in MeOH (9.5 mL) at rt under an argon atmosphere. Vinyl acetate (1.05 mL, 11.353 mmol) was added, and the reaction mixture was heated at 45 °C for 18 h.
  • Example 54 Propyl 4-methyl-2-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)propanamido)thiazole-5-carboxylate
  • 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 oC and stirred for 30 min before 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. Stirred at 100 oC overnight.
  • Example 54.2 To a mixture of 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]propanoic acid (30.00 mg, 0.1006 mmol), EDC.HCl (38.56 mg, 0.2011 mmol), HOBt (27.18 mg, 0.2011 mmol) and propyl 2-amino-4-methyl- thiazole-5-carboxylate [Example 63.1] (30.21 mg, 0.1509 mmol) was added under nitrogen atmosphere DMF (0.40 mL). The resulting solution was stirred at 70 °C overnight. LCMS showed total conversion.
  • Example 55 N-(5-cyanothiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propenamide 38 mg (54%) colorless solid.
  • Example 56 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(1- methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)propenamide 14 mg (47%) colorless solid.
  • 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
  • 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 for 15 min at 0 °C.
  • 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 under microwave irradiation for 30 min at 90 °C. Volatiles were removed under reduced pressure.
  • Example 57.4. An analogous procedure to Example 54.2 using 1-methyl-5-pentyl- pyrazol-3-amine and 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]- propanoic acid afforded 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)-N-(1-methyl-5-pentyl-1H-pyrazol-3-yl)propanamide (10.2 mg, 34%, 0.0228 mmol) as a colorless solid.
  • Example 58 N-(5-(tert-butyl)-4-methylthiazol-2-yl)-3-((7-(5-methyl-2H-tetrazol-2- yl)isoquinolin-1-yl)amino)propenamide
  • Example 58.1. 7-Aminoisoquinoline (720.85 mg, 5 mmol) was dissolved in a mixture of 50% aqueous hydrofluroboric 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.
  • Example 58.2. To a solution of acetamidine hydrochloride (155.64 mg, 1.6463 mmol) and potassium carbonate (1.14 g, 8.2315 mmol) in DMSO (8.00 mL) was added isoquinoline-7-diazonium tetrafluoroborate (400.00 mg, 1.6463 mmol) in portions. After stirring for 1.5 h at rt, potassium iodide (409.93 mg, 2.4694 mmol) and iodine (501.41 mg, 1.9756 mmol) were added. Stirred at rt for 1.5 h before a solution of brine and sodium thiosulfate were added to the mixture. The product was extrated with EtOAc.
  • Example 58.3. 7-(5-methyltetrazol-2-yl)isoquinoline (120.00 mg, 0.5681 mmol) was dissolved in CHCl 3 (1.54 mL) and cooled in an ice bath.3-Chloroperoxybenzoic acid (0.15 g, 0.6818 mmol) was added. The reaction was stirred at rt for 2 h. K 2 CO 3 (0.31 g, 2.2725 mmol) was added, stirred for 0.5 h before filtering. The filtrate was concentrated in vacuo.
  • Example 58.4. 7-(5-methyltetrazol-2-yl)-2-oxido-isoquinolin-2-ium (120.00 mg, 0.5281 mmol) and beta-alanine tert-butyl ester hydrochloride (124.72 mg, 0.6866 mmol) were dissolved in dry DCM (2.80 mL). DIPEA (0.43 mL, 2.4822 mmol) was added followed by PyBroP (369.30 mg, 0.7922 mmol) and the flask stirred at rt overnight.1 equivalent of PyBrop, amine and DIPEA were added, the mixture was stirred at 30 °C for 20 h. The solvent was removed in vacuo.
  • Example 58.5 tert-Butyl 3-[[7-(5-methyltetrazol-2-yl)-1-isoquinolyl]amino]- propanoate (85.00 mg, 0.2398 mmol) and potassium hydroxide (134.57 mg, 2.3984 mmol) were dissolved in THF (1.20 mL). Few drops of water and MeOH were added. The reaction was stirred at 50 °C for 2 h. Further potassium hydroxide (134.57 mg, 2.3984 mmol) and more water were added, stirred at 50 °C for 3 h.
  • Example 58.6. 3-[[7-(5-methyltetrazol-2-yl)-1-isoquinolyl]amino]propanoic acid (60.00 mg, 0.2011 mmol), EDC (116.84 mg, 0.6034 mmol), HOBt (92.41 mg, 0.6034 mmol) and 5-tert-butyl-4-methyl-thiazol-2-ylamine (102.75 mg, 0.6034 mmol) were dissolved in dry DMF (2.01 mL). DIPEA (176.05 uL, 1.0057 mmol) was added and the reaction mixture was stirred at 50 °C for 21 h.
  • DIPEA 176.05 uL, 1.0057 mmol
  • Example 59 N-(3-((5-(tert-butyl)-4-methylthiazol-2-yl)amino)-3-oxopropyl)-3-(5- methyl-2H-tetrazol-2-yl)benzamide
  • Example 59.1. Ethyl 3-amino benzoate (0.81 mL, 5 mmol) was dissolved in a mixture of water (1.00 mL) and 50% aqueous hydrofluroboric 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.
  • Example 59.2. To a solution of acetamidine hydrochloride (0.42 g, 4.47 mmol) and potassium carbonate (3.09 g, 22.35 mmol) in DMSO (21.72 mL) was added 3- (ethoxycarbonyl)benzenediazonium tetrafluoroborate (1.18 g, 4.47 mmol) in portions. After stirring for 1.5 h at rt, potassium iodide (1113.04 mg, 6.7051 mmol) and iodine (1361.45 mg, 5.364 mmol) were added. Stirred at rt for 1.5 h before a solution of brine and sodium thiosulfate were added to the mixture.
  • 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 rt and diluted with a mixture of water and EtOAc.
  • DIPEA 235.30 uL, 1.3442 mmol
  • 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
  • Example 60.1 Ethyl 3-amino benzoate (0.81 mL, 5 mmol) was dissolved in a mixture of water (1.00 mL) and 50% aqueous hydrofluroboric acid (1.90 mL, 30.293 mmol). Sodiumnitrite (689.90 mg, 10 mmol), dissolved in water (1.00 mL), was added dropwise.
  • Example 60.2. To a solution of acetamidine hydrochloride (0.39 g, 4.167 mmol) and potassium carbonate (2.88 g, 20.835 mmol) in DMSO (20.25 mL) was added 3- ethoxycarbonylbenzenediazonium; tetrafluoroboron (1.10 g, 4.167 mmol) in portions. After stirring for 1.5 h at rt potassium iodide (1.04 g, 6.2505 mmol) and iodine (1.27 g, 5.0004 mmol) were added, stirred at rt for 1.5 h. A solution of brine and sodium thiosulfate were added to the mixture.
  • Example 60.4. 3-(5-methyltetrazol-2-yl)benzoic acid (264.00 mg, 1.2929 mmol), 2- (7-aza-1H-benzotriazole-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).
  • HATU 2- (7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • N,N-Diisopropylethylamine (0.68 mL, 3.8787 mmol) was added, and the reaction mixture was stirred at rt over 3 d. EtOAc and NaHCO 3 solution were added. The product was extracted with EtOAc, washed with water, dried over MgSO 4 .
  • Example 60.5 tert-Butyl (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[3-(5- methyltetrazol-2-yl)benzoyl]amino]hexanoate was used in analogous procedures to Example 152.6 - Example 152.8 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 (36 mg, 56%, 0.0722 mmol) as a colorless powder.
  • Example 61 Ethyl 2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)- thiazole-5-carboxylate
  • ethyl 2-aminothiazole-5-carboxylate 37.11 mg, 0.2155 mmol
  • 3- [[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid [Example 63.3] (50.00 mg, 0.1816 mmol) in DMF (0.91 mL) was added HOBt (49.09 mg, 0.3633 mmol) and EDC (56.40 mg, 0.3633 mmol).
  • the mixture was stirred for 18 h at 60 °C.
  • the reaction mixture was partitioned between water (50 mL) and EtOAc (40 mL). The organic was washed with water (40 mL), 1N HCl (20 mL), aqueous saturated bicarbonate (20 mL), and brine (20 mL). The organic layer was dried over sodium sulfate and concentrated.
  • Example 62 Methyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate To 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid [Example 63.3] (99.00 mg, 0.3597 mmol), methyl 2-amino-4-methyl-thiazole-5-carboxylate (73.49 mg, 0.4267 mmol) and HOBt (97.19 mg, 0.7193 mmol) in DMF (1.80 mL) under nitrogen atmosphere was added 3-(ethyliminomethyleneamino)-N,N- dimethylpropan-1-amine hydrochloride (137.89 mg, 0.7193 mmol).
  • Example 63 Propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate
  • 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 successively added and the solution was stirred at 60 °C for 1 h.
  • Example 63.2 To methyl 3-aminopropanoate hydrochloride (546.89 mg, 3.9181 mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (800.00 mg, 3.9181 mmol) in DMF (19.59 mL) was added DIPEA (2.74 mL, 15.672 mmol) followed by HATU (1382.69 mg, 5.8772 mmol). Stirred at rt for 20 h. Diluted with EtOAc (200 mL) and washed with water (250 mL). The aqueous phase was extracted with fresh EtOAc (100 mL).
  • Example 63.3 To methyl 3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoate (1.12 g, 3.8715 mmol) in THF (19.26 mL) was added water (19.26 mL) followed by lithium hydroxide hydrate (0.65 g, 15.486 mmol). After stirring for 1 h 20 min the THF removed in vacuo. The solution was acidified to pH 3 with 1M Citric acid solution and extracted with EtOAc (2 x 100 mL). The organics were combined, washed with brine (150 mL) and dried over MgSO 4 .
  • Example 63.4 Propyl 2-amino-4-methyl-thiazole-5-carboxylate (24.00 mg, 0.1198 mmol), 1-hydroxybenzotriazole (32.39 mg, 0.2397 mmol), 3-(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]propanoic acid (42.88 mg, 0.1558 mmol) were dissolved in dry DMF (0.60 mL) at rt for 60 h.
  • Example 64 N-(3-((5-butyl-4-methylthiazol-2-yl)amino)-3-oxopropyl)-3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzamide 31 mg (27%). HPLC/MS m/z: 428.18 [M+H] + , Rt (R): 1.44 min.
  • Example 65 Ethyl 4-methyl-2-(3-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)butanamido)thiazole-5-carboxylate
  • Ethyl 3-amino-3-methyl-butanoate hydrochloride was used to prepare ethyl 4- methyl-2-(3-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)butan- amido)thiazole-5-carboxylate (40 mg, 33%, 0.0848 mmol) as a colorless solid.
  • Example 66 Isopropyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate
  • Example 66.1 Prepared in an analogous procedure to Example 63 using 2-amino- 4-methyl-thiazole-5-carboxylic acid to afford 4-methyl-2-[3-[[3-(5-methyl-1,2,4- oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylic acid (84 mg, 62%, 0.2022 mmol) as a brown powder.
  • Example 67 2-Methoxyethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate 23 mg (50%) colorless, amorphous solid. HPLC/MS m/z: 474.1 [M+H] + , Rt (S): 2.59 min.
  • Example 68 Isobutyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate 18 mg (40%) colorless powder.
  • Example 69 4-Methoxybutyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate 30 mg (62%) colorless powder.
  • Example 70 Propyl 4-methyl-2-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)ethyl)carbamoyl)thiazole-5-carboxylate
  • Example 70.1 A solution of 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole (60.00 mg, 0.2442 mmol) and ethylenediamine (0.33 mL, 4.8848 mmol) in NMP (0.98 mL) in a 0.5-2 mL microwave vial was heated under microwave irradiation for 1 h at 160 °C . Volatiles were removed under reduced pressure.
  • 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 under nitrogen atmosphere DMF (0.79 mL).
  • Example 71 Ethyl 1-methyl-3-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)ethyl)carbamoyl)-1H-pyrazole-5-carboxylate
  • 1-methyl-1H-pyrazole-3,5-dicarboxylic acid 5-ethyl ester 65.00 mg, 0.3280 mmol
  • HATU 187.06 mg, 0.4920 mmol
  • DIPEA 0.11 mL, 0.6560 mmol
  • DMF 0.82 mL
  • Example 72 Propyl 1-methyl-3-((2-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)ethyl)carbamoyl)-1H-pyrazole-5-carboxylate
  • 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 at rt in THF (0.75 mL) and water (0.75 mL) and hydroxylithium hydrate (24.27 mg, 0.5785 mmol) was added.
  • Example 73 1-Methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)propanamido)-N-propyl-1H-pyrazole-5-carboxamide
  • 2-methyl-5-[2-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]- ethylcarbamoyl]pyrazole-3-carboxylic acid formate [Example 72.1] (30.00 mg, 0.0642 mmol), HOBt (19.64 mg, 0.1284 mmol) and propylamine (0.03 mL, 0.3209 mmol) in DMF (0.64 mL) was stirred at rt for 16 h.2 eq of EDC.HCl, 2 eq of HOBt and 5 eq of propylamine were added and the resulting solution was stirred
  • Example 74 Propyl 4-methyl-2-(methyl(2-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)ethyl)carbamoyl)thiazole-5-carboxylate
  • Example 74.1. A solution of 3-(1-chloro-7-isoquinolyl)-5-methyl-1,2,4-oxadiazole [Example 45] (50.00 mg, 0.2035 mmol) and N-(2-aminoethyl)-N-methyl carbamic acid tert-butylester (0.73 mL, 4.0707 mmol) in NMP (0.81 mL) in a 0.5-2 mL microwave vial was heated under microwave irradiation for 1 h at 160 °C.
  • 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 successively added and the solution was stirred at 60 °C for 1 h. The solution was then cooled down to rt, added to water (75 mL), extracted with EtOAc (3 x 50 mL).
  • Example 74.4 A solution of isopropylmagnesium chloride - lithium chloride complex (1.53 mL, 1.9933 mmol) was added to a solution of propyl 2-bromo-4- methyl-thiazole-5-carboxylate (405.00 mg, 1.5333 mmol) in dry THF (10.00 mL) at - 78 °C. The resulting solution was stirred for 10 min at -78 °C and then 4-formyl morpholine (0.39 mL, 3.8332 mmol) was added. After 15 min of stirring the solution was quenched with a saturated NH 4 Cl solution (20 mL) and extracted with EtOAc (2 x 15 mL).
  • Example 74.5 t-BuOH (2.85 mL) was added to a solution of propyl 2-formyl-4- methyl-thiazole-5-carboxylate (80.00 mg, 0.3751 mmol) and 2-methyl-2-butene (1.19 mL, 11.254 mmol) in THF (3.01 mL). The resulting solution was stirred at rt for 10 min. A freshly prepared solution of sodium chlorite (111.96 mg, 1.238 mmol) and sodium dihydrogen phosphate hydrate (155.30 mg, 1.1254 mmol) in water (0.56 mL) was added and the solution was stirred at rt for 15 min.
  • sodium chlorite 111.96 mg, 1.238 mmol
  • sodium dihydrogen phosphate hydrate 155.30 mg, 1.1254 mmol
  • Example 74.6 To a stirring solution containing 4-methyl-5-propoxycarbonyl- thiazole-2-carboxylic acid (24.27 mg, 0.1059 mmol), N-methyl-N'-[7-(5-methyl- 1,2,4-oxadiazol-3-yl)-1-isoquinolyl]ethane-1,2-diamine (30.00 mg, 0.1059 mmol) and HATU (60.39 mg, 0.1588 mmol) in DMF (0.53 mL) was added DIPEA (0.04 mL, 0.2118 mmol). The resulting solution was stirred at rt for 4.5 h.
  • Example 75 N-(5-(tert-butyl)-4-methylthiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol- 3-yl)isoquinolin-1-yl)amino)propenamide
  • Example 75.1 To sodium 3-aminopropanoate (795.82 mg, 7.1644 mmol) in a 50 mL RBF fitted with an air condenser was added NMP (5.97 mL).
  • Example 75.2 To 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]- propanoic acid (20.00 mg, 0.0670 mmol) was added 5-tert-butyl-4-methyl-thiazol-2- ylamine (34.25 mg, 0.2011 mmol), PyBrop (75.01 mg, 0.1609 mmol) followed by dry DMF (0.34 mL) and DIPEA (42.04 uL, 0.2414 mmol). The resulting solution was stirred at rt overnight. Water was added (2 mL) and the residue was extracted with DCM (3 x 1 mL) using small separator phase column.
  • Example 76 N-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol- 3-yl)isoquinolin-1-yl)amino)propenamide 7 mg (30%) pale-yellow solid.
  • Example 77 N-(5-(tert-butyl)isoxazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propenamide 10 mg (41%) colorless solid. HPLC/MS m/z: 421.20, [M+H] + , Rt (S): 2.41 min.
  • Example 78 N-(5-cyclopropylisoxazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propenamide 9 mg (41%) colorless solid.
  • Example 79 N-(5-ethylisoxazol-3-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamide 1 mg (4%) colourless oil.
  • Example 80 N-(5-(tert-butyl)thiazol-2-yl)-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamide 8 mg (27%).
  • 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 9.5 mg (30%) colorless solid.
  • 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 13 mg (45%) colorless solid.
  • Example 83 N-[5-(3-methoxyoxetan-3-yl)-4-methyl-thiazol-2-yl]-3-[[7-(5-methyl- 1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide
  • Example 83.1 To a microwave vial was added 2-amino-4-methylthiazole (500.00 mg, 4.3794 mmol), p-toluene sulfonic acid (83.31 mg, 0.4379 mmol), 2,5- hexanedione (0.52 mL, 4.3794 mmol) and toluene (15.87 mL).
  • Example 83.2 1.6 M n-Buli in hexane (0.98 mL, 1.5612 mmol) 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 stirred for 45 min (temperature warmed up a bit to -20 °C. The temperature was then lowered to -48 °C and 3-oxetanone (75.00 mg, 1.0408 mmol) in a solution in THF (4 mL) was added and the reaction mixture stirred for 30 min.
  • 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 oC. The reaction mixture was stirred at 0 oC for 15 min followed by the addition of iodomethane (0.13 mL, 2.0807 mmol). The reaction was warmed up to rt and left stirring overnight. The reaction mixture was then partitioned between water (50 mL) and EtOAc (40 mL).
  • 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 in the microwave for 15 min at 90 °C. The volatiles were carefully evaporated to dryness. The obtained crude was purified by SCX-II cartridge (2 g, 15 mL). The basic fraction was evaporated to dryness.
  • Example 83.5 Using 5-(3-methoxyoxetan-3-yl)-4-methyl-thiazol-2-amine and the procedure for Example 45.7 afforded N-[5 -(3-methoxyoxetan-3-yl)-4-methyl-thiazol- 2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanamide (1.2 mg, 3%) as a colorless, amorphous solid. HPLC/MS m/z: 481.16 [M+H] + , Rt (T): 1.04 min.
  • Example 84 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-N-[4-methyl- 5-(3-propoxyoxetan-3-yl)thiazol-2-yl]propenamide
  • Example 84.1 2-(2,5-dimethylpyrrol-1-yl)-4-methyl-5-(3-propoxyoxetan-3- yl)thiazole was prepared using iodopropane in the procedure from Example 83.2- (2,5-dimethylpyrrol-1-yl)-4-methyl-5-(3-propoxyoxetan-3-yl)thiazole (162.5 mg, 99%, 0.5303 mmol) as a light brown gum.
  • Example 84.3 Using 4-methyl-5-(3-propoxyoxetan-3-yl)thiazol-2-amine amine and the procedure for Example 45.7 afforded 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]-N-[4-methyl-5-(3-propoxyoxetan-3-yl)thiazol-2-yl]propanamide (17 mg, 71%) as a light beige solid.
  • Example 85 N,4-dimethyl-2-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]propanoylamino]-N-propyl-thiazole-5-carboxamide
  • Example 85.1 2-Amino-4-methyl-thiazole-5-carboxylic acid (100.00 mg, 0.6322 mmol), DIPEA (0.44 mL, 2.5288 mmol), HATU (223.09 mg, 0.9483 mmol) were suspended in dry DMF (3.61 mL) under nitrogen before N-methylpropan-1-amine (0.10 mL, 0.9483 mmol) was added.
  • Example 86 N-[5-(cyclohexen-1-yl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3- yl)-1-isoquinolyl]amino]propenamide
  • 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
  • HOBt 18.12 mg, 0.1341 mmol
  • Example 87 N-[5-(1-methoxycyclohexyl)thiazol-2-yl]-3-[[7-(5-methyl-1,2,4- oxadiazol-3-yl)-1-isoquinolyl]amino]propenamide
  • Example 88 Ethyl 4-isopropyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate
  • 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]- propanoic acid [Example 63.3] (35 mg, 0.13 mmol)
  • ethyl 2-amino-4-isopropyl- thiazole-5-carboxylate 25 mg, 0.12 mmol
  • DIPEA 0.030 mL, 0.17 mmol
  • HATU 57 mg, 0.15 mmol
  • Example 89 tert-Butyl-4-methyl-2-(3-(3-(1-methyl-1H-pyrazol-4- yl)benzamido)propanamido)thiazole-5-carboxylate Using 3-(1-methylpyrazol-4-yl)benzoic acid and a procedure from Example 63.3 afforded 3-[[3-(1-methylpyrazol-4-yl)benzoyl]amino]propanoic acid which was used in the procedure above to afford tert-butyl 4-methyl-2-(3-(3-(1-methyl-1H-pyrazol-4- yl)benzamido)propanamido)thiazole-5-carboxylate (25 mg, 26%, 0.0532 mmol) as a pale-yellow powder.
  • Example 90 Methyl 4-ethyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate
  • 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]- propanoic acid [Example 63.3] (35 mg, 0.13 mmol)
  • methyl 2-amino-4-ethyl- thiazole-5-carboxylate 23 mg, 0.12 mmol
  • DIPEA 0.030 mL, 0.17 mmol
  • HATU 57 mg, 0.15 mmol
  • Example 91 Ethyl 2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoylamino]-4-(trifluoromethyl)thiazole-5-carboxylate
  • 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]- propanoic acid [Example 63.3] (35 mg, 0.13 mmol)
  • ethyl 2-amino-4- (trifluoromethyl)thiazole-5-carboxylate 28 mg, 0.12 mmol
  • DIPEA 0.030 mL, 0.17 mmol
  • HATU 57 mg, 0.15 mmol
  • Example 92 Ethyl 4-ethyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate To a stirred solution of 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]- propanoic acid [0] (35 mg, 0.13 mmol), ethyl 2-amino-4-ethyl-thiazole-5-carboxylate (23 mg, 0.12 mmol) and DIPEA (0.030 mL, 0.17 mmol) in DMF (0.98 mL) was added HATU (57 mg, 0.15 mmol) at rt and the resulting mixture stirred for 23 h.
  • 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
  • Example 93.1. To a stirred solution of 3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoic acid [Example 63.3] (600 mg, 2.18 mmol), 5-bromo-4- methyl-thiazol-2-amine (421 mg, 2.18 mmol) and DIPEA (0.570 mL, 3.27 mmol) in DMF (16.8 mL) was added HATU (1078 mg, 2.83 mmol) at rt and the resulting mixture stirred for 20 h.
  • Example 93.2 Nitrogen gas was bubbled through a mixture of N-[3-[(5-bromo-4- methyl-thiazol-2-yl)amino]-3-oxo-propyl]-3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamide (50 mg, 0.11 mmol) and [(E)-2-cyclopentylvinyl]boronic acid (23 mg, 0.17 mmol) in 1,4-dioxane (1.11 mL) and 2 M aqueous sodium carbonate (0.22 mL, 0.44 mmol) for 5 min.
  • 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 Nitrogen gas was bubbled through a mixture of N-[3-[(5-bromo-4-methyl-thiazol-2- yl)amino]-3-oxo-propyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide (50 mg, 0.11 mmol) [Example 93.1] and 2-[(E)-3-methoxyprop-1-enyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (33 mg, 0.17 mmol) in 1,4-dioxane (1.11 mL) and 2 M aqueous sodium carbonate (0.22 mL, 0.44 mmol)
  • 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 Nitrogen gas was bubbled through a mixture of N-[3-[(5-bromo-4-methyl-thiazol-2- yl)amino]-3-oxo-propyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide (50 mg, 0.11 mmol) [Example 93.1], 4,4,5,5-tetramethyl-2-(1-phenylvinyl)-1,3,2-dioxaborolane (38 mg, 0.17 mmol) in 1,4-dioxane (1.11 mL) and 2 M aqueous sodium carbonate (0.22 mL, 0.44 mmol) for 5 min.
  • Example 96 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]-N-[5- (1,1,2,2,2-pentafluoroethyl)thiazol-2-yl]cyclobutanecarboxamide
  • 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 mixed and heated to 80 °C. Hydroxylamine hydrochloride (3.61 g, 51.9 mmol) was added. The reaction mixture was continued to stir at 80 °C for 1.5 h.
  • Example 96.2 Four individual 20 mL microwave vials were each charged with a quarter of the following: N'-hydroxyisoquinoline-7-carboxamidine (3.67 g, 19.6 mmol) was mixed with acetonitrile (40 mL) and acetic anhydride (2.2 mL, 23.5 mmol) under an argon atmosphere. Each portion of the reaction mixture was heated at 180 °C under microwave irradiation for 10 min.
  • Example 96.3 3-(7-isoquinolyl)-5-methyl-1,2,4-oxadiazole (3.59 g, 17.0 mmol) was suspended in anhydrous chloroform (57 mL) under an argon atmosphere and cooled in an ice bath.3-Chloroperoxybenzoic acid (4.57 g, 20.4 mmol) was added. The stirred reaction mixture was allowed to warm to ambient temperature and continued to stir overnight. Potassium carbonate (9.40 g, 68.0 mmol) was added. The mixture was stirred at rt for 4 h before filtering through a pad of anhydrous MgSO 4 .
  • Example 96.4 5-Methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] (900.00 mg, 3.9609 mmol) and methyl cis-3-amino- cyclobutanecarboxylate hydrochloride (820.01 mg, 4.9511 mmol) were mixed in DCM (7.92 mL) at rt 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 rt for 3 d.
  • Example 96.5 Methyl 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]- cyclobutanecarboxylate (1000.00 mg, 2.9554 mmol), THF (11.82 mL), MeOH (5.91 mL) and water (11.82 mL) were mixed at ambient temperature. LiOH monohydrate (248.02 mg, 5.9109 mmol) was added, and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo. Purified by reverse phase column chromatography (eluent: 5-30% MeOH in water).
  • Example 96.6 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]- cyclobutanecarboxylic acid formate (40.00 mg, 0.1080 mmol) and bis(tetramethylene)fluoroformamidinium (68.30 mg, 0.2160 mmol) were mixed in DCM (0.43 mL) at rt under 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.
  • Example 97 N-(5-bromo-4-methyl-thiazol-2-yl)-3-[[7-(5-methyl-1,2,4-oxadiazol-3- yl)-1-isoquinolyl]amino]cyclobutanecarboxamide 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [Example 96] (265.00 mg, 0.8171 mmol) and bis(tetramethylene)fluoro- formamidinium (335.86 mg, 1.0622 mmol) were mixed in DCM (3.27 mL) at rt under nitrogen atmosphere for 10 min.
  • 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
  • Example 98.1. 5-Methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] (900 mg, 3.96 mmol) and methyl cis-3-amino-cyclobutanecarboxylate hydrochloride (820 mg, 4.95 mmol) were mixed in anhydrous DCM (7.9 mL) at rt under an argon atmosphere.
  • Example 98.2. Methyl 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]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.
  • Example 99 Propyl4-methyl-2-((1s,3s)-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amin o)cyclobutane-1-carboxamido)thiazole-5-carboxylate
  • Preparation as described for Example 47.5 to afford 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.
  • 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
  • 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
  • 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 Preparation as described for 0 using 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]cyclobutanecarboxylic acid [Example 96] and 5-isobutyl-4-methyl- thiophen-2-amine. Purification by reverse flash chromatography. Yield: 41 mg (35%).
  • 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
  • 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
  • Example 104.1 To 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).
  • Example 104.2 tert-Butyl 2-[[3-(tert-butoxycarbonylamino)cyclo- butanecarbonyl]amino]-4-methyl-thiazole-5-carboxylate (152.00 mg, 0.3694 mmol) was dissolved in tert-butanol (1.34 mL). HCl in dioxane (2.77 mL, 11.081 mmol) was added and the reaction mixture was stirred at rt for 1 h. The volatiles were removed under vacuum.
  • Example 104.3 3-(5-Methyl-1,2,4-oxadiazol-3-yl)benzoic acid (15.00 mg, 0.0735 mmol) and BTFFH (30.20 mg, 0.0955 mmol) were mixed in DCM (0.15 mL) at rt under argon. DIPEA (0.06 mL, 0.3306 mmol) was added, and the reaction mixture was stirred for 30 min. tert-Butyl 2-[(3-aminocyclobutanecarbonyl)amino]-4-methyl- thiazole-5-carboxylate (22.88 mg, 0.0735 mmol) was added. The vial was capped, and the reaction was heated to 80 °C for 45 min.
  • Example 105 tert-Butyl 2-((1s,3s)-3-(3-(1,2,4-oxadiazol-3- yl)benzamido)cyclobutane-1-carboxamido)-4-methylthiazole-5-carboxylate 14 mg (39%).
  • 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 20 mg (55%) colorless, amorphous solid. HPLC/MS m/z: 498.18, [M+H] + , Rt (U): 3.13 min.
  • Example 107 tert-Butyl-4-methyl-2-((1s,3s)-3-(3-(2-methyl-2H-tetrazol-5- yl)benzamido)cyclobutane-1-carboxamido)thiazole-5-carboxylate 20 mg (50%). HPLC/MS m/z: 498.19, [M+H] + , Rt (U): 3.20 min.
  • Example 108 tert-Butyl 2-((1s,3s)-3-((7-chloroisoquinolin-1-yl)amino)cyclobutane-1- carboxamido)-4-methylthiazole-5-carboxylate
  • Example 108.1 7-Chloroisoquinoline (0.15 g, 0.9169 mmol) was dissolved in CHCl 3 (2.86 mL) and cooled in an ice bath. mCPBA (0.24 g, 1.0885 mmol) was added. The reaction was stirred in icebath for 2 h. Warmed to rt and further CHCl 3 (1 mL) was added.
  • Example 108.2. 7-Chloro-2-oxido-isoquinolin-2-ium (30 mg, 0.1670 mmol) was dissolved/suspended in DCM (0.70 mL) and tert-butyl 2-[(3-aminocyclobutane- carbonyl)amino]-4-methyl-thiazole-5-carboxylate [Example 104] (57.22 mg, 0.1837 mmol) was added, quickly followed by DIPEA (0.09 mL, 0.5011 mmol). To this solution was added PyBroP (101.23 mg, 0.2171 mmol) and the mixture was stirred overnight at rt.
  • Example 109 tert-Butyl 4-methyl-2-((1s,3s)-3-((7-(trifluoromethyl)isoquinolin-1- yl)amino)cyclobutane-1-carboxamido)thiazole-5-carboxylate 16 mg (22%) yellow powder.
  • Example 110 tert-Butyl 4-methyl-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate
  • 2-Amino-4-methyl-thiazole-5-carboxylic acid (3.00 g, 18.97 mmol)
  • DMAP 232 mg, 1.90 mmol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.36 g, 22.76 mmol) were dissolved in anhydrous DMF (38 mL) under an argon atmosphere.
  • Example 111 tert-Butyl 4-methyl-2-[methyl-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate
  • 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.
  • Example 111.2 Preparation as described for 0 using 3-[[7-(5-methyl-1,2,4- oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [0] (34 mg, 0.104 mmol) and tert-butyl 4-methyl-2-(methylamino)thiazole-5-carboxylate (30 mg, 0.104 mmol).
  • Example 112 tert-Butyl 4-chloro-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate
  • Example 112.1 tert-Butyl (5-carboxy-4-chloro-1,3-thiazol-2-yl)carbamate (500 mg, 1.79 mmol) and DMAP (22 mg, 0.179 mmol) were mixed in anhydrous DMF (3.6 mL) at rt under an argon atmosphere.1-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (413 mg, 2.15 mmol) and anhydrous 2-methyl-2- propanol (3.4 mL, 35.9 mmol) were added successively.
  • the reaction mixture was heated at 60 °C. The reaction was stopped after 3 h due to the formation of two by- products.
  • the reaction mixture was cooled to rt, mixed with 0.5 M HCl (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with saturated NaCl (3 x 20 mL), dried over anhydrous MgSO 4 , 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.
  • Example 112.2 tert-butyl 2-(tert-butoxycarbonylamino)-4-chloro-thiazole-5- carboxylate (100 mg, 0.299 mmol) and anhydrous 2-methyl-2-propanol (1.1 mL, 11.95 mmol) were mixed at rt under an argon atmosphere.4 M HCl in dioxane (2.2 mL, 8.96 mmol) was added and the reaction mixture was quickly cooled down in an ice bath and was then allowed to slowly warm to rt.
  • Example 112.3 Preparation as described for 0 using 3-[[7-(5-methyl-1,2,4- oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [0] (47 mg, 0.144 mmol) and tert-butyl 2-amino-4-chloro-thiazole-5-carboxylate hydrochloride (30 mg, 0.111 mmol). Purification by reverse flash chromatography. Yield: 2.8 mg (5%) off- white solid. HPLC/MS m/z: 541.1420 [M+H] + , Rt (U): 2.96 min.
  • Example 113 N-tert-butyl-4-chloro-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxamide
  • Example 113.1. tert-Butyl (5-carboxy-4-chloro-1,3-thiazol-2-yl)carbamate (480 mg, 1.72 mmol) and BTFFH (708 mg, 2.24 mmol) were mixed in anhydrous DCM (3.4 mL) in a microwave vial at rt under an argon atmosphere.
  • Example 113.3 Preparation as described for 0 using 3-[[7-(5-methyl-1,2,4- oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [Example 96] (47 mg, 0.144 mmol) and 2-amino-N-tert-butyl-4-chloro-thiazole-5-carboxamide hydrochloride (30 mg, 0.111 mmol). Purification by reverse flash chromatography followed by SCX-2 filtration. Yield: 19 mg (31%) colourless, amorphous solid. HPLC/MS m/z: 540.1576 [M+H] + , Rt (U): 2.77 min.
  • Example 114 [(1R)-2,2,2-trifluoro-1-methyl-ethyl] 4-methyl-2-[[3-[[7-(5-methyl-1,2,4- oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5- carboxylate
  • Example 114.1 (2R)-1,1,1-Trifluoropropan-2-ol (250 mg, 2.19 mmol), DMAP (27 mg, 0.22 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (462 mg, 2.41 mmol) were mixed in anhydrous DMF (4.4 mL) at rt under an argon atmosphere.2-Amino-4-methylthiazole-5-carboxylic acid (381 mg, 2.41 mmol) was added, and the reaction mixture was heated at 60 °C overnight.
  • Example 114.2 Preparation as described for 0 using 3-[[7-(5-methyl-1,2,4- oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [0] (30 mg, 0.093 mmol) and [(1R)-2,2,2-trifluoro-1-methyl-ethyl] 2-amino-4-methyl-thiazole-5- carboxylate (26 mg, 0.102 mmol). Purification by reverse flash chromatography followed by SCX-2 filtration. Yield: 37 mg (69%) off-white solid. HPLC/MS m/z: 561.1533 [M+H] + , Rt (U): 2.93 min.
  • Example 115 [(1S)-2,2,2-trifluoro-1-methyl-ethyl] 4-methyl-2-[[3-[[7-(5-methyl-1,2,4- oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5- carboxylate
  • Example 115.1 Preparation as described in 0 using (2S)-1,1,1-trifluoropropan-2-ol (250 mg, 2.19 mmol) and 2-amino-4-methylthiazole-5-carboxylic acid (381 mg, 2.41 mmol). Purification by reverse flash chromatography. Yield: 69 mg (12%) off-white solid.
  • Example 116 Ethyl-4-(difluoromethyl)-2-[[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]cyclobutanecarbonyl]amino]thiazole-5-carboxylate
  • 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 an argon atmosphere. The reaction mixture was heated at 100 °C by microwave irradiation for 1 h.
  • Example 116.2 Preparation as described for 0 using 3-[[7-(5-methyl-1,2,4- oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [0] (30 mg, 0.093 mmol) and ethyl 2-amino-4-(difluoromethyl)thiazole-5-carboxylate (23 mg, 0.102 mmol). Purification by reverse flash chromatography. Yield: 31 mg (63%) colorless powder. HPLC/MS m/z: 529.1456 [M+H] + , Rt (X): 2.86 min.
  • Example 117 N-(5-tert-butyl-4-methyl-thiazol-2-yl)-3-[(7-methyl-1- isoquinolyl)amino]cyclobutanecarboxamide
  • Example 117.1 cis-3-Aminocyclobutanecarboxylic acid hydrochloride (463 mg, 3.05 mmol) and sodium carbonate (1.08 g, 10.2 mmol) were mixed in anhydrous NMP (4.07 mL) under an argon atmosphere and stirred at rt for 10 min.1-Chloro-7- methylisoquinoline (362 mg, 2.04 mmol) was added and the reaction mixture was heated at 170 °C the reaction was stopped after 48 h due to the formation of by- products.
  • 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
  • Example 118.1 Methyl 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate [0] (60.00 mg, 0.1397 mmol) was suspended in MeOH (1.00 mL) and water (1.00 mL) before sodium hydroxide (111.77 mg, 2.7943 mmol) was added.
  • Example 118.2. To 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylic acid (14.00 mg, 0.0337 mmol) in anhydrous DMF (0.70 mL) was added EDC.HCl (7.43 mg, 0.0388 mmol) and HOBt (5.46 mg, 0.0404 mmol). The reaction mixture was stirred under nitrogen for 30 min at rt before the addition of acetamide oxime (3.25 mg, 0.0438 mmol).
  • reaction mixture was stirred ar rt for 17 h where upon LCMS showed good conversion to [(Z)-1-aminoethylideneamino] 4-methyl-2-[3-[[3-(5-methyl-1,2,4- oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate.
  • a condenser was added, and the reaction was then heated to 100 °C behind a blast shield under nitrogen for 21 h to perform the cyclisation.
  • Example 119 3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(5-(5- propyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)propenamide
  • Example 119.1. N-(5-cyanothiazol-2-yl)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]propanamide [0] (37.40 mg, 0.0922 mmol) and TEA (0.01 mL, 0.0922 mmol) were heated at 80 °C in [bmim]OAc (0.18 mL).
  • Example 119.2. Butyric acid (0.01 mL, 0.0597 mmol), N-[5-[(Z)-N'- hydroxycarbamimidoyl]thiazol-2-yl]-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]propanamide (21.80 mg, 0.0497 mmol), and EDC.HCl (11.44 mg, 0.0597 mmol) were suspended in a mixture of MeCN (0.17 mL) and THF (0.17 mL) under nitrogen atmosphere. The resulting solution was stirred at rt for 17 h.
  • Example 119.3. To a solution of N-[(Z)-N-hydroxy-C-[2-[3-[[7-(5-methyl-1,2,4- oxadiazol-3-yl)-1-isoquinolyl]amino]propanoylamino]thiazol-5- yl]carbonimidoyl]butanamide (25.29 mg, 0.0497 mmol) in DMSO (0.30 mL) was added potassium hydroxide (11.16 mg, 0.1989 mmol). The resulting solution was stirred at rt for 1.5 h. Additional potassium hydroxide (4 eq.) was added, and the resulting solution was stirred at rt for 1.5 h.
  • Example 120 Propyl-1-methyl-3-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)-1H-pyrazole-5-carboxylate 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid [0] (49.58 mg, 0.1801 mmol), propyl 5-amino-2-methyl-pyrazole-3-carboxylate (30.00 mg, 0.1637 mmol) and HATU (87.17 mg, 0.2292 mmol) were dissolved in dry DMF (1.09 mL) at rt.
  • Example 121 Propyl-4-methyl-2-(N-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate 15 mg (14%), colorless powder. HPLC/MS m/z: 472.2, [M+H] + , Rt (R): 1.42 min.
  • Example 122 Cyclopentyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylic acid [0] (30.00 mg, 0.0722 mmol) was dissolved in dry DCM (1.00 mL) at rt. Oxalyl dichloride (0.06 mL, 0.7222 mmol) followed by a few drops of DMF were added.
  • reaction mixture was stirred at rt for 2 h before the solvent was removed under reduced pressure, and cyclopentanol (1.00 mL) was added.
  • the reaction mixture was stirred at rt for 4 h.
  • the solvent was removed under reduced pressure and the residue was purified by reverse phase column chromatography (eluent: 30-100% MeOH/H 2 O + 0.1% formic acid) to afford cyclopentyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate (8 mg, 23%, 0.0165 mmol) as an off-white powder.
  • Example 123 Hexyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate
  • Example 123.1. 4-Methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylic acid [0] (60.00 mg, 0.1444 mmol) was dissolved in dry DMF (1.00 mL) at rt.
  • Example 123.2 Hexan-1-ol (0.60 mL, 4.7803 mmol) was added to (2,3,4,5,6- pentafluorophenyl) 4-methyl-2-[3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate (20.00 mg, 0.0344 mmol) at rt. DMF (0.50 mL) was added. The reaction mixture was stirred at rt for 20 min, at 65 °C for 2 h and 100 °C for 3 h. DMAP (3mg) was added, and the reaction mixture was stirred at 100 °C for 1 h.
  • Example 124 Cyclohexyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate 11 mg (36%), colorless powder.
  • Example 125 4-aminobutyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate hydrochloride tert-butyl N-(4-hydroxybutyl)carbamate was used in an analogous procedure followed by deprotection using HCl in dioxane (1.04 mL, 50 eq., 4.1762 mmol) at rt for 3 h.
  • Example 126 3-(4-methoxyphenyl)propyl 4-methyl-2-(3-(3-(5-methyl-1,2,4- oxadiazol-3-yl)benzamido)propanamido)thiazole-5-carboxylate 20 mg (67%), colorless powder.
  • Example 127 4-(2-methoxyethoxy)butyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol- 3-yl)benzamido)propanamido)thiazole-5-carboxylate 23 mg (61%), cream coloured powder.
  • Example 128 Methyl-2-methyl-5-[3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoylamino]pyrazole-3-carboxylate 42 mg (56%), colorless fluffy powder. HPLC/MS m/z: 413.16 [M+H] + , Rt (R): 1.15 min.
  • 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
  • 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 overnight at 80 °C.
  • 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 using 4-methyl-5-(1- methylbutyl)thiazol-2-amine (12 mg, 28%, 0.0272 mmol) as a brown powder in an analogous procedure to 0. HPLC/MS m/z: 442.2, [M+H] + , Rt (R): 1.49 min.
  • Example 130 4-Acetamidobutyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate Acetyl acetate (6.58 uL, 0.0696 mmol) and 4-aminobutyl 4-methyl-2-[3-[[3-(5- methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoylamino]thiazole-5-carboxylate hydrochloride [0] (28.00 mg, 0.0535 mmol) were dissolved in dry THF (0.50 mL) at rt.
  • Example 131 Propyl-1-methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)propanamido)-1H-pyrazole-5-carboxylate formate 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid [0] (16.05 mg, 0.0538 mmol), HOBt (14.54 mg, 0.1076 mmol), EDC.HCl (20.63 mg, 0.1076 mmol) and propyl 5-amino-2-methyl-pyrazole-3-carboxylate (11.83 mg, 0.0646 mmol) were dissolved in dry DMF (0.29 mL).
  • Example 132 Tert-butyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate 13 mg (36%), slightly yellow powder.
  • Example 133 Ethyl-3-methyl-5-[3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoylamino]thiophene-2-carboxylate 6.8 mg (8%), amorphous colorless solid. HPLC/MS m/z: 443.14 [M+H] + , Rt (R): 1.32 min.
  • Example 134 Ethyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)-N- propylpropanamido)thiazole-5-carboxylate
  • Example 134.1 Sodium triacetoxyborohydride (227.61 mg, 1.0739 mmol) was added to a solution of ethyl 2-amino-4-methyl-thiazole-5-carboxylate (100.00 mg, 0.5370 mmol) and propanal (0.12 mL, 1.6109 mmol) in DCE (3.58 mL).
  • Example 134.2 Using ethyl 4-methyl-2-(propylamino)thiazole-5-carboxylate in a procedure analogous to 0 afforded ethyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol- 3-yl)benzamido)-N-propylpropanamido)thiazole-5-carboxylate (15 mg, 11%, 0.0309 mmol) as a colorless solid.
  • Example 135 Ethyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)propanamido)-1H-pyrazole-5-carboxylate.
  • 3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]propanoic acid [0] (30.00 mg, 0.1006 mmol) and PyBrop (93.77 mg, 0.2011 mmol) was added Ethyl 5- amino-1h-pyrazole-3-carboxylate (18.72 mg, 0.1207 mmol) dissolved in anhydrous DMF (0.63 mL).
  • Example 136 6-Hydroxyhexyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-5- (trifluoromethyl)benzamido)propanamido)thiazole-5-carboxylate
  • Example 136.1 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) nitrogen was bubbled for 15 min.
  • 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 for 15 min at 80 °C.
  • Example 136.3 Acetic acid (0.08 mL, 1.4722 mmol), methyl 3-(N- hydroxycarbamimidoyl)-5-(trifluoromethyl)benzoate (386.00 mg, 1.4722 mmol) and EDC.HCl (310.45 mg, 1.6194 mmol) were dissolved in MeCN (4.82 mL) and THF (4.82 mL) under nitrogen atmosphere. The solution was stirred overnight at rt. There was still starting material. EDC.HCl (0.2 eq) and acetic acid (0.2 eq) were added, and the solution was stirred at rt for further 3 h.
  • Example 136.5 3-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)-5- (trifluoromethyl)benzoyl]amino]propanoic acid was prepared using an analogous procedure to 0 using 3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)benzoic acid.
  • Example 136.6 Procedure analogous to 0 using hexane-1,6-diol afforded 6- hydroxyhexyl 4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-5- (trifluoromethyl)benzamido)propanamido)thiazole-5-carboxylate (43 mg, 80%, 0.0737 mmol) as a cream-coloured powder.
  • Example 138 Cyclopentyl-1-methyl-3-(3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamido)-1H-pyrazole-5-carboxylate
  • 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 successively added 1M DCC (0.43 mL, 0.4251 mmol) and cyclopentanol (0.32 mL, 3.5428 mmol).
  • Example 138.2. Cyclopentyl 5-amino-2-methyl-pyrazole-3-carboxylate used in an analogous procedure to 0 to afford cyclopentyl 2-methyl-5-[3-[[7-(5-methyl-1,2,4- oxadiazol-3-yl)-1-isoquinolyl]amino]propanoylamino]pyrazole-3-carboxylate (8.8 mg, 27%, 0.0180 mmol) as a colorless solid.
  • Example 139 3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido ⁇ -N-[4-methyl- 5-(trifluoromethyl)-1,3-thiazol-2-yl]propenamide
  • Example 139.1. 4-Methyl-5-(trifluoromethyl)-1,3-thiazol-2-amine (142.5 mg, 0.782 mmol), Boc- ⁇ -alanine (177.6 mg, 0.939 mmol) and HATU (446.0 mg, 1.173 mmol) were dissolved in DMF (2.0 mL).
  • N-Ethyldiisopropylamine (202.1 mg, 1.564 mmol) was added, and the brown solution was stirred at rt for 3 h.
  • the reaction mixture was diluted with ethyl acetate (30 mL), washed with water and brine, dried with sodium sulfate, filtered, and evaporated to dryness.
  • the oily residue was purified by flash chromatography to yield 199 mg light brown solid, which was suspended in dioxane (3.0 mL), treated with HCl in 1,4-dioxane (4 M, 3.2 mL) and stirred at rt for 2 h.
  • 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; hexafluoro phosphate (257.4 mg, 0.677 mmol) were placed in a vial and suspended in DMF (2.5 mL).
  • N-Ethyldiisopropylamine (310.0 ⁇ L, 1.805 mmol) was added and the clear brown solution was stirred at rt overnight.
  • the reaction mixture was diluted with ethyl acetate (40 mL), washed with water and brine, dried with sodium sulfate, filtered, and evaporated to dryness.
  • Example 140 Ethyl-2-((2-(3-(5-ethyl-1,2,4-oxadiazol-3- yl)benzamido)ethyl)carbamoyl)-4-methylthiazole-5-carboxylate
  • Example 140.1 A solution of chloro(isopropyl)magnesium; chlorolithium (3.60 mL, 4.6779 mmol) was added to a solution of ethyl 2-bromo-4-methyl-thiazole-5- carboxylate (0.90 g, 3.5984 mmol) in dry THF (5 mL) at -78 °C.
  • the reaction mixture was stirred for 1.5 h at rt.
  • the reaction mixture was quenched with a satured solution of Na 2 S 2 O 3 .
  • the organic layer was dried over MgSO 4 and concentrated under reduced pressure to afford 5-ethoxycarbonyl-4-methyl-thiazole-2-carboxylic acid (382 mg, 72%, 1.7748 mmol) which was used without further purification.
  • 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 rt. The reaction mixture was stirred overnight at rt.
  • Example140.4 HCl in dioxane (0.59 mL, 2.3501 mmol) was added to a solution of ethyl 2-[2-(tert-butoxycarbonylamino)ethylcarbamoyl]-4-methyl-thiazole-5- carboxylate (42.00 mg, 0.1175 mmol) in dry dioxane (0.59 mL) at rt. The reaction mixture was stirred overnight at rt. The solvent was removed under reduced pressure to give ethyl 2-(2-aminoethylcarbamoyl)-4-methyl-thiazole-5-carboxylate as a colorless solid. No further purification.
  • Example 140.5 Ethyl 2-(2-aminoethylcarbamoyl)-4-methyl-thiazole-5-carboxylate (28.00 mg, 0.1088 mmol), 3-(5-ethyl-1,2,4-oxadiazol-3-yl)benzoic acid (28.49 mg, 0.1306 mmol), HOBt (29.41 mg, 0.2176 mmol) and EDC (33.79 mg, 0.2176 mmol) were dissolved in dry DMF (0.54 mL) at rt. The reaction mixture was stirred overnight at rt.
  • Example 141 Ethyl-4-methyl-2-((2-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)ethyl)carbamoyl)thiazole-5-carboxylate 48 mg (51%), colorless solid.
  • Example 142 Ethyl-(R)-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)butanamido)thiazole-5-carboxylate
  • Example 142.1. To tert-Butyl (3R)-3-aminobutanoate (155.97 mg, 0.9795 mmol) was added anhydrous DMF (4.90 mL), 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (200.00 mg, 0.9795 mmol) DIPEA (0.51 mL, 2.9386 mmol) and HATU (345.68 mg, 1.47 mmol).
  • 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 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.
  • 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 condensor, needle and empty balloon added, and stirred for 18 h at 60 °C. LCMS showed the desired product present. Water (50 mL) was added.
  • Example 143 Ethyl-(S)-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)butanamido)thiazole-5-carboxylate 15 mg (10%).
  • 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 tert-Butyl 2-(4-amino-1-methyl-4-piperidyl)acetate and 3-chloro-5-(5-methyl-1,2,4- oxadiazol-3-yl)benzoic acid afforded 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 (7 mg, 20%, 0.0122 mmol) as a colorless solid.
  • Example 145 Ethyl-4-methyl-2-(2-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate
  • Example 145.1 To tert-butoxycarbonyl tert-butyl carbonate (2.07 g, 9.4931 mmol), 3-amino-2-methyl-propanoic acid hydrate (1.15 g, 9.4931 mmol) in dry THF (9.49 mL) was added TEA (1.46 mL, 10.443 mmol). The reaction was stirred at rt for the weekend.
  • Example 145.2 To 3-(tert-butoxycarbonylamino)-2-methyl-propanoic acid (100.00 mg, 0.4920 mmol) was added ethyl 2-amino-4-methyl-thiazole-5-carboxylate (91.63 mg, 0.4920 mmol), HOBt (132.97 mg, 0.9841 mmol) and dry DMF (2.42 mL). After stirring EDC.HCl (188.64 mg, 0.9841 mmol) was added. Stirred under nitrogen for 18 h at 60 °C. Water (50 mL) added and extracted with EtOAc (2 x 40 mL).
  • Example 145.3 To ethyl 2-[[3-(tert-butoxycarbonylamino)-2-methyl- propanoyl]amino]-4-methyl-thiazole-5-carboxylate (57mg, 0.15 mmol) in dioxane (0.77 mL), was added 4M HCl in dioxane (0.77 mL, 3.0691 mmol) dropwise, while stirring at rt. The mixture was stirred 2.5 h at rt before concentrating in vacuo to give ethyl 2-[(3-amino-2-methyl-propanoyl)amino]-4-methyl-thiazole-5-carboxylate (42mg) as a colorless powder.
  • Example 146 4-(3-((5-(ethoxycarbonyl)-4-methylthiazol-2-yl)amino)-1-(3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzamido)-3-oxopropyl)piperidin-1-ium formate
  • Example 146.1 To tert-butyl 4-(1-amino-3-ethoxy-3-oxo-propyl)piperidine-1- carboxylate (125.05 mg, 0.4163 mmol) and 3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoic acid (85.00 mg, 0.4163 mmol) in a 100 mL RBF under nitrogen atmosphere was added DMF (2.08 mL) followed by HATU (146.91 mg, 0.6244 mmol) and DIPEA (0.22 mL, 1.2489 mmol).
  • Example 146.2 To tert-butyl 4-[3-ethoxy-1-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]-3-oxo-propyl]piperidine-1-carboxylate (84.89 mg, 0.1745 mmol) in THF (0.87 mL) was added water (0.87 mL) followed by lithium hydroxide hydrate (29.32 mg, 0.6988 mmol). After stirring for 2.5 h water (20 mL) was added and THF was removed in vacuo.
  • Example 146.3 To a solution of ethyl 2-amino-4-methyl-thiazole-5-carboxylate (35.74 mg, 0.1919 mmol), EDC.HCl (66.89 mg, 0.3490 mmol) in dry DMF (0.87 mL) was added 3-(1-tert-butoxycarbonyl-4-piperidyl)-3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoic acid (80.00 mg, 0.1745 mmol) and HOBt (47.15 mg, 0.3490 mmol). The mixture was stirred for 18.5 h at 60 °C.
  • Example 147 4-(3-((5-(ethoxycarbonyl)-4-methylthiazol-2-yl)amino)-1-(3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzamido)-3-oxopropyl)-1-methylpiperidin-1-ium formate
  • Example 148 Ethyl-2-[[(3R)-4-amino-3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]butanoyl]amino]-4-methyl-thiazole-5-carboxylate
  • Example 148.1 To a solution of ethyl 2-amino-4-methyl-thiazole-5-carboxylate (203.47 mg, 1.0926 mmol), Z-beta-Dab(Boc)-OH (350.00 mg, 0.9932 mmol) in dry DMF (4.97 mL) was added EDC.HCl (380.81 mg, 1.9865 mmol) and HOBt (268.41 mg, 1.9865 mmol).
  • Example 149 Ethyl-4-methyl-2-[[(3S,4R)-4-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]pyrrolidine-3-carbonyl]amino]thiazole-5-carboxylate; formic acid
  • Example 149.1. (3R,4S)-1-benzyl-4-(tert-butoxycarbonylamino)pyrrolidine-3- carboxylic acid (120.00 mg, 0.3746 mmol) suspended in methanol (3.75 mL, 0.3746 mmol) and five drops of H 2 SO 4 added. Heated in microwave for 60 min at 75 oC.
  • Example 149.2. Procedure from 0 using methyl (3R,4S)-4-amino-1-benzyl- pyrrolidine-3-carboxylate. Purified by reverse phase column chromatography (eluent: 20-80% MeOH in water (+0.1% formic acid modifier in both) afforded methyl (3R,4S)-1-benzyl-4-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]- pyrrolidine-3-carboxylate (94 mg, 95%, 0.2236 mmol) as a colorless powder. HPLC/MS m/z: 421.19, [M+H] + , Rt (R): 0.92 min.
  • Example 149.3. To methyl (3R,4S)-1-benzyl-4-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]pyrrolidine-3-carboxylate (40.00 mg, 0.0951 mmol) in THF (0.54 mL) was added water (0.54 mL) followed by lithium hydroxide hydrate (15.97 mg, 0.3805 mmol). After stirring for 4 h before water (20 mL) was added and the THF removed in vacuo. The solution was acidified with 1M citric acid solution and extracted with EtOAc (3 x 15 mL).
  • Example 149.4. To (3R,4S)-1-benzyl-4-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]pyrrolidine-3-carboxylic acid (25.00 mg, 0.0615 mmol), ethyl 2- amino-4-methyl-thiazole-5-carboxylate (12.60 mg, 0.0677 mmol), HOBt (16.62 mg, 0.1230 mmol), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (23.58 mg, 0.1230 mmol) under nitrogen was added DMF (0.31 mL) and the reaction mixture heated at 60 °C overnight.
  • DMF 0.31 mL
  • Example 149.5 To ethyl 2-[[(3S,4R)-1-benzyl-4-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]pyrrolidine-3-carbonyl]amino]-4-methyl-thiazole-5-carboxylate (11.00 mg, 0.0191 mmol) in a microwave vial under nitrogen was added dry DCE (0.25 mL) followed by 1-Chloroethyl chloroformate (6.20 uL, 0.0574 mmol) [ 3 drops]. The vial was heated at 90 oC for 1.5 h after which the solvent was evaporated and replaced with MeOH (0.75 mL).
  • Example 150 Ethyl-(S)-2-(6-amino-3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)hexanamido)-4-methylthiazole-5-carboxylate
  • Example 150.1 To 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (20.72 mg, 0.1015 mmol) and HATU (38.59 mg, 0.1015 mmol) under a nitrogen atmosphere was added dry DMF (0.51 mL) and DIPEA (0.04 mL, 0.2030 mmol).
  • Example 150.2 To (3S)-6-(tert-butoxycarbonylamino)-3-[[3-(5-methyl-1,2,4- oxadiazol-3-yl)benzoyl]amino]hexanoic acid (40.00 mg), ethyl 2-amino-4-methyl- thiazole-5-carboxylate (18.95 mg, 0.1017 mmol) was added HOBt (25.00 mg, 0.1850 mmol) and EDC.HCl (35.46 mg, 0.1850 mmol). A nitrogen atmosphere was introduced followed by dry DMF (0.52 mL). The mixture was stirred for 18.5 h overnight at 60 °C.
  • Example 150.3 Ethyl 2-[[(3S)-6-(tert-butoxycarbonylamino)-3-[[3-(5-methyl-1,2,4- oxadiazol-3-yl)benzoyl]amino]hexanoyl]amino]-4-methyl-thiazole-5-carboxylate (40.00 mg) was dissolved in dioxane (1.50 mL) under nitrogen and 4M HCl in dioxane (1.50 mL, 6 mmol) was added. After 2 h the volatiles were removed, and the crude product purified by reverse phase column chromatography (eluent: 30- 90% MeOH in water (+0.1% formic acid modifier in both)).
  • Example 151 Popyl-(S)-2-(6-amino-3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)hexanamido)-4-methylthiazole-5-carboxylate Synthesised in an analogous manner to 0 afforded propyl (S)-2-(6-amino-3-(3-(5- methyl-1,2,4-oxadiazol-3-yl)benzamido)hexanamido)-4-methylthiazole-5- carboxylate (13.5 mg, 0.0262 mmol). HPLC/MS m/z: 515.2 [M+H] + , Rt (Q): 2.54 min.
  • Example 152 Propyl 4-methyl-2-[[(3S)-6-(methylamino)-3-[[3-(5-methyl-1,2,4- oxadiazol-3-yl)benzoyl]amino]hexanoyl]amino]thiazole-5-carboxylate
  • tert-butyl methyl(4-oxobutyl)carbamate (990 mg) as a colourless oil.
  • the product was used in the next step without further purification.
  • the reaction mixture was heated to 120 °C and stirred for 16 h.
  • the solvent was removed under reduced pressure and silica was added.
  • the silica was added to a 50 g SNAP column and was eluted with a gradient of cyclohexane and EtOAc (15-40%) to give tert-butyl (E)-6-((tert- butoxycarbonyl)(methyl)amino)hex-2-enoate (1.02 g, 70% after 2 steps) as a yellow oil.
  • Example 152.8 Propyl 2-[[(3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[3-(5- methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]hexanoyl]amino]-4-methyl-thiazole-5- carboxylate (102.00 mg, 0.1622 mmol) was dissolved in dry DCM (1.62 mL). Trifluoroacetic acid (248.29 uL, 3.2446 mmol) was added and the reaction mixture was stirred at rt for 45 min.
  • Example 153 Propyl-(R)-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)-6-(methylamino)hexanamido)thiazole-5-carboxylate Using (R)-( ⁇ )-N-Benzyl- ⁇ -methylbenzylamine, propyl (R)-4-methyl-2-(3-(3-(5- methyl-1,2,4-oxadiazol-3-yl)benzamido)-6-(methylamino)hexanamido)thiazole-5- carboxylate (45 mg, 67%) was obtained as a colorless powder.
  • Example 154 Tert-butyl 4-methyl-2-[[(3S)-6-(methylamino)-3-[[3-(5-methyl-1,2,4- oxadiazol-3-yl)benzoyl]amino]hexanoyl]amino]thiazole-5-carboxylate 15 mg (88%), colorless amorphous powder. HPLC/MS m/z: 543.24 [M+H] + , Rt (T): 1.26 min.
  • Example 158 Propyl (S)-2-(6-(dimethylamino)-3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)hexanamido)-4-methylthiazole-5-carboxylate
  • Example 159 Propyl (S)-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)-6-morpholinohexanamido)thiazole-5-carboxylate
  • Example 159.1. Synthesised in an analogous manner to 0 from methyl (3S)-3- amino-6-(tert-butoxycarbonylamino)hexanoate [0] to afford methyl (3S)-6-(tert- butoxycarbonylamino)-3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]hexanoate (281 mg, 76%, 0.6293 mmol) as a colorless solid.
  • Example 159.3. To methyl (3S)-6-amino-3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]hexanoate (44.00 mg, 0.1270 mmol) under a nitrogen atmosphere was added dry MeCN (0.85 mL), triethylamine (35.41 uL, 0.2541 mmol) and 1- bromo-2-(2-bromoethoxy)ethane (23.95 uL, 0.1905 mmol). The mixture was heated at 80 °C overnight.
  • Example 159.4. Synthesised in an analogous manner to ethyl 2-[[(3S,4R)-1-benzyl- 4-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]amino]pyrrolidine-3-carbonyl]amino]-4- methyl-thiazole-5-carboxylate.
  • Example 160 Propyl (S)-2-(2-amino-3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate
  • Example 160.1 Synthesised from (S)-tert-Butyl-3-amino-2-((tert- butoxycarbonyl)amino)propanoate in an analogous manner to 0 to afford tert-butyl (2S)-2-(tert-butoxycarbonylamino)-3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]propanoate (133 mg, 78%, 0.2979 mmol) as a clear gum.
  • Example160.4 Propyl (S)-2-(2-((tert-butoxycarbonyl)amino)-3-(3-(5-methyl-1,2,4- oxadiazol-3-yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate formate (20.00 mg, 0.0349 mmol) was dissolved in n-propanol (0.50 mL) and 4M HCl in dioxane (0.50 mL, 2 mmol) was added. The reaction was stirred for 2 h at rt before the volatiles were removed in vacuo.
  • Example 161 (S)-N-(2-amino-3-((5-(tert-butyl)-4-ethylthiazol-2-yl)amino)-3- oxopropyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide Synthesised in an analogous manner to 0 using 5-tert-butyl-4-ethyl-1,3-thiazol-2- amine.
  • Example 162 Propyl (S)-2-(5-(dimethylamino)-3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)pentanamido)-4-methylthiazole-5-carboxylate
  • Example 162.1 (3S)-3-(benzyloxycarbonylamino)-5-tert-butoxy-5-oxo-pentanoic acid (348.00 mg, 1.0315 mmol) under nitrogen was dissolved in THF (1.21 mL) and cooled in an ice-salt bath.1M Borane in THF (6.19 mL, 6.1891 mmol) was added dropwise over 20 min and the reaction mixture stirred at -5 oC for 2.5 h.
  • Example 162.3 Sodium triacetoxyborohydride (152.34 mg, 0.7188 mmol) was added to a solution of tert-butyl (3S)-3-(benzyloxycarbonylamino)-5-oxo-pentanoate (154.00 mg, 0.4792 mmol) and dimethylamine (2M in THF) (0.36 mL, 0.7188 mmol) in THF (4.79 mL) under nitrogen. Acetic acid (5 drops) was added, and the white suspension was stirred overnight at rt. MeOH/water added and volatiles were removed in vacuo. Purified by ion exchange SCX-II column chromatography washing with MeOH before eluting basic components with 2M NH 3 in MeOH.
  • Example 162.5 To tert-butyl (3S)-3-amino-5-(dimethylamino)pentanoate (25.00 mg, 0.1156 mmol), 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (25.96 mg, 0.1271 mmol), and HATU (48.34 mg, 0.1271 mmol) under nitrogen was added dry DMF (0.77 mL) and DIPEA (0.04 mL, 0.2311 mmol). The reaction was stirred overnight at rt. LCMS showed no further conversion.
  • Example 162.6 tert-Butyl (3S)-5-(dimethylamino)-3-[[3-(5-methyl-1,2,4-oxadiazol- 3-yl)benzoyl]amino]pentanoate; formic acid (17.00 mg, 0.0422 mmol) was stirred at rt in trifluoroacetic acid (1.00 mL, 0.0422 mmol) for 2 h. Evaporated to dryness. Toluene (15 mL) added and evaporated to dryness in vacuo twice to azeotrope of remaining TFA. Crude product taken straight on to next step.
  • Example 162.7 To (3S)-5-(dimethylamino)-3-[[3-(5-methyl-1,2,4-oxadiazol-3- yl)benzoyl]amino]pentanoic acid (14.00 mg, 0.0404 mmol) and 1-[fluoro(pyrrolidin- 1-ium-1-ylidene)methyl]pyrrolidine hexafluorophosphate (23.00 mg, 0.0727 mmol) was added dry DCM (0.17 mL) and DIPEA (0.04 mL, 0.2223 mmol).
  • Example 163 Propyl (S)-2-(6-amino-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)hexanamido)-4-methylthiazole-5-carboxylate
  • Example 163.1 To Fmoc-L-beta-Lys(Boc)-OH (1.00 g, 2.1343 mmol) under a nitrogen atmosphere was added anhydrous MeOH (21.34 mL) and the solution cooled in an ice bath before the dropwise addition of 2M TMS-Diazomethane in ether (7.5 mL) until the solution just retained a yellow colour.
  • Example 163.2 To methyl (3S)-6-(tert-butoxycarbonylamino)-3-(9H-fluoren-9- ylmethoxycarbonylamino)hexanoate (300.00 mg, 0.6217 mmol) under nitrogen was added dry DMF (3.89 mL) followed by piperidine (193.97 uL, 1.9636 mmol). The reaction was stirred at rt for 6 h. The volatiles were removed in vacuo and the crude product purified by reverse phase column chromatography (eluent: 20-40% MeOH in water (+0.1% formic acid modifier in both)).
  • Example 163.4 propyl (S)-2-(6-amino-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)hexanamido)-4-methylthiazole-5-carboxylate formate was prepared by an analogous method to 0. Purification by prep-HPLC afforded propyl (S)-2-(6-amino-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)hexanamido)-4-methylthiazole-5-carboxylate formate (1.63 mg, 0.0028 mmol).
  • Example 165 Cyclopentyl (S)-4-methyl-2-(3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)-6-(methylamino)hexanamido)thiazole-5-carboxylate 7 mg (55%), colorless powder.
  • Example 166 1,3-Difluoropropan-2-yl (S)-4-methyl-2-(3-((7-(5-methyl-1,2,4- oxadiazol-3-yl)isoquinolin-1-yl)amino)-6-(methylamino)hexanamido)thiazole-5- carboxylate 10 mg (37%), colorless powder.
  • Example 167 Isopropyl (S)-4-methyl-2-(3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)-6-(methylamino)hexanamido)thiazole-5-carboxylate 20 mg (79%), colorless powder. HPLC/MS m/z: 552.3, [M+H] + , Rt (T): 1.15 min.
  • Example 168 tert-Butyl (S)-4-methyl-2-(3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)-6-(methylamino)hexanamido)thiazole-5-carboxylate 13 mg (38%), colorless powder.
  • Example 170 3,3-Difluorocyclopentyl 4-methyl-2-((S)-3-((7-(5-methyl-1,2,4- oxadiazol-3-yl)isoquinolin-1-yl)amino)-6-(methylamino)hexanamido)thiazole-5- carboxylate 67 mg (74%), cream-coloured powder.
  • Example 171 (S)-N-(5-(tert-butyl)-4-methylthiazol-2-yl)-3-((7-(5-methyl-1,2,4- oxadiazol-3-yl)isoquinolin-1-yl)amino)-6-(methylamino)hexanamide
  • Example 171.1 5-methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [0] (120 mg, 0.5281 mmol) was dissolved/suspended in dry DCM (1.76 mL) and added to a RBF containing tert-butyl (3S)-3-amino-6-[tert- butoxycarbonyl(methyl)amino]hexanoate (183.83 mg, 0.5809 mmol), quickly followed by DIPEA (0.34 mL, 1.9805 mmol).
  • Example 171.2 tert-Butyl (3S)-6-[tert-butoxycarbonyl(methyl)amino]-3-[[7-(5- methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]hexanoate (160.00 mg, 0.3044 mmol) and potassium hydroxide (136.63 mg, 2.4351 mmol) were dissolved in THF (1.79 mL) at rt. Few drops of water (enough to dissolve KOH) were added and the resulting solution was stirred at 50 °C for 3.5 h.8 eq of KOH were added. Few drops of MeOH were added and the resulting solution was stirred at 50 °C overnight.
  • Example 172 Propyl (S)-4-methyl-2-(3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)-6-(methylamino)hexanamido)thiazole-5-carboxylate (7.2 mg, 43%, 0.0131 mmol) as a colorless solid.
  • Example 173 Propyl (R)-2-(2-amino-3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate formate
  • Example 173.1. To 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (67.44 mg, 0.3303 mmol), (R)-ethyl 3-amino-2-(CBZ-amino)propanoate HCl (100.00 mg, 0.3303 mmol) and HATU (125.59 mg, 0.3303 mmol) was added dry DMF (1.65 mL) and DIPEA (0.17 mL, 0.9909 mmol).
  • Example 173.2 Ethyl (2R)-2-(benzyloxycarbonylamino)-3-[[3-(5-methyl-1,2,4- oxadiazol-3-yl)benzoyl]amino]propanoate (118.00 mg, 0.2608 mmol) was dissolved in THF (1.3 mL) and water (1.3 mL) was added. Lithium hydroxide hydrate (131.32 mg, 3.1296 mmol) was added and then additional THF (0.63 mL). Stirred at rt for 4 h before the volatiles were removed in vacuo. Purified by reverse phase column chromatography (eluent: 20-80% MeOH in water (+0.1% formic acid modifier in both)).
  • Example 173.3 To propyl 2-amino-4-methyl-thiazole-5-carboxylate (50.87 mg, 0.2540 mmol), HOBt (62.40 mg, 0.4618 mmol), and 3-(ethyliminomethyleneamino)- N,N-dimethyl-propan-1-amine hydrochloride (88.53 mg, 0.4618 mmol) under nitrogen atmosphere was added (2R)-2-(benzyloxycarbonylamino)-3-[[3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzoyl]amino]propanoic acid (98.00 mg, 0.2309 mmol) in DMF (1.15 mL) and the reaction mixture was stirred at 60 °C for 20 h.
  • Example 173.4 A 1.9 M solution of HBr in AcOH was made by mixing 0.33 mL of 33% wt HBr in AcOH [ ⁇ 5.7 M] and 0.66 mL of AcOH (fumes).0.5 mL of this solution was added to propyl 2-[[(2R)-2-(benzyloxycarbonylamino)-3-[[3-(5-methyl-1,2,4- oxadiazol-3-yl)benzoyl]amino]propanoyl]amino]-4-methyl-thiazole-5-carboxylate (22.00 mg, 0.0363 mmol) which was stirred at rt for 75 min. Ether (3 mL) was added and the white precipitate was removed by filtration.
  • Example 174 Propyl (S)-2-(2-amino-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamido)-4-methylthiazole-5-carboxylate
  • Example 174.1 5-Methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] (253 mg, 1.1135 mmol) was dissolved/suspended in DCM (3.71 mL) and tert-butyl (2S)-3-amino-2-(tert-butoxycarbonylamino)propanoate (362.33 mg, 1.3918 mmol) added, quickly followed by DIPEA (0.73 mL, 4.1755 mmol).
  • Example 174.2 Propyl (S)-2-(2-amino-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamido)-4-methylthiazole-5-carboxylate was prepared by an analogous method to 0 from tert-butyl (2S)-2-(tert- butoxycarbonylamino)-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]propanoate.
  • Example 175 Propyl (S)-2-(2-(dimethylamino)-3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)-4-methylthiazole-5-carboxylate formate
  • Example 175.1 H-Dap(Boc)-OMe HCl (250.00 mg, 0.9815 mmol) was suspended in N,N-Diisopropylethylamine (1.66 mL, 9.4731 mmol) and iodomethane (0.18 mL, 2.9445 mmol) was added. The mixture was stirred at rt overnight.
  • Example 175.2 Methyl (S)-3-((tert-butoxycarbonyl)amino)-2-(dimethylamino)- propanoate (110.00 mg, 0.4466 mmol) was dissolved in dry MeOH (0.25 mL) and 4M HCl in dioxane (0.11 mL, 0.4466 mmol) was added. Stirred for 5 h at rt before volatiles were carefully removed in vacuo to afford methyl (S)-3-amino-2-(dimethyl- amino)propanoate hydrochloride which was used without purification. HPLC/MS m/z: 147.1 [M+H] + , Rt (Q): 0.15 min.
  • Example 175.3 Methyl (S)-3-amino-2-(dimethylamino)propanoate hydrochloride was utilised in an analogous synthesis to 0 to afford propyl (S)-2-(2- (dimethylamino)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamido)propanamido)-4- methylthiazole-5-carboxylate formate (17 mg, 16%, 0.0311 mmol) as a colorless powder.
  • Example 176 Propyl (R)-2-(2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamido)-4-methylthiazole-5-carboxylate
  • Example 176.1 To (2R)-3-(tert-butoxycarbonylamino)-2-hydroxy-propanoic acid (182.00 mg, 0.8869 mmol), propyl 2-amino-4-methyl-thiazole-5-carboxylate (195.37 mg, 0.9756 mmol), HOBt (239.67 mg, 1.7738 mmol) and EDC.HCl (340.04 mg, 1.7738 mmol) was added DMF (4.43 mL), the vial capped, and the reaction mixture heated at 50 °C for 16 h.
  • Example 176.2 To propyl 2-[[(2R)-3-(tert-butoxycarbonylamino)-2-hydroxy- propanoyl]amino]-4-methyl-thiazole-5-carboxylate (220.00 mg, 0.5678 mmol) was added propanol (2.03 mL) followed by 4M HCl in dioxane (0.18 mL). Stirred at rt for 1.5 h before further 4M HCl in dioxane (1.8 mL) was added. Stirred for 1 h 40 min at rt before the volatiles were removed in vacuo.
  • Example 176.3 5-methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [0] (65.00 mg, 0.2861 mmol) and propyl 2-[[(2R)-3-amino-2-hydroxy-propanoyl]amino]- 4-methyl-thiazole-5-carboxylate (82.20 mg, 0.2861 mmol) were suspended in dry DCM (2.0 mL). PyBroP (173.37 mg, 0.3719 mmol) and DIPEA (186.85 uL, 1.0727 mmol) were added and a nitrogen atmosphere introduced. Stirred at rt for 22 h.
  • Example 177 tert-Butyl (R)-2-(2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamido)-4-methylthiazole-5-carboxylate
  • tert-butyl 2-amino-4-methyl-thiazole-5-carboxylate [Example 110.1] in an analogous procedure to Example 176 to afford tert-butyl (R)-2-(2-hydroxy-3- ((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamido)-4- methylthiazole-5-carboxylate (12 mg, 10%, 0.0233 mmol) as a colorless powder.
  • Example 178 Propyl (S)-2-(2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamido)-4-methylthiazole-5-carboxylate Prepared using N-tert-Butyloxycarbonyl-(S)-isoserine in an analogous procedure to Example 176 to afford propyl (S)-2-(2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamido)-4-methylthiazole-5-carboxylate (26 mg, 25%, 0.0513 mmol) as a colorless powder.
  • Example 179 (S)-2-hydroxy-N-(5-isobutyl-4-methylthiazol-2-yl)-3-((7-(5-methyl- 1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propenamide 6.8 mg (12%). HPLC/MS m/z: 467.19, [M+H] + , Rt (U): 2.75 min.
  • Example 180 tert-Butyl (S)-2-(2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamido)-4-methylthiazole-5-carboxylate 10 mg (25%). HPLC/MS m/z: 511.18, [M+H] + , Rt (U): 2.79 min.
  • Example 181 tert-Butyl (S)-2-(2-hydroxy-3-((7-(1-methyl-1H-pyrazol-4- yl)isoquinolin-1-yl)amino)propanamido)-4-methylthiazole-5-carboxylate
  • Example 181.1 7-Bromo-2-oxido-isoquinolin-2-ium (342.00 mg, 1.5264 mmol), 1- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1H-pyrazole (412.89 mg, 1.9844 mmol) were dissolved in dioxane (7.63 mL) and 2M aqueous Na 2 CO 3 (3.7 mL) was added.
  • Example 181.2 Prepared from 7-(1-methylpyrazol-4-yl)-2-oxido-isoquinolin-2-ium using procedure from Example 176 to afford tert-butyl (S)-2-(2-hydroxy-3-((7-(1- methyl-1H-pyrazol-4-yl)isoquinolin-1-yl)amino)propanamido)-4-methylthiazole-5- carboxylate (34 mg, 43%, 0.0669 mmol).
  • Example 182 (S)-2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)-N-(1-methyl-5-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-pyrazol-3- yl)propenamide
  • Example 182.1 2-Methyl-5-nitro-pyrazole-3-carbonitrile (310.00 mg, 2.038 mmol), hydroxylamine hydrochloride (0.57 g, 8.152 mmol), and sodium hydrogen carbonate (1.37 g, 16.304 mmol) were mixed in dry ethanol (10.19 mL).
  • Example 182.2 N'-hydroxy-2-methyl-5-nitro-pyrazole-3-carboxamidine (380.00 mg, 2.0525 mmol) was dissolved in dry DMF (6.84 mL). Butyric anhydride (0.34 mL, 2.0525 mmol) was added, the reaction mixture was stirred at rt for 2.5 h. Butyric anhydride (0.17 mL, 0.5 eq) was added and the reaction mixture was stirred at 40 °C for 2 h. Water was added, the product was extracted with EtOAc, dried over MgSO 4 and concentrated in vacuo.
  • Example 182.3 N-[(Z)-N-hydroxy-C-(2-methyl-5-nitro-pyrazol-3- yl)carbonimidoyl]butanamide (480.00 mg, 1.8807 mmol) was dissolved in MeCN (9.40 mL). Potassium hydroxide (211.05 mg, 3.7613 mmol) was added, stirred at rt for 0.5 h. Water and EtOAc were added. The product was extracted with EtOAc, dried over MgSO 4 and concentrated in vacuo to give 3-(2-methyl-5-nitro-pyrazol-3- yl)-5-propyl-1,2,4-oxadiazole (380 mg, 85%, 1.6019 mmol) as a colorless powder.
  • Example 182.5 1-Methyl-5-(5-propyl-1,2,4-oxadiazol-3-yl)pyrazol-3-amine was used in a similar procedure to Example 176 to afford (S)-2-hydroxy-3-((7-(5-methyl- 1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(1-methyl-5-(5-propyl-1,2,4- oxadiazol-3-yl)-1H-pyrazol-3-yl)propanamide (53 mg, 57%, 0.1053 mmol) as a pale- yellow powder.
  • Example 183 (S)-2-hydroxy-N-(1-methyl-5-(5-propyl-1,2,4-oxadiazol-3-yl)-1H- pyrazol-3-yl)-3-((7-methylisoquinolin-1-yl)amino)propanamide
  • Example 183.1 A mixture of 1-chloro-7-methylisoquinoline (2.00 g, 10.696 mmol) in dry THF (112.59 mL) was degassed by bubbling nitrogen for 5 min.
  • Example 183.3 Prepared from 1-methyl-5-(5-propyl-1,2,4-oxadiazol-3-yl)pyrazol-3- amine [Example 182] and 7-methyl-2-oxido-isoquinolin-2-ium to afford (S)-2- hydroxy-N-(1-methyl-5-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-pyrazol-3-yl)-3-((7- methylisoquinolin-1-yl)amino)propanamide (48 mg, 56%, 0.1102 mmol).
  • Example 184 tert-Butyl (R)-2-(2-hydroxy-3-((7-methylisoquinolin-1- yl)amino)propanamido)-4-methylthiazole-5-carboxylate
  • Example 184.1 To anhydrous methanol (11.32 mL) at -10°C under nitrogen, was carefully added thionyl chloride (1.18 mL, 16.153 mmol). After stirring for 5 min (R)- 3-amino-2-hydroxypropanoic acid (0.68 g, 6.4611 mmol) was added in three portions. The reaction mixture was stirred at -10 °C for 5 min before being allowed to warm to rt and stirred overnight.
  • Example 184.2 7-Methylisoquinoline 2-oxide [Example 183] (200.00 mg, 1.2564 mmol) and methyl (2R)-3-amino-2-hydroxy-propanoate hydrochloride (293.22 mg, 1.8847 mmol) were dissolved/suspended in DCM (4.19 mL). DIPEA (1.04 mL, 5.9681 mmol) was added followed by PyBrop (761.44 mg, 1.6334 mmol) and stirred for 56 h. Purified by silica gel column chromatography (eluent: 0-20% (EtOAc/MeOH 3/1) in cyclohexane).
  • Example 184.4 (2R)-2-hydroxy-3-[(7-methyl-1-isoquinolyl)amino]propanoic acid (33.00 mg, 0.1340 mmol) was suspended in dry DCM (1.34 mL) in a microwave vial.1-Hydroxybenzotriazole (45.27 mg, 0.3350 mmol) was added followed by 3- (ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (64.22 mg, 0.3350 mmol).
  • Example 185 tert-Butyl (S)-2-(2-hydroxy-3-((7-methylisoquinolin-1- yl)amino)propanamido)-4-methylthiazole-5-carboxylate Prepared using (S)-methyl-3-amino-2-hydroxypropanoate hydrochloride to afford tert-butyl (S)-2-(2-hydroxy-3-((7-methylisoquinolin-1-yl)amino)propanamido)-4- methylthiazole-5-carboxylate (6 mg, 13%, 0.0136 mmol) as a colorless solid.
  • Example 186 Propyl (S)-2-(2-methoxy-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamido)-4-methylthiazole-5-carboxylate Prepared using 5-methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] and methyl (2S)-3-amino-2-methoxyproponate hydrochloride in an analogous procedure to Example 184 to afford propyl (S)-2-(2-methoxy-3-((7-(5- methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamido)-4-methylthiazole- 5-carboxylate (5 mg, 23%, 0.0098 mmol) as an off-white
  • Example 187 (S)-N-(5-(tert-butyl)-4-methylthiazol-2-yl)-2-hydroxy-3-((7-(5-methyl- 1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propenamide Prepared using 5-methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96], methyl (2S)-3-amino-2-hydroxy-propanoate hydrochloride and 5-tert- butyl-4-methyl-thiazol-2-ylamine to afford (S)-N-(5-(tert-butyl)-4-methylthiazol-2-yl)- 2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide (36 mg, 49%, 0.0772 mmol).
  • Example 188 (S)-2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)-N-(1-methyl-5-pentyl-1H-pyrazol-3-yl)propenamide Prepared using 5-methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96], methyl (2S)-3-amino-2-hydroxy-propanoate hydrochloride and 1- methyl-5-pentyl-pyrazol-3-amine to afford (S)-2-hydroxy-3-((7-(5-methyl-1,2,4- oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(1-methyl-5-pentyl-1H-pyrazol-3- yl)propanamide (9 mg, 22%,
  • Example 189 (R)-2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)-N-(1-methyl-5-pentyl-1H-pyrazol-3-yl)propenamide Prepared using 5-methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] and 1-methyl-5-pentyl-pyrazol-3-amine to afford (R)-2-hydroxy-3-((7- (5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)-N-(1-methyl-5-pentyl-1H- pyrazol-3-yl)propanamide (5.7 mg, 20%, 0.0123 mmol).
  • Example 190 (R)-N-(5-(tert-butyl)-4-methylthiazol-2-yl)-2-hydroxy-3-((7-(5-methyl- 1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide Prepared using 5-methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] and 5-tert-butyl-4-methyl-thiazol-2-ylamine to afford (R)-N-(5-(tert- butyl)-4-methylthiazol-2-yl)-2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)propanamide (2.8 mg, 12%, 0.0058 mmol).
  • Example 191 (R)-2-hydroxy-N-(5-isobutyl-4-methylthiazol-2-yl)-3-((7-(5-methyl- 1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)propenamide Prepared using 5-methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] and 4-methyl-5-(2-methylpropyl)-1,3-thiazol-2-amine hydrochloride to afford (R)-2-hydroxy-N-(5-isobutyl-4-methylthiazol-2-yl)-3-((7-(5-methyl-1,2,4- oxadiazol-3-yl)isoquinolin-1-yl)amino)propanamide (19 mg, 43%, 0.0407 mmol).
  • Example 192 (R)-2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1- yl)amino)-N-(4-methyl-5-(1-(trifluoromethyl)cyclopropyl)thiazol-2-yl)propanamide Prepared using 5-methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] and 4-methyl-5-[1-(trifluoromethyl)cyclopropyl]thiazol-2-amine [Example 51.1] to afford (R)-2-hydroxy-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)-N-(4-methyl-5-(1-(trifluoromethyl)cyclopropyl)thiazol-2- yl)propan
  • Example 193 tert-Butyl 2-[(3S)-4-cyano-3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]form ⁇ amido ⁇ -butanamido]-4-methyl-1,3-thiazole-5-carboxylate
  • Example 193.1 To a stirred solution of 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (15.00 g, 73.464 mmol) and 1,5-dimethyl 3-aminopentanedioate hydrochloride (15.55 g, 73.473 mmol) in DMF (150.0 mL) were added TCFH (30.92 g, 110.200 mmol) and 1-methyl-1H-imidazole (18.1 g, 220.452 mmol), and the resulting mixture was stirred at rt for 16 h.
  • Example 193.2 To a solution of 1,5-dimethyl 3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]-formamido ⁇ pentanedioate (10.00 g, 27.674 mmol) in THF (80.0 mL) and water (40.0 mL) was added lithium hydroxide (662.8 mg, 27.674 mmol), and the resulting mixture was stirred at rt for 16 h. The mixture was acidified to pH5 with 2N aqueous HCl solution, and the resulting mixture was extracted with dichloromethane/methanol - 10:1.
  • Example 193.3 5-methoxy-3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido ⁇ - 5-oxopentanoic acid (4.00 g, 11.517 mmol) and ammonium chloride (924 mg, 17.274 mmol) were dissolved in DMF (40.0 mL). Diethylamine (4.46 g, 34.520 mmol) and HATU (6.57 g, 17.279 mmol) were added, and the resulting mixture was stirred at rt for 16 h. The resulting mixture was diluted with water (40 mL) and extracted with dichloromethane/methanol - 10:1.
  • Example 193.4 A solution of methyl 4-carbamoyl-3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]-formamido ⁇ butanoate (800.0 mg, 2.31 mmol) in EtOH (10.0 mL) was treated with a solution of lithium hydroxide (276.6 mg, 11.549 mmol) in water (4.0 mL). The resulting mixture was stirred at rt for 1 h. The mixture was acidified to pH5 with 2N aqueous HCl solution. The aqueous layer was extracted with dichloromethane.
  • Example 193.5 A stirred solution of 4-carbamoyl-3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]-formamido ⁇ butanoic acid (300.0 mg, 0.903 mmol) in DMF (5.0 mL) was cooled to 0 °C. POCl 3 (277.0 mg, 1.807 mmol) was added dropwise at 0 °C. After complete addition the reaction mixture was warmed to rt and stirred for 4 h. The reaction mixture was quenched by the addition of water (5 mL) at rt.
  • Example 193.6 A stirred solution of 4-cyano-3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]form-amido ⁇ butanoic acid (220.0 mg, 0.700 mmol) and tert-butyl 2-amino- 4-methyl-1,3-thiazole-5-carboxylate (150.0 mg, 0.700 mmol) in DMF (3.0 mL) was treated with [chloro(dimethylamino)methylidene]dimethylazanium; hexafluoro- ⁇ 5- phosphanuide (294.6 mg, 1.050 mmol) and 1-methyl-1H-imidazole (172.4 mg, 2.100 mmol) and the resulting mixture was stirred at rt for 2 h.
  • Example 194 tert-Butyl 2-[(3R)-4-cyano-3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]form-amido ⁇ butanamido]-4-methyl-1,3-thiazole-5-carboxylate 36 mg (24%) as a colorless solid.
  • Example 195 Propan-2-yl 2-[(3S)-4-cyano-3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]form-amido ⁇ butanamido]-4-methyl-1,3-thiazole-5-carboxylate 114 mg (8%) as a colorless solid.
  • Example 196 Propan-2-yl 2-[(3R)-4-cyano-3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]form-amido ⁇ butanamido]-4-methyl-1,3-thiazole-5-carboxylate 120 mg (8%) as a pale-yellow solid. HPLC/MS m/z: 497.15 [M+H] + , Rt (C): 1.01 min.
  • Example 197 Methyl 2-[(3S)-4-cyano-3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]formamido ⁇ butanamido]-4-methyl-1,3-thiazole-5-carboxylate 40.5 mg (24%) as a colorless solid.
  • Example 198 Methyl 2-[(3R)-4-cyano-3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]formamido ⁇ butanamido]-4-methyl-1,3-thiazole-5-carboxylate 2 mg (7%) as a colorless solid.
  • Example 199 Propan-2-yl 2-[(3S)-4-cyano-N-methyl-3- ⁇ [3-(5-methyl-1,2,4- oxadiazol-3-yl)phenyl]-formamido ⁇ butanamido]-4-methyl-1,3-thiazole-5-carboxylate 5.5 mg (10%) as a colorless solid.
  • Example 200 Propan-2-yl 2-[(3R)-4-cyano-N-methyl-3- ⁇ [3-(5-methyl-1,2,4- oxadiazol-3-yl)phenyl]-formamido ⁇ butanamido]-4-methyl-1,3-thiazole-5-carboxylate 3.8 mg (6%) as a colorless solid.
  • Example 201 tert-Butyl 2-[(3S)-4-cyano-3- ⁇ [3-(1-methyl-1H-pyrazol-4- yl)phenyl]formamido ⁇ butanamido]-4-methyl-1,3-thiazole-5-carboxylate Separation of the enantiomers was performed by preparative chiral HPLC (column: Chiral Cellulose-SB, 4.6x100 mm, 3.0 ⁇ m; eluent: tert-butyl methyl ether (containing 0.1% diethylamine)/i-PrOH - 60:40). 20 mg (8%) as a colorless solid.
  • Example 210 Propan-2-yl 2-[(3S)-4-cyano-3- ⁇ [7-(1-methyl-1H-pyrazol-4- yl)isoquinolin-1-yl]amino ⁇ butanamido]-4-methyl-1,3-thiazole-5-carboxylate Separation of the enantiomers was performed by preparative chiral HPLC (column: (R,R) WHELK-O1, 4.6x50 mm, 3.5 ⁇ m, eluent: hexane (containing 0.1% diethylamine)/EtOH - 50:50). 15 mg (9%) as a colorless solid.
  • Example 212 tert-Butyl 2-[(3R)-4-cyano-3- ⁇ [6-(1-methyl-1H-pyrazol-4-yl)pyridin-2- yl]formamido ⁇ butanamido]-4-methyl-1,3-thiazole-5-carboxylate 7 mg (10%) as a colorless solid.
  • Example 213 Propan-2-yl 2-[(3S)-4-cyano-3- ⁇ [6-(1-methyl-1H-pyrazol-4-yl)pyridin- 2-yl]formamido ⁇ butanamido]-4-methyl-1,3-thiazole-5-carboxylate Separation of the enantiomers was performed by preparative chiral HPLC (column: CHIRALPAK IA-3, 4.6x50 mm, 3 ⁇ m, eluent: hexane (containing 0.1% diethylamine)/EtOH - 60:40). 24 mg (22%) as a colorless solid.
  • Example 215 Ethyl 4-methyl-2-(3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]form- amido ⁇ pentanamido)-1,3-thiazole-5-carboxylate 30 mg (12%) as a colorless solid.
  • Example 216 (3R)-4- ⁇ [5-(methoxycarbonyl)-4-methyl-1,3-thiazol-2-yl]carbamoyl ⁇ -3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido ⁇ butanoic acid 15 mg (19%) as a colorless solid.
  • Example 217 (3S)-4- ⁇ [5-(methoxycarbonyl)-4-methyl-1,3-thiazol-2-yl](methyl)- carbamoyl ⁇ -3- ⁇ [3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]formamido ⁇ butanoic acid 33 mg (16%) as a colorless solid.
  • Example 218 tert-Butyl 2-((1s,3s)-N-ethyl-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)cyclobutanecarboxamido)-4-methylthiazole-5-carboxylate formate
  • Example 218.1 To a solution of tert-butyl acetoacetate (0.80 mL, 4.7998 mmol) in H 2 O (24.00 mL) held at 70 °C was added 1,3,5-tribromo-1,3,5-triazinane-2,4,6- trione (702.24 mg, 1.9199 mmol) in small portions and the mixture was stirred at 70 °C for 1 h.
  • Example 218.2 Preparation as described for example Example 48 using 3-[[7-(5- methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutanecarboxylic acid [Example 96] (40.00 mg, 0.1233 mmol) and tert-butyl 2-(ethylamino)-4-methyl- thiazole-5-carboxylate (32.88 mg, 0.1357 mmol). Purification by reverse flash chromatography followed by SCX-2 filtration. Compound was subjected to normal column chromatography (0-20% MeOH:DCM). Compound was again purified by reverse phase flash chromatography (5-80 % MeOH in water [0.1% FA]).
  • Example 219 Ethyl 4-methyl-2-(N-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamido)propanamido)thiazole-5-carboxylate
  • Example 219.1 To a stirred solution of 3-(tert-butoxycarbonylamino)propanoic acid (430.00 mg, 2.2726 mmol), and HOBt (614.15 mg, 4.5452 mmol) in dry DMF (11.36 mL), under a nitrogen atmosphere at rt, were added EDC (705.60 mg, 4.5452 mmol) and ethyl 4-methyl-2-(methylamino)thiazole-5-carboxylate (540.00 mg, 2.6965 mmol) sequentially.
  • Example 219.2 To ethyl 2-[3-(tert-butoxycarbonylamino)propanoyl-methyl-amino]- 4-methyl-thiazole-5-carboxylate (400.00 mg, 1.0769 mmol) in dioxane (5.38 mL), was added 4M HCl in dioxane (5.38 mL, 21.537 mmol) dropwise, whilst stirring at rt. After 2 h volatiles were removed under vaccum to afford ethyl 2-[3- aminopropanoyl(methyl)amino]-4-methyl-thiazole-5-carboxylate. Taken on straight away to the next step to avoid decomposition.
  • Example 220 Propyl 4-methyl-2-(((1s,3s)-3-((7-(5-methyl-1,2,4-oxadiazol-3- yl)isoquinolin-1-yl)amino)cyclobutyl)carbamoyl)thiazole-5-carboxylate
  • Example 220.1 5-Methyl-3-(2-oxidoisoquinolin-2-ium-7-yl)-1,2,4-oxadiazole [Example 96] (375 mg, 1.65 mmol), tert-butyl (cis-3-aminocyclobutyl)carbamate (384 mg, 2.06 mmol) and DIPEA (1.08 mL, 6.19 mmol) were mixed in anhydrous DCM (6.6 mL) at rt under an argon atmosphere.
  • Example 220.2 tert-Butyl N-[3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1- isoquinolyl]amino]cyclobutyl]carbamate (431 mg, 1.09 mmol) was dissolved in anhydrous DCM (2.2 mL) at rt under an argon atmosphere. Trifluoroacetic acid (0.83 mL, 10.9 mmol) was added, and the reaction mixture was stirred for 3 h. Volatiles were removed under reduced pressure. The crude material was dissolved in MeOH and filtered through a 2 g SCX-2 cartridge. The compound was released with 7 M ammonia in MeOH.
  • Example 220.3 2-Bromo-4-methyl-thiazole-5-carboxylic acid (0.90 g, 4.05 mmol) and DMAP (0.05 g, 0.405 mmol) were suspended in anhydrous DMF (8.1 mL) at rt under an argon atmosphere.1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.93 g, 4.86 mmol) and propan-1-ol (6.1 mL, 81.06 mmol) were added successively and the reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to rt and mixed with water (50 mL).
  • Example 220.4 N1-[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]cyclobutane- 1,3-diamine (30 mg, 0.102 mmol), propyl 2-bromo-4-methyl-thiazole-5-carboxylate (28 mg, 0.107 mmol), XantPhos-Pd G4 precatalyst (4.9 mg, 0.005 mmol) and anhydrous 1,4-dioxane (0.51 mL) were mixed in a microwave vial. The vial was capped, evacuated, and back filled with argon. Then, the vial was evacuated again and fitted with a balloon filled with carbon monoxide.
  • Example 221 (1r,3r)-N-(5-(tert-butyl)-4-methylthiazol-2-yl)-1-hydroxy-3-((7-(5- methyl-1,2,4-oxadiazol-3-yl)isoquinolin-1-yl)amino)cyclobutane-1-carboxamide
  • Example 221.1 tert-Butyl 3-oxocyclobutylcarbamate (500 mg, 2.70 mmol) and zinc iodide (43 mg, 0.14 mmol) were mixed at rt under an argon atmosphere. Anhydrous THF (13.50 mL) was added.
  • Trimethylsilylcyanide (0.41 mL, 3.24 mmol) was added, and the reaction mixture was stirred at rt for 60 h.
  • the reaction mixture was concentrated under reduced pressure and mixed with EtOAc (50 mL), washed with saturated NaHCO 3 (20 mL) and saturated NaCl (2 x 20 mL), dried over anhydrous MgSO 4 and concentrated under reduced pressure to yield 554 mg (97%) of the crude tert-butyl N-(3-cyano-3-hydroxy-cyclobutyl)carbamate, which was used in the next reaction without further purification.
  • 1 H NMR showed a ⁇ 2:3 mixture of both stereoisomers.
  • Example 221.2 tert-Butyl N-(3-cyano-3-hydroxy-cyclobutyl)carbamate (554 mg, 2.61 mmol) was heated to reflux in a 1:1 mixture of concentrated HCl/AcOH (20 mL) for 2 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to yield 420 mg (96%) of (3-carboxy-3-hydroxy-cyclobutyl)ammonium chloride as an off-white solid, which was used in the next reaction without further purification. HPLC/MS m/z: 132.0661 [M+H] + , Rt (S): 0.31 min. Note: 1 H NMR showed a ⁇ 1:4 mixture of both stereoisomers.
  • Example 221.3 3-Amino-1-hydroxycyclobutane-1-carboxylic acid hydrochloride (360 mg, 2.15 mmol), sodium carbonate (759 mg, 7.16 mmol), and 3-(1-chloro-7- isoquinolyl)-5-methyl-1,2,4-oxadiazole [Example 45] (352 mg, 1.43 mmol) were mixed in anhydrous NMP (2.9 mL) under an argon atmosphere. The reaction mixture was heated at 130 °C for 48 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure.
  • Example 221.4 5-tert-Butyl-4-methyl-thiazol-2-ylamine (76 mg, 0.45 mmol) and 1- hydroxy-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-1-isoquinolyl]amino]cyclobutane- carboxylic acid (78 mg, 0.22 mmol) were mixed in anhydrous DMF (0.46 mL) at 0 °C under an argon atmosphere. PyBOP (140 mg, 0.27 mmol) and DIPEA (0.12 mL, 0.67 mmol) were added, and the stirred reaction mixture was allowed to slowly reach ambient temperature. The reaction was continued to stir overnight.

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Publication number Priority date Publication date Assignee Title
WO2024042007A1 (en) * 2022-08-23 2024-02-29 Merck Patent Gmbh Substituted bicycles as hset inhibitors

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