VASOPRESSIN V1A ANTAGONISTS

The present invention concerns compounds inter alia according to general formula 1a. Compounds according to the invention are vasopressin V1a receptor antagonists. Pharmaceutical compositions of the compounds are useful as treatment of dysmenorrhoea.

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Description

Priority is claimed from EP patent application number 04104062 and U.S. patent application No. 60/603,557, both filed 24 Aug. 2004.

FIELD OF THE INVENTION

The present invention relates to compounds with vasopressin V1a antagonist activity and to pharmaceutical compositions comprising such compounds. The present invention also relates to the use of vasopressin V1a antagonists for the treatment of certain physiological disorders, such as Raynaud's disease and dysmenorrhoea (primary dysmenorrhoea and/or secondary dysmenorrhoea).

BACKGROUND

The neurophyseal hormones vasopressin (VP) and oxytocin (OT) are cyclic nonapeptides secreted by the posterior pituitary gland.

Only one OT receptor has so far been well characterised, while three VP receptors are known. These are designated the V1a, V1b and V2 receptors.

Vasopressin acts on the blood vessels, where it is a potent vasoconstrictor, and on the kidneys, where it promotes water reuptake leading to an antidiuretic effect.

The V1a, V1b, and V2, as well as the OT receptors, are members of the super-family of seven transmembrane receptors known as G-protein coupled receptors. The V1a receptor mediates phospholipase C activation and intracellular calcium mobilisation. Localisation of the receptors includes blood platelets, blood vessels, hepatocytes, brain and uterus-cervix. Thus a V1a antagonist may have effects on any or all of these tissues. For example, selective V1a antagonists have been cited as having clinical utility in dysmenorrhoea, pre-term labour, hypertension, Raynaud's disease, brain oedema, motion sickness, hyperlipemia, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.

With respect to dysmenorrhoea it has been proposed that myometrial activity is markedly increased in women with dysmenorrhoea during menstruation. It is proposed that the myometrial ischemia caused by increased uterine contractility might explain the menstrual pain. Furthermore, on the first day of menstruation, higher plasma concentrations of vasopressin have been measured in dysmenorroeic women than in controls.

In healthy women without dysmenorrhoea, intravenous infusion of lysine-vasopressin resulted in decreased uterine blood flow, increased uterine contractility and slight to moderate dysmenorrhoea-like pain, these effects being inhibited by a selective human V1a receptor antagonist. (Bossmar, T. et al., BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY (1997 April), 104(4), 471-7). Also, it is known that vasopressin contracts human uterine arteries in a dose-dependent and V1a-mediated fashion.

The above evidence suggests that a V1a antagonist would be an appropriate and effective treatment for dysmenorrhoea (primary dysmenorrhoea and/or secondary dysmenorrhoea). Further evidence is taken from the clinical study carried out on the selective V1a antagonist SR49059 (“Effect of SR49059, an orally active V1a vasopressin receptor antagonist, in the prevention of dysmenorrhea”. Brouard, R. et al., BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY (2000), 107(5), 614-619). It was found that there was a dose-related decrease in pain and a dose-related decrease in the amount of additional pain-killer taken compared to patients taking placebo.

The International Patent Application WO 03/016316 A1, published 27 Feb. 2003, discloses a number of compounds which are claimed to be oxytocin agonists and to find use in the treatment of male erectile dysfunction. No V1a antagonist activity is reported. The European Patent Application EP 1 449 844 A1, published 25 Aug. 2004, discloses a number of compounds which are claimed to be V1a antagonists and to find use in the treatment of primary dysmenorrhoea.

There exists a need for treatments for conditions which are associated with the V1a receptors. There further continues to exist a need for alternative V1a antagonists. Simple synthesis and oral availability are additional desirable characteristics.

DISCLOSURE OF THE INVENTION

According to an aspect, the present invention relates to compounds, preferably VP antagonists, and in particular specific antagonists of the V1a receptor, and pharmaceutically acceptable salts thereof.

According to another aspect, the present invention relates to pharmaceutical compositions comprising these compounds, which compositions are useful for the treatment of, inter alia, dysmenorrhoea (primary dysmenorrhoea and/or secondary dysmenorrhoea).

According to another aspect, the present invention relates to the use of the compounds for the manufacture of a pharmaceutical composition for treatment of dysmenorrhoea.

According to further aspects, the present invention relates to the medical use and to the use of the above mentioned compounds and compositions in therapy and to therapeutic methods wherein the above mentioned compounds and compositions are used.

DETAILED DESCRIPTION OF THE INVENTION

According to an aspect the invention concerns a compound according to general formula 1a, or a compound which is a tautomer or a pharmaceutically acceptable salt thereof,

wherein G is a group selected among general formula 2a, 3a, 4a, 5a, and 6a,

wherein:
A1 is selected among CH2, CH(OH), NH, N-alkyl, O and S;
A2 is selected among CH2, CH(OH), C(═O) and NH;
A3 and A12 are independently selected among S, NH, N-alkyl, —C(R8)═CH—, —C(R8)═N—, —N═C(R8)— and —CH═C(R8)—;
A4 and A13 are independently selected among C(R9) and N;
A5 and A14 are independently selected among C(R10) and N;
A6 is selected among CH2, NH, N-alkyl and O;
A7 and A11 are independently selected among C and N;
A8 and A9 are independently selected among CH, N, NH, N(CH2)bR11 and S;
A10 is selected among —CH═CH—, CH, N, NH, N—(CH2)b—R11 and S;
wherein the ring constituted by A7, A8, A9, A10 and A11 is aromatic;
R1, R2 and R3 are independently selected among H, alkyl, O-alkyl, NO2, F, Cl and Br;
R4 is selected among H, alkyl, aryl, heteroaryl, —(CH2)c—R12, and

R5 and R6 are independently selected among alkyl, aryl, —(CH2)f-aryl, and —(CH2)f-heteroaryl;
R7 is selected among H, alkyl, aryl, heteroaryl, and —(CH2)g—R14;
R8, R9 and R10 are independently selected among H, alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, NH(alkyl), N(alkyl)2; with the provisos that when G is 3a, and R4 is H, alkyl, aryl, heteroaryl or —(CH2)c—R12, then the ring containing A3, A4 and A5 is substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, NH(alkyl) or N(alkyl)2; and
when G is 4a, R4 is H, alkyl, aryl, heteroaryl or —(CH2)c—R12, and A8 is NH, NCH3 or S, then the ring containing A3, A4 and A5 is substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, NH(alkyl) or N(alkyl)2;
R11 and R12 are independently selected among H, alkyl, aryl, heteroaryl, F, OH, O-alkyl, S-alkyl, O-acyl, NH2, NH-alkyl, N (alkyl)2 NH-acyl, N (alkyl)-acyl, CO2H, CO2-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, CN and CF3;
R13 is selected among H, alkyl, aryl, heteroaryl, —(CH2)h—R15 and Z—R16;
R14 and R15 are independently selected among H, alkyl, alkenyl, aryl, heteroaryl, F, OH, O-alkyl, S-alkyl, O-acyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)-acyl, CO2H, CO2-alkyl, CO-alkyl, CO-aryl, CONH2, CONH-alkyl, CON(alkyl)2, alkenyl-CO2-alkyl, alkenyl-aryl, CN and CF3;
R16 is selected among H, alkyl, alkenyl, aryl, heteroaryl, O-aryl, —(CH2)i—R17, cyclopropyl-aryl and O—(CH2)i—R17;
R17 is selected among H, alkyl, aryl, heteroaryl, F, OH, O-alkyl, S-alkyl, O-acyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)-acyl, CO2H, CO2-alkyl, CONH2, CONH-alkyl, CON(alkyl)2 CN and CF3;
W is selected among O and NH;
X is selected among (CH2)m, C(═O) and S(═O)j
Y is selected among O, S, NH and N-alkyl;
Z is selected among —C(═O), —C(═O)—O and —S(═O)k;
a is selected among 1 and 2;
b and c are independently selected among 0, 1, 2 and 3;
d, e and f are independently selected among 1 and 2;
g, h and i are independently selected among 1, 2 and 3;
j and k are independently selected among 1 and 2; and
m and n are independently selected among 0, 1 and 2.

According to an aspect, R16 may further be selected among O-alkyl and O-alkenyl, and Z is different from —C(═O)—O.

It appears that the compounds of formula 1a of claim 1 are subject to the following constraints. When G is 3a, and R4 is H, alkyl, aryl, heteroaryl or —(CH2)c—R12, then the ring containing A3, A4 and A5 is substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, NH(alkyl) or N(alkyl)2. When G is 4a, R4 is H, alkyl, aryl, heteroaryl or —(CH2)c—R12, and A8 is NH, NCH3 or S. then the ring containing A3, A4 and A5 is substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, NH(alkyl) or N(alkyl)2. The ring constituted by A7, A8, A9, A10 and A11 is aromatic, and accordingly the groups must satisfy certain requirements. When A10 is —CH═CH— the ring is a six membered ring. As such, it can only comprise atoms of the type —C(R)═ and —N═. Hence A7 and A11 must both be C and A8 and A9 must be either CH or N. When A10 is not —CH═CH— then the ring is a five-membered ring. In this case one, and only one, of the atoms in the ring must be S or a trigonal nitrogen. In this context, a “trigonal nitrogen” is a nitrogen atom linked covalently to three different atoms. Two of these atoms are the immediate neighbours to the nitrogen atom in the five-membered ring. The third is a hydrogen, carbon or other atom linked to the five-membered ring. Thus it follows that, when A10 is not —CH═CH— then one (and only one) of A7, A8, A9, A10 and A11 must be S or a trigonal nitrogen. Hence the selection of A7, A8, A9, A10 and A11 is subject to the following restrictions. If A10 is not —CH═CH— then one of A8, A9 and A10 is NH, N—(CH2)b-R11 or S or one of A7 and A11 is N. Not more than one of A8, A9 and A10 may be NH, N—(CH2)b-R11 or S. A7 and A11 may not both simultaneously be N. Neither A7 nor A11 may be N if one of A8, A9 and A10 is NH, N—(CH2)b-R11 or S.

According to aspects of the invention, additional and preferred embodiments of the invention are as set out below, in the description and the claims.

The term “alkyl” includes saturated hydrocarbon residues including:

    • linear groups up to 10 atoms (C1-C10). Examples of such alkyl groups include, but are not limited to, C1—methyl, C2—ethyl, C3—propyl and C4—n-butyl;
    • branched groups of between 3 and 10 atoms (C3-C10). Examples of such alkyl groups include, but are not limited to, C3—iso-propyl, C4—sec-butyl, C4—iso-butyl, C4—tert-butyl and C5—neo-pentyl;
    • cyclic groups of between 3 and 8 atoms (C3-C8). Examples of such groups include but are not limited to, C3—cyclopropyl, C4—cyclobutyl, C5—cyclopentyl and C6—cyclohexyl;
    • combinations of linear, branched and cyclic groups. Examples of such groups include, but are not limited to,

The term “alkoxy” is used to denote O-alkyl groups.

The term “alkenyl” includes monounsaturated hydrocarbon residues including

    • linear groups of between two and six atoms (C2-C6). Examples of such alkenyl groups include, but are not limited to, C2—vinyl, C3—1-propenyl, C3—allyl and C4—2-butenyl;
    • branched groups of between 3 and 8 atoms (C3-C8). Examples of such alkenyl groups include, but are not limited to, C4—2-methyl-2-propenyl and C6—2,3-dimethyl-2-butenyl;
    • cyclic groups of between 3 and 8 atoms (C3-C8). Examples of such groups include, but are not limited to, C5—3-cyclopentenyl and C6—1-cyclohexenyl.

The term “aryl” includes optionally substituted phenyl and optionally substituted naphthyl. Examples of such aryl groups include, but are not limited to, phenyl, 2-tolyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,5-difluorophenyl, 1-naphthyl and 2-naphthyl.

The term “heteroaryl” includes optionally substituted heterocycles. Such heteroaryl groups include, but are not limited to, pyridyl, 2-chloropyridyl, 4-methylpyridyl, thienyl, 3-chlorothienyl, 2,3-dimethylthiophenyl, furyl, 2-methylfuryl, pyrrole, N-methylpyrrole, oxazole, imidazole, pyrazole and triazole.

The term “acyl” denotes a group R—C(═O), where R is H, a saturated or unsaturated hydrocarbon moiety of up to seven carbon atoms or an optionally substituted phenyl, optionally substituted pyridyl or optionally substituted thienyl group. Examples of acyl groups include, but are not limited to: formyl, acetyl, pivaloyl, benzoyl and nicotinoyl.

Certain compounds of the present invention are capable of forming salts with acids or bases. For example, compounds containing one or more basic nitrogen atoms can form addition salts with mineral and organic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulphonic acid, citric acid and benzoic acid. Compounds containing acidic groups can form salts with bases. Examples of such salts include the sodium, potassium, calcium, triethylammonium and tetraethylammonium salts. Furthermore, compounds that have both acidic and basic groups can form internal salts (zwitterions). Insofar as these salts are pharmaceutically acceptable, they are included within the scope of the invention.

Certain compounds within the scope of the present invention may exist as tautomers. For example, where G1 is general formula 4a (4b, 4c, 4d) and X2 is NH the resulting imidazole can exist as its tautomer which is defined by G1 as general formula 5a (5b, 5c, 5d) and X2 as NH. All such tautomers are considered to be within the scope of the present invention.

The compounds according to the present invention may have one or more stereogenic centres (“asymmetric carbon atoms”) and so may exhibit optical isomerism. The scope of the present invention includes all epimers, enantiomers and diastereomers of compounds according to the present invention, including single isomers, mixtures and racemates.

According to an aspect, it is preferred that G is selected among:

According to an aspect, it is further preferred that G is selected among:

According to an aspect, it is preferred that at least one of R1, R2 and R3 is other than hydrogen; preferably one of R1, R2 and R3 is selected among methyl, chlorine and fluorine, and the others are hydrogen.

According to different aspects, it is preferred that W is NH; R4 is alkyl; d is 2 and e is 2; R13 is alkyl; and/or n is 0.

According to an aspect, it is preferred that R2 is H, R4 is a piperidine where d is 2 and e is 2, W is NH, X is C(═O) and n is 0, as shown in formula 18a:

wherein R1 is selected among methyl, chlorine and fluorine, and R3 is H; or R1 is H, and R3 is selected among methyl, chlorine and fluorine, and R13 is alkyl.

According to an aspect, it is preferred that X is C(═O), n is 0 and R4 is a piperidine where d is 2 and e is 2, as shown in formula 19a:

wherein G is selected among general formulae 7a to 17a, and R13 is alkyl.

According to an aspect, it is preferred that R2 is H and W is NH as shown in formula 20a:

wherein either R1 is selected among methyl, chlorine and fluorine, and R3 is H; or R1 is H, and R3 is selected among methyl, chlorine and fluorine; and G is selected from general formulae 7a to 17a.

According to an aspect, it is preferred that R2 is H, W is NH and X is C(═O) as shown in formula 21a:

wherein R1 is selected among methyl, chlorine and fluorine, and R3 is H; or R1 is H, and R3 is selected among methyl, chlorine and fluorine; and R4 is alkyl.

According to an aspect, it is preferred that X is C(═O) as shown in formula 22a:

wherein G is selected among general formulae 7a to 17a, and R4 is alkyl.

According to an aspect, it is preferred that R2 and R3 are both H, W is NH and X is C(═O) as shown in formula 23a:

wherein G is selected among general formulae 9a, 10a, 15a, 16a and 17a, R1 is selected among methyl, chlorine and fluorine, and R4 is alkyl.

According to an aspect, it is preferred that R2 and R3 are both H, R4 is a piperidine where d is 2 and e is 2, W is NH, X is C(═O) and n is 0 as shown in formula 24a:

wherein G is selected among general formulae 9a, 10a, 15a, 16a and 17a, R1 is selected among methyl, chlorine and fluorine, and R13 is alkyl.

According to an aspect, particularly preferred compounds are provided in claim 17.

According to an aspect of the present invention, it relates to the compounds of claim 18. According to an aspect, the ring containing A3, A4 and A5 according to general formulae 2b and 3b is substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, NH(alkyl) or N(alkyl)2.

It appears that the compounds of formula 1b of claim 18 are subject to following constraints. As the ring constituted by A7, A8, A9, A10 and A11 is aromatic, the groups must satisfy certain requirements. When A10 is —CH═CH— the ring is a six membered ring. As such, it can only comprise atoms of the type —C(R)═ and —N═. Hence A7 and A11 must both be C and A8 and A9 must be either CH or N. When A10 is not —CH═CH— then the ring is a five-membered ring. In this case one, and only one, of the atoms in the ring must be S or a trigonal nitrogen. In this context, a “trigonal nitrogen” is a nitrogen atom linked covalently to three different atoms. Two of these atoms are the immediate neighbours to the nitrogen atom in the five-membered ring. The third is a hydrogen, carbon or other atom linked to the five-membered ring. Thus it follows that, when A10 is not —CH═CH— then one, and only one, of A7, A8, A9, A10 and A11 must be S or a trigonal nitrogen. Hence the selection of A7, A8, A9, A10 and A11 is subject to the following restrictions. If A10 is not —CH═CH— then one of A8, A9 and A10 is NH, N—(CH2)d—R5 or S or one of A7 and A11 is N. Not more than one of A8, A9 and A10 may be NH, N—(CH2)d—R5 or S. A7 and A11 may not both simultaneously be N. Neither A7 nor A11 may be N if one of A8, A9 and A10 is NH, N—(CH2)d—R5 or S.

According to an aspect, particularly preferred compounds are provided in claim 30.

According to an aspect of the present invention, it relates to the compounds of claim 31. It appears that the compounds of formula 1c of claim 31 are subject to following constraints. The ring constituted by A7, A8, A9, A10 and A11 is aromatic, and accordingly the groups must satisfy certain requirements. When A10 is —CH═CH— the ring is a six membered ring. As such, it can only comprise atoms of the type —C(R)═ and —N═. Hence A7 and A11 must both be C and A8 and A9 must be either CH or N. When A10 is not —CH═CH— then the ring is a five-membered ring. In this case one, and only one, of the atoms in the ring must be S or a trigonal nitrogen. In this context, a “trigonal nitrogen” is a nitrogen atom linked covalently to three different atoms. Two of these atoms are the immediate neighbours to the nitrogen atom in the five-membered ring. The third is a hydrogen, carbon or other atom linked to the five-membered ring. Thus it follows that, when A10 is not —CH═CH— then one (and only one) of A7, A8, A9, A10 and A11 must be S or a trigonal nitrogen. Hence the selection of A7, A8, A9, A10 and A11 is subject to the following restrictions. If A10 is not —CH═CH— then one of A8, A9 and A10 is NH, N—(CH2), —R6 or S or one of A7 and A11 is N. Not more than one of A8, A9 and A10 may be NH, N—(CH2)c—R6 or S. A7 and A11 may not both simultaneously be N. Neither A7 nor A11 may be N if one of A8, A9 and A10 is NH, N—(CH2)c—R6 or S.

According to an aspect, particularly preferred compounds are provided in claim 45.

According to an aspect of the present invention, it relates to the compounds of claim 46. It appears that the compounds of formula 1d of claim 46 are subject to the following constraints. The ring constituted by A7, A8, A9, A10 and A11 is aromatic, and accordingly the groups must satisfy certain requirements. When A10 is —CH═CH— the ring is a six membered ring. As such, it can only comprise atoms of the type —C(R)═ and —N═. Hence A7 and A11 must both be C and A8 and A9 must be either CH or N. When A10 is not —CH═CH— then the ring is a five-membered ring. In this case one, and only one, of the atoms in the ring must be S or a trigonal nitrogen. In this context, a “trigonal nitrogen” is a nitrogen atom linked covalently to three different atoms. Two of these atoms are the immediate neighbours to the nitrogen atom in the five-membered ring. The third is a hydrogen, carbon or other atom linked to the five-membered ring. Thus it follows that, when A10 is not —CH═CH— then one (and only one) of A7, A8, A9, A10 and A11 must be S or a trigonal nitrogen. Hence the selection of A7, A8, A9, A10 and A11 is subject to the following restrictions. If A10 is not —CH═CH— then one of A8, A9 and A10 is NH, N—(CH2), —R11 or S or one of A7 and A11 is N. Not more than one of A8, A9 and A10 may be NH, N—(CH2)c—R11 or S. A7 and A11 may not both simultaneously be N. Neither A7 nor A11 may be N if one of A8, A9 and A10 is NH, N—(CH2)c—R11 or S.

According to an aspect, particularly preferred compounds are provided in claim 69.

The particularly preferred compounds of the invention are V1a antagonists of high activity.

According to an aspect, at least one of the compounds, identified as follows, is not part of the present invention: claim 1 and ex. 286 (3-Pyridin-3-yl-4,5-dihydro-isoxazole-5-carboxylic acid [4-(4-dimethylamino-benzylcarbamoyl)-phenyl]-amide) of U.S. Pat. No. 6,583,141; ex. 5 and 6 of WO 02/04403 (N-[4-(N-Methyl-N-phenylaminocarbonyl)-phenylmethyl]-3-(4′-trifluormethylbiphenyl-2-carbonylamino)benzoic acid amide and N-[4-(N-Methyl-N-phenylaminocarbonyl)-phenylmethyl]-3-(biphenyl-2-carbonylamino)benzoic acid amide); abstract, J. Org. Chem. USSR, vol. 18, no. 6, 1982, p. 1115-1119 (p-(N,N-diethylcarbamoyloxy)-N,N-diethylbenzamide); p. 3, 1. 16-p. 4, 1. 11, ex. 1-4, 11, and 14-19 of WO 01/29005; p. 3, 1. 9-p. 5, 1. 23, ex. 11, 28-31, 38, and 71-77 of WO 02/00626; and p. 3, 1. 1-p. 4, 1. 17, ex. 12-18 of WO 03/016316.

According to an aspect, the invention concerns a pharmaceutical composition comprising a compound according to the invention as an active agent.

The invention is further related to pharmaceutical compositions incorporating a compound according to the invention used as a V1a antagonist, which compositions are particularly useful for medical indications such as the treatment of dysmenorrhoea (primary dysmenorrhoea and/or secondary dysmenorrhoea), pre-term labour, hypertension, Raynaud's disease, brain oedema, motion sickness, hyperlipemia, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.

Any excipients used will depend on the intended nature of the formulation, which will, in turn, depend on the intended route of administration. Administration may be oral, transmucosal (such as sublingual, buccal, intranasal, vaginal and rectal), transdermal or by injection (such as subcutaneous, intramuscular and intravenous). Oral administration is generally preferred. For oral administration, the formulation may be a tablet, a capsule or a sachet. Other formulations include dry powders, solutions, suspensions, suppositories and the like.

According to an aspect, the invention concerns the use of a compound of the invention for the manufacture of a medicament for the treatment of a disease selected among dysmenorrhoea (primary dysmenorrhoea and/or secondary dysmenorrhoea), pre-term labour, hypertension, Raynaud's disease, brain oedema, motion sickness, hyperlipemia, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.

The compounds according to the present invention may be useful for treatment of several diseases, disorders or conditions. The term “treatment” used herein relates to both treatment in order to cure or alleviate a disease, disorder or a condition, and to treatment in order to prevent the development of a disease, disorder or a condition. The treatment may either be performed in an acute or in a chronic way. The human or animal to be treated, i.e. the patient, may be any human or non-human mammal in need of treatment according to the invention.

The administration of the compositions of the present invention will generally be under the control of a physician. The physician will determine the amount of composition to be administered and the dosing schedule, taking into account the patient's physical condition and the therapeutic goals.

Further aspects of the invention relates to methods of treatment of the above mentioned diseases, disorders or conditions. According to a method according to the invention a therapeutically effective amount of the compound, or of the pharmaceutical composition described above, is administered to a patient in need of this treatment. According to different aspects of the invention, it concerns a method of treatment of a disorder selected among dysmenorrhoea (primary dysmenorrhoea and/or secondary dysmenorrhoea), pre-term labour, hypertension, Raynaud's disease, brain oedema, motion sickness, hyperlipemia, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure.

The term “therapeutically effective amount” relates to an amount that will lead to the desired therapeutical effect. The therapeutically effective amount will be determined by the attending physician taking into consideration all appropriate factors. Generally a single dose will comprise between 0.1 mg and 1000 mg, preferably between 1 mg and 250 mg, of the active compound according to the invention. The dose may be given on a single occasion or repeatedly. When given repeatedly, it may be given at regular intervals, such as once, twice or three times daily, or on demand, according to the condition being treated.

The pharmaceutical composition according to the present invention may be presented in any form that is known in the art. For example, the formulation may be presented as a tablet, capsule, powder, suppository, cream, solution or suspension, or in a more complex form such as an adhesive patch. The formulation will generally include one or more excipients, such as diluents, bulking agents, binding agents, dispersants, solvents, preservatives, flavouring agents and the like. The formulation may also include one or more additional pharmacologically active species. Preferably the formulation includes no such additional active agents.

When used as therapeutic agents, the compositions of the present invention may be administered by any appropriate route that is known in the art. For example, they may be administered by the oral, buccal, sublingual, rectal, intra-vaginal, nasal, pulmonary or transdermal routes. Alternatively, they may be given by injection, including intravenous, subcutaneous and intramuscular injection.

The compounds of the present invention can be prepared using standard chemical manipulations. These are described in detail in WO 03/016316 A1, pages 12-17. (Hudson, P. J. et al., “Diazacycloalkanes as Oxytocin Agonists”).

The following examples are to be considered as enabling and not limiting for the invention.

EXAMPLES

The following abbreviations are used:

  • AIBN 2,2′-azobisisobutyronitrile
  • Boc carboxylic acid tert-butyl ester or tert-butoxycarbonyl amino
  • Bu butyl-alkyl residues may be further denoted as n (normal, i.e. unbranched), i (iso) and t (tertiary)
  • DIEA N,N-diisopropylethylamine
  • DMAP 4-(dimethylamino)pyridine
  • DMF dimethylformamide
  • Et ethyl
  • EtOAc ethyl acetate
  • HOBt 1-hydroxybenzotriazole
  • HPLC High performance liquid chromatography H hour(s)
  • Me methyl
  • Min minute(s)
  • MS mass spectrum
  • NMR nuclear magnetic resonance spectrum—NMR spectra were recorded in CDCl3 at a frequency of 270 MHz unless otherwise indicated
  • OVA ornithine vasotocin analogue
  • pet. petroleum ether boiling in the range 60-80° C.
  • Ether
  • Ph phenyl
  • Pn pentyl
  • Pr propyl
  • THF tetrahydrofuran
  • Tos toluene-4-sulphonyl
  • WSCD water-soluble carbodiimide (N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride

Examples E1-E125 describe the synthesis of intermediates and compounds of the present invention. Example A describes how compounds can be assayed based on their ability to inhibit the cellular consequences of AVP stimulation on intact cells. Example B describes tablets for oral administration comprising a compound according to the invention.

Example E1 6-Chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene Example E1.1 5-(4-Chloro-2-nitro-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

Sodium hydride (60% dispersion in oil, 7.28 g, 180 mmol) was added portionwise to a solution of ethyl 5-amino-1-methylpyrazole-4-carboxylate (21.8 g, 148 mmol) in anhydrous THF at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 h. A solution of 4-chloro-2-fluoronitrobenzene (22.6 g, 129 mmol) in anhydrous THF (50 ml) was added dropwise. The resultant deep purple solution was stirred at room temperature for 18 h then poured into ice-cold 1N hydrochloric acid. The resulting mixture was extracted with dichloromethane (200 ml×2), and the combined organic extracts were washed with brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 60% pet ether:40% EtOAc) to yield the title compound (27.5 g, 62%).

Example E1.2 5-(2-Amino-4-chloro-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

Zinc powder (26.17 g, 400 mmol) was added to a suspension of 5-(4-chloro-2-nitro-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester from Example E1.1 (26.0 g, 80 mmol) in methanol/acetic acid (10:1, 330 ml) at room temperature. After the exothermic reaction which followed, the resulting suspension was stirred at room temperature for 18 h before being filtered through Celite® filter agent. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc, and the solution was washed with saturated NaHCO3 and brine, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 65% EtOAc:35% pet ether to 80% EtOAc:20% pet ether) to yield the title compound (18.41 g, 78.0%).

Example E1.3 6-Chloro-3-methyl-4,9-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-10-one

Sodium(methylsulphinyl)methanide (53.4 mmol) was prepared from sodium hydride (60% dispersion in oil, 2.14 g, 53.4 mmol) and anhydrous dimethyl sulphoxide (35 ml) by heating at 65° C. until a solution was observed. To this was added a solution of 5-(2-amino-4-chloro-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester from Example E1.2 (9.02 g, 30.5 mmol) in anhydrous dimethyl sulphoxide (20 ml), and stirring continued at 65° C. for 30 min. The mixture was poured into ice (200 ml), and the resulting solid collected and purified by recrystallisation from methanol/EtOAc to yield the title compound (5.56 g, 73.3%).

Example E1.4 6-Chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene

To a suspension of 6-chloro-3-methyl-4,9-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-10-one from Example E1.3 (5.56 g, 22.4 mmol) in anhydrous THF (200 ml) at 0° C. was added lithium aluminium hydride (4.24 g, 112 mmol), and the resulting suspension was heated at reflux for 18 h, then allowed to cool to room temperature. A further portion of lithium aluminium hydride (4.24 g, 112 mmol) was added, and the mixture was heated at reflux for 18 h. The mixture was cooled to 0° C., 35% ammonia solution (10 ml) was added dropwise over 15 min and the mixture was stirred at room temperature for 30 min. The resulting suspension was filtered through Celite® filter agent and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 0.5% 35% ammonia:5% methanol:dichloromethane) to yield the title compound (3.88 g, 74%).

Example E2 3,6-Dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene Example E2.1 1-Methyl-5-(4-methyl-2-nitro-phenylamino)-1H-pyrazole-4-carboxylic acid ethyl ester

Sodium hydride (60% dispersion in oil, 7.28 g, 180 mmol) was added portionwise to a solution of ethyl 5-amino-1-methylpyrazole-4-carboxylate (21.8 g, 148 mmol) in anhydrous THF at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 h then a solution of 3-fluoro-4-nitrotoluene (20 g, 129 mmol) in anhydrous THF (50 ml) was added dropwise. The resultant deep purple solution was stirred at room temperature for 18 h then poured into ice-cold 1N hydrochloric acid. The resulting mixture was extracted with dichloromethane (200 ml×2), and the combined organic extracts were washed with brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 60% pet ether:40% EtOAc) to yield the title compound (28.00 g, 61%).

Example E2.2 5-(2-Amino-4-methyl-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

Tin (II) chloride (86.65 g, 457.0 mmol) was added to a solution of 1-methyl-5-(4-methyl-2-nitro-phenylamino)-1H-pyrazole-4-carboxylic acid ethyl ester from Example E2.1 (28.00 g, 91.4 mmol) in methanol and the mixture heated at reflux for 3 days. The solvent was removed in vacuo and the residue taken up in EtOAc (400 ml) and cooled to 0° C. 35% Ammonia solution was added to pH 14, and the mixture was stirred for 15 min before being filtered through Celite® filter agent. The filtrate was washed with 2M NH3 and brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 6% methanol:94% dichloromethane rising to 10% methanol:90% dichloromethane) to yield the title compound (12.8 g, 52%).

Example E2.3 3,6-Dimethyl-4,9-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-10-one

Sodium(methylsulphinyl)methanide (22.7 mmol) was prepared from sodium hydride (60% dispersion in oil, 912 mg, 22.7 mmol) and anhydrous dimethyl sulphoxide (5.5 ml) by heating at 65° C. until a solution was observed. To this was added a solution of 5-(2-amino-4-methyl-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester from Example E2.2 (3.56 g, 13.0 mmol) in anhydrous dimethyl sulphoxide (10 ml), and stirring continued at 65° C. for 30 min. The mixture was then poured into ice (200 ml), the resulting solid collected and purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield the title compound (1.12 g, 38%).

Example E2.4 3,6-Dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene

To a suspension of 3,6-dimethyl-4,9-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-10-one from Example E2.3 (2.35 g, 10.3 mmol) in anhydrous THF (100 ml) at 0° C. was added lithium aluminium hydride (1.56 g, 41.2 mmol), and the resulting suspension was heated at reflux for 18 h then allowed to cool to room temperature. A further portion of lithium aluminium hydride (781 mg, 20.6 mmol) was added, and the mixture was heated at reflux for 3 h. The mixture was cooled to 0° C., 35% ammonia solution (10 ml) was added dropwise over 15 min and the mixture was stirred at room temperature for 30 min. The resulting suspension was filtered through Celite® filter agent and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield the title compound (1.60 g, 72%).

Examples E2a-g are described in WO 03/016316 A1, (Hudson, P. et al. “Diazacycloalkanes as Oxytocin Agonists”), pages 26-31.

Example E2h 4-(tert-Butoxycarbonylamino-methyl)-3-methyl-benzoic acid Example E2h.1 4-Cyano-3-methyl-benzoic acid methyl ester

A mixture of 4-cyano-3-methyl-benzoic acid from Example E2d (1.5 g, 9.3 mmol) and thionyl chloride (5 ml, 68.5 mmol) in dichloromethane (20 ml) was heated at reflux for 2 h then solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (25 ml). Methanol (10 ml) was added and the solution was stirred at room temperature for 2 h then concentrated in vacuo. The residue was redissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to yield the title compound (1.6 g, 100%).

Example E2h.2 4-Aminomethyl-3-methyl-benzoic acid methyl ester

A solution of 4-cyano-3-methyl-benzoic acid methyl ester from Example E2h.1 (1.6 g, 9.3 mmol) in methanol (50 ml) to 0° C. was treated with cobalt(II) chloride hexahydrate (5.1 g, 18.6 mmol). The mixture was stirred for 15 min at room temperature then sodium borohydride (3.5 g, 93 mmol) was added portionwise. The reaction mixture was stirred for 90 min then concentrated NH3 (5 ml) was added dropwise. The mixture was warmed up to room temperature over 30 min, filtered through Celite® filter agent, washed with methanol and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:10% methanol:89% dichloromethane) to yield the title compound (670 mg, 37%).

Example E2h.3 4-(tert-Butoxycarbonylamino-methyl)-3-methyl-benzoic acid methyl ester

Di-tert-butyl dicarbonate (900 mg, 4.1 mmol) was added to a solution of 4-aminomethyl-3-methyl-benzoic acid methyl ester from Example E2h.2 (670 mg, 3.7 mmol) in dichloromethane (50 ml) and triethylamine (to pH9) at room temperature. The mixture was stirred for 1 h then concentrated in vacuo. The residue was redissolved in EtOAc, washed with 0.3N KHSO4 then brine, dried and concentrated in vacuo to yield the title compound (1.04 g, 100%).

Example E2h.4 4-(tert-Butoxycarbonylamino-methyl)-3-methyl-benzoic acid

4-(tert-Butoxycarbonylamino-methyl)-3-methyl-benzoic acid methyl ester from Example E2h.3 (1.04 g, 3.7 mmol) was dissolved in dioxan (20 ml). 1N NaOH solution (5.6 ml, 5.6 mmol) was added and the mixture was stirred for 18 h at room temperature then concentrated in vacuo. The residue was redissolved in EtOAc, washed with 1N KHSO4 then brine, dried and concentrated in vacuo to yield the title compound (800 mg, 81%).

Example E3 4-(tert-Butoxycarbonylamino-methyl)-3-fluoro-benzoic acid Example E3.1 3-Fluoro-4-methylbenzoic acid methyl ester

Thionyl chloride (9.62 g, 81 mmol) was added to a solution of 3-fluoro-4-methylbenzoic acid (5.0 g, 32.4 mmol) in toluene (50 ml). The mixture was stirred at room temperature for 1.5 h and heated at reflux for 3 h. The solvent was removed in vacuo and the residue was taken up in methanol (30 ml) and CH2Cl2 (30 ml) and stirred for 18 h. The mixture was evaporated in vacuo and the residue was taken up in EtOAc (50 ml), washed with saturated NaHCO3 solution (3×75 ml), dried and evaporated in vacuo to yield the title compound (4.5 g, 83%).

Example E3.2 4-Bromomethyl-3-fluorobenzoic acid methyl ester

3-Fluoro-4-methylbenzoic acid methyl ester from Example E3.1 (4.5 g, 26.6 mmol) was dissolved in carbon tetrachloride (150 ml). AIBN (457 mg, 2.7 mmol) and N-bromosuccinimide (5.2 g, 29.3 mmol) were added and the mixture was heated at reflux for 18 h. The mixture was allowed to cool and further portions of AIBN (457 mg, 2.7 mmol) and N-bromosuccinimide (5.2 g, 29.3 mmol) were added. The mixture was heated at reflux for 56 h. The mixture was allowed to cool and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% EtOAc:90% pet ether) to yield the title compound (2.7 g, 41%).

Example E3.3 4-Azidomethyl-3-fluorobenzoic acid methyl ester

Sodium azide (609 mg) was added to a solution of 4-bromomethyl-3-fluorobenzoic acid methyl ester from Example E3.2 (2.1 g, 8.5 mmol) in DMF (30 ml). The mixture was stirred for 18 h, diluted with EtOAc, washed with water and brine and concentrated in vacuo to give a colourless oil identified as the title compound (1.8 g, 100%).

Example E3.4 4-Aminomethyl-3-fluorobenzoic acid methyl ester

Hydrogen was passed through a degassed solution of 4-azidomethyl-3-fluorobenzoic acid methyl ester from Example E3.3 (2.11 g, 10 mmol) in methanol containing 10% palladium on carbon for 2 h. The reaction mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to give a colourless oil identified as the title compound (1.51 g, 83%).

Example E3.5 4-(tert-Butoxycarbonylamino-methyl)-3-fluorobenzoic acid methyl ester

To a solution of 4-aminomethyl-3-fluorobenzoic acid methyl ester from Example E3.4 (1.5 g, 8.2 mmol) in dichloromethane (20 ml) were added di-tert-butyl Bicarbonate (2.3 g, 11 mmol) and triethylamine (1.4 ml, 10 mmol). The mixture was stirred for 18 h, washed with 0.3M KHSO4 and brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% EtOAc:90% pet. ether) to give a white solid identified as the title compound (1.4 g, 60%).

Example E3.6 4-(tert-Butoxycarbonylamino-methyl)-3-fluorobenzoic acid

To a solution of 4-(tert-butoxycarbonylamino-methyl)-3-fluorobenzoic acid methyl ester from Example E3.5 (640 mg, 2.25 mmol) in dioxan (40 ml) was added 1N NaOH (4.5 ml, 4.5 mmol). The mixture was stirred for 18 h, diluted with EtOAc, washed with 1N KHSO4, water and brine and concentrated in vacuo to give a white solid identified as the title compound (608 mg, 100%).

Example E4 1-(3,3-Dimethyl-butyl)-piperazine dihydrochloride Example E4.1 4-(3,3-Dimethyl-butyl)-piperazine-1-carboxylic acid tert-butyl ester

To a solution of 1-boc-piperazine (8.19 g, 43.9 mmol) in methanol/acetic acid (99:1, v/v, 100 ml) was added 3,3-dimethylbutyraldehyde (4.0 g, 40.0 mmol) and the resulting mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (3.27 g, 51.9 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was dissolved in EtOAc and the resulting solution was washed with saturated NaHCO3, water and brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% EtOAc) to yield the title compound (9.1 g, 84%).

Example E4.2 1-(3,3-Dimethyl-butyl)-piperazine dihydrochloride

A solution of 4-(3,3-dimethyl-butyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E4.1 (9.1 g, 31.8 mmol) in methanol (100 ml) was treated with 4N HCl/dioxan (100 ml) and the mixture was stirred at room temperature for 30 min then concentrated in vacuo. The residue was triturated with diethyl ether and the resulting solid recrystallised from methanol/diethyl ether to yield 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride (7.4 g, 90%).

Example E5 2-Methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene Example E5.1 2-(Toluene-4-sulfonylamino)-benzoic acid methyl ester

Methyl anthranilate (110 g, 0.73 mol) was dissolved in dichloromethane (1 litre) at 0° C. and triethylamine (115 ml, 0.8 mol) was added. Tosyl chloride (133 g, 0.745 mol) was added portionwise at 0° C. The reaction mixture was stirred for 30 min at 0° C. and 64 h at room temperature. The mixture was reduced in vacuo. The residue was dissolved in EtOAc and the organic layer was washed with 5% KHCO3(aq) solution, 1N HCl solution and brine, dried, filtered and concentrated in vacuo. The residue was crystallised from EtOAc/hexane to yield the title compound (181 g, 81%).

Example E5.2 2-[(3-Ethoxycarbonyl-propyl)-(toluene-4-sulfonyl)-amino]-benzoic acid methyl ester

2-(Toluene-4-sulfonylamino)-benzoic acid methyl ester from Example E5.1 (100 g) was dissolved in DMF (250 ml). Potassium carbonate (125 g) and ethyl 4-bromobutanoate (60 g) were added and the mixture was heated at 80° C. for 18 h. The mixture was cooled to room temperature, filtered and reduced in vacuo. The residue was partitioned between chloroform and 1M HCl solution. The aqueous layer was extracted with chloroform. The organic layers were combined, washed with brine, dried, filtered and concentrated in vacuo. The material was crystallised from EtOAc/hexane and dried in a vacuum oven at 60° C. for 3 hours to yield the title compound (98.6 g, 72%).

Example E5.3 5-Hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester and 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester

2-[3-Ethoxycarbonyl-propyl)-(toluene-4-sulfonyl)-amino]-benzoic acid methyl ester from Example E5.2 (98.6 g, 0.235 mol) was taken up in warm toluene (600 ml) and was added dropwise to a mixture of potassium tert-butoxide (40 g) in toluene (1 litre) refluxing under Dean-Stark conditions. The mixture was heated at reflux under Dean-Stark conditions for 1 h further and cooled to room temperature. It was diluted with EtOAc (500 ml) and washed with 1M HCl solution, saturated NaHCO3(aq) and brine. The organic layer was dried, filtered and reduced in vacuo. The residue was precipitated from EtOAc/hexane and dried in a vacuum oven to yield a mixture of 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester and 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (53.5 g).

Example E5.4 1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[b]azepin-5-one

A mixture of 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester and 5-hydroxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester from Example E5.3 were heated at reflux in a mixture of ethanol (100 ml), acetic acid (300 ml), concentrated HCl (100 ml) and water (50 ml) for 18 h. The mixture was cooled to room temperature, diluted with water (800 ml) and extracted with chloroform. The combined organic extracts were dried, filtered and reduced in vacuo. The residue was crystallised twice from methanol to yield the title compound (44 g, 60% over two steps).

Example E5.5 1,2,3,4-Tetrahydro-benzo[b]azepin-5-one

Polyphosphoric acid (25 g) was heated at 100° C. under nitrogen until it could be stirred. 1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[b]azepin-5-one from Example E5.4 (2.6 g, 8.26 mmol) was added portionwise and the reaction mixture was heated at 100° C. for 1.5 h. It was poured into ice and basified with 2M NaOH(aq). The aqueous layer was extracted twice with dichloromethane. The organic extracts were combined, washed with brine, dried and reduced in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 40% EtOAc:60% hexane) to yield the title compound (1.05 g, 79%).

Example E5.6 1-Benzoyl-1,2,3,4-tetrahydro-benzo[b]azepin-5-one

1,2,3,4-Tetrahydro-benzo[b]azepin-5-one from Example E5.5 (480 mg, 2.98 mmol) was dissolved in a mixture of dichloromethane (30 ml) and triethylamine (1.3 ml). Benzoyl chloride (0.46 g, 3.28 mmol) was added and the reaction mixture was heated for at reflux for 2 h. The mixture was cooled and reduced in vacuo. The residue was dissolved in EtOAc and washed with 1M KHSO4(aq), water and brine. The organic layer was dried, filtered and reduced in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% hexane) to yield the title compound (440 mg, 56%).

Example E5.7 1-Benzoyl-4-bromo-1,2,3,4-tetrahydro-benzo[b]azepin-5-one

1-Benzoyl-1,2,3,4-tetrahydro-benzo[b]azepin-5-one from Example E5.6 (54.2 g, 205 mmol), N-bromosuccinimide (3.6 g, 20.4 mmol) and bromine (11.1 ml, 214.7 mmol) were dissolved in dichloromethane (1.0 litre). Triethylamine (30 ml, 215 mmol) was added dropwise over 30 minutes then the reaction mixture was heated at reflux for 4 h. Additional bromine (1.1 ml, 21.5 mmol) and triethylamine (3.0 ml, 21.5 mmol) were added and the reaction mixture was heated at reflux for a further 4 h. Additional bromine (1.1 ml, 21.5 mmol) and triethylamine (3.0 ml, 21.5 mmol) were added again and the reaction mixture was heated at reflux for a further 4 h. On cooling to room temperature, the reaction solution was washed with 5% aqueous sodium metabisulfate solution (150 ml) and the aqueous phase was diluted with water (600 ml). The organic phase was separated, washed with saturated Na—HCO3(aq), dried over sodium sulphate and filtered. The filtrate was diluted with EtOAc (100 ml), filtered through a silica pad (eluant; CH2Cl2) and reduced in vacuo to yield the title compound (73.6 g) which was used without further purification.

Example E5.8 6-Benzoyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene

1-Benzoyl-4-bromo-1,2,3,4-tetrahydro-benzo[b]azepin-5-one (67.5 g, 200 mmol) from Example E5.7, acetamidine hydrochloride (92.7 g, 980 mmol) and potassium carbonate (136.0 g, 980 mmol) were suspended in acetonitrile (2.0 litres) and heated at reflux for 17 h under nitrogen. Additional acetamidine hydrochloride (18.5 g, 200 mmol) and potassium carbonate (27.7 g, 200 mmol) were added and the reaction mixture was heated at reflux for a further 6 h. Additional acetamidine hydrochloride (18.5 g, 200 mmol) and potassium carbonate (27.7 g, 200 mmol) were added again and the reaction mixture was heated at reflux for a further 6 h. On cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in dichloromethane (1.4 litres), washed with water (500 ml), dried over sodium sulfate, filtered and reduced in vacuo. The crude products were purified by flash chromatography on silica gel, (eluant; 45% EtOAc:45% acetonitrile:10% methanol) to yield the title compound (26.7 g, 34%) and 6-benzoyl-2-methyl-5,6-dihydro-4H-1-oxa-3,6-diaza-benzo[e]azulene (3.3 g, 4%).

Example E5.9 2-Methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene

6-Benzoyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene from Example E5.8 (160 mg, 0.53 mmol) was dissolved in a 6M HCl/dioxan solution (50 ml) and heated at reflux for 18 h. The reaction mixture was cooled to room temperature and reduced in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3(aq) and the layers were separated. The organic layer was washed with brine, dried, filtered and reduced in vacuo to yield the title compound (69 mg, 66%).

Example E5a 1-Benzyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene Example E5a.1 (1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-phenyl-methanone

Sodium hydride (60% dispersion in oil, 905 mg, 22.5 mmol) was placed in anhydrous THF (200 ml) and cooled down to 0° C. 6-Benzoyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene from Example E5.8 (4.9 g, 16.1 mmol) was added dropwise and the mixture was stirred for 1 h at room temperature. Benzyl bromide (2.31 ml, 19.3 mmol) and potassium iodide (1.34 g, 8.0 mmol) were added and the mixture was stirred for 16 h. The solution was diluted with EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (5.73 g, 90%).

Example E5a.2 1-Benzyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene

(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-phenyl-methanone from Example E5a.1 (5.73 g, 14.6 mmol) was placed in methanol (50 ml) and a 6M HCl aqueous solution (200 ml) was added. The reaction mixture was heated at reflux for 18 h then concentrated in vacuo. The residue was dissolved in dichloromethane, basified with saturated NaHCO3 then washed with brine, dried and concentrated in vacuo to yield the title compound (3.30 g, 78%).

Example E6 2-Methyl-5,6-dihydro-4H-1-oxa-3,6-diaza-benzo[e]azulene

6-Benzoyl-2-methyl-5,6-dihydro-4H-1-oxa-3,6-diaza-benzo[e]azulene from Example E5.8 (1.0 g, 3.25 mmol) was reacted with a 6M HCl/dioxan solution (100 ml) using an analogous procedure to that described for Example E5.9 to yield the title compound (540 mg, 82%).

Example E7 2-Methyl-5,6-dihydro-4H-3-thia-1,6-diaza-benzo[e]azulene Example E7.1 (2-Methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulen-6-yl)-phenyl-methanone

To a solution of 1-benzoyl-4-bromo-1,2,3,4-tetrahydrobenzo[b]azepin-5-one (1.0 g, 2.9 mmol) from Example E5.7 in ethanol (50 ml) was added thioacetamide (0.75 g, 10=01). The solution was stirred for 16 h. The resultant suspension was reduced in volume by evaporation and cooled. The precipitate was collected by filtration and the solid was washed with cold ethanol and dried to yield the title compound as a white solid (0.65 g, 70%).

Example E7.2 2-Methyl-5,6-dihydro-4H-3-thia-1,6-diaza-benzo[e]azulene

A suspension of (2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulen-6-yl)-phenyl-methanone from Example E7.1 (0.42 g, 1.3 mmol) in 6M hydrochloric acid (45 ml) was heated at reflux for 16 h. The solution was cooled and treated with saturated NaHCO3(aq) (100 ml). Additional solid NaHCO3 was added until the solution was basic. The mixture was extracted with dichloromethane and the organic extracts were dried and reduced in vacuo to yield the title compound as a yellow oil (0.21 g, 76%).

Example E8 4-(3,3-Dimethyl-butyl)-piperazine-1-carboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide Example E8.1 [4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-carbamic acid tert-butyl ester

A solution of 4-(tert-butoxycarbonylamino-methyl)-3-fluorobenzoic acid from Example E3.1 (538 mg, 2.0 mmol) and DMAP (220 mg, 1.8 mmol) in dichloromethane (20 ml) at room temperature was treated with DIEA (0.93 ml, 5.4 mmol) and WSCD (460 mg, 2.4 mmol), and the resulting solution was stirred at room temperature for 1 h. 3,6-Dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E2 (385 mg, 1.8 mmol) was added and the resulting solution was heated at reflux for 20 h and allowed to cool to room temperature. The solution was diluted with dichloromethane, washed with saturated NaHCO3 and brine and concentrated in vacuo. The residue was purified by preparative HPLC (eluant 10% methanol:90% dichloromethane) to yield the title compound (265 mg, 32%).

Example E8.2 (4-Aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride

[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-carbamic acid tert-butyl ester from Example E8.1 (237 mg, 0.51 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (205 mg, 100%).

Example E8.3 4-(3,3-Dimethyl-butyl)-piperazine-1-carboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide

DIEA (0.10 ml, 0.60 mmol) and 1,1′-carbonyldiimidazole (28 mg, 0.17 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E8.2 (57 mg, 0.14 mmol) in DMF (5.0 ml) and the mixture was stirred at room temperature for 4 h. 1-(3,3-Dimethyl-butyl)-piperazine dihydrochloride from Example E4 (38 mg, 0.16 mmol) was added and the mixture was stirred at room temperature for 24 h and concentrated in vacuo. The residue was dissolved in EtOAc and the resulting solution was washed with brine and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 10% methanol:90% dichloromethane) to give a white solid identified as the title compound (45 mg, 56%).

Example E9 4-(tert-Butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid

To a solution of 4-aminomethyl-cyclohexanecarboxylic acid (20.0 g, 127.39 mmol) in dioxan (400 ml) was added 1N KHCO3 (300 ml, 300=01) and di-tert-butyl dicarbonate (33.3 g, 129.57 mmol). The mixture was stirred for 18 h and concentrated in vacuo. The aqueous residue was washed with ether, then acidified with 1N KHSO4 and extracted with EtOAc (×3). The combined organic extracts were washed with water and brine and concentrated in vacuo to give a white solid identified as the title compound (31.9 g, 98%).

Example E10 Cyclopropanecarboxylic acid [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-amide Example E10.1 [4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester

A solution of 4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid from Example E9 (510 mg, 2.0 mmol) in dichloromethane (25 ml) at room temperature was treated with DIEA (0.70 ml, 4.0 mmol), PyBrop (2.40 g, 5.1 mmol), and 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (422 mg, 1.8 mmol) and the resulting solution was heated at reflux for 20 h and allowed to cool to room temperature. The solution was diluted with dichloromethane, washed with brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc) to yield the title compound (775 mg, 91%).

Example E10.2 (4-Aminomethyl-cyclohexyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride

A solution of [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester from Example E10.1 (775 mg, 1.63 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (655 mg, 100%).

Example E10.3 Cyclopropanecarboxylic acid [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-amide

DIEA (0.50 ml, 2.90 mmol) and cyclopropanecarbonyl chloride (0.045 ml, 0.50 mmol) were added to a solution of (4-aminomethyl-cyclohexyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E10.2 (220 mg, 0.53 mmol) in dichloromethane (5 ml). The mixture was stirred for 2 h then diluted with dichloromethane, washed with water and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia/10% methanol/90% dichloromethane) to give a white solid identified as the title compound (132 mg, 60%).

Example E11 3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene Example E11.1 1-Methyl-5-(2-nitro-phenylamino)-1H-pyrazole-4-carboxylic acid ethyl ester

Sodium hydride (60% dispersion in oil, 7.0 g, 170 mmol) was added portionwise to a suspension of 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (21.1 g, 125 mmol) in anhydrous THF (300 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 0.75 h then cooled to 0° C. 1-fluoro-2-nitrobenzene (17.6 g, 125 mmol) was added and the resultant suspension was stirred at room temperature for 18 h. EtOAc and 0.3M KHSO4 were added and separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant 50% hexanes/50% ethyl acetate) to yield the title compound (20.8 g, 58%).

Example E11.2 5-(2-Amino-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

1-Methyl-5-(2-nitro-phenylamino)-1H-pyrazole-4-carboxylic acid ethyl ester (20.8 g, 72 mmol) from Example E11.1 was dissolved in methanol (330 ml) and hydrogenated over 10% Pd/C catalyst for 4 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to give a white solid identified as the title compound (16.2 g, 87%).

Example E11.3 3-Methyl-4,9-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-10-one

Sodium(methylsulphinyl)methanide (29.7 mmol) was prepared from sodium hydride (60% dispersion in oil, 1.19 g, 29.7 mmol) and anhydrous dimethyl sulphoxide (7 ml) by heating at 65° C. until a solution was observed. To this was added a solution of 5-(2-amino-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester from Example E11.2 (3.63 g, 16.9 mmol) in anhydrous dimethyl sulphoxide (10 ml), and stirring continued at 65° C. for 2.5 h. The mixture was poured into ice (100 ml), and the resulting solid collected and purified by recrystallisation from methanol/EtOAc/60-80 pet ether to yield the title compound (1.46 g, 40%).

Example E11.4 3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene

To a suspension of 3-methyl-4,9-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-10-one from Example E11.3 (3.01 g, 14.1 mmol) in anhydrous THF (100 ml) at 0° C. was added lithium aluminium hydride (2.13 g, 56.2 mmol), and the resulting suspension was heated at reflux for 18 h, then allowed to cool to room temperature. The mixture was cooled to 0° C., 35% ammonia solution (10 ml) was added dropwise over 15 min and the mixture was stirred at room temperature for 30 min. The resulting suspension was filtered through Celite® filter agent and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% methanol:chloroform rising to 5% methanol:chloroform) to yield the title compound (1.60 g, 57%).

Example E12 [4-(Isobutylamino-methyl)-cyclohexyl]-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone

A solution of isobutyraldehyde (0.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E10.2 (1.88 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=396.4

Example E13 [4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-carbamic acid 4-nitro-benzyl ester

A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride (Compound number 149) (1.95 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=533.3

Example E14 (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-(4-hexylaminomethyl-cyclohexyl)-methanone

A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E10.2 (2.05 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=458.4

Example E15 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid Example E15.1 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid ethyl ester

3,3-Dimethylbutyraldehyde (5.26 ml, 42.0 mmol) was added to a solution of ethyl isonipecotate (6.6 g, 42.0 mmol) in methanol/acetic acid (99:1, v/v, 50 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (3.43 g, 54.6 mmol) was added, and the mixture was stirred at room temperature for 4 days then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 25% EtOAc:75% cyclohexane) to yield the title compound (7.16 g, 71%).

Example E15.2 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid

Lithium hydroxide monohydrate (1.37 g, 32.6 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid ethyl ester from Example E15.1 (7.16 g, 29.7 mmol) in THF (50 ml) and water (5 ml). The mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 90% dichloromethane:9% methanol:1% acetic acid) to yield the title compound (5.51 g, 87%).

Example E15a 1-Cyclopropylmethyl-piperidine-4-carboxylic acid

The title compound was prepared from cyclopropanecarboxaldehyde and ethyl isonipecotate using similar procedures to those described for Example E15.

Example E16 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid [4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-amide Example E16.1 4-(3,3-Dimethyl-butyl)-piperazine-4-carboxylic acid [4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-amide

HBTU (84 mg, 0.22 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid from Example E15 (42 mg, 0.17 mmol) in DMF (5 ml) and DIEA (to pH9). The mixture was stirred at room temperature for 1 h. (4-Aminomethyl-cyclohexyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride (Compound Number 150) (42 mg, 0.11 mmol) was added and the mixture was stirred at room temperature for 18 h. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 10% methanol:90% dichloromethane) to give a white solid identified as the title compound (34 mg, 57%).

Example E17 N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride

A solution of 4-({[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-carbamoyl}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound Number 228) (259 mg, 0.45 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (230 mg, 93%).

Example E18 N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-methanesulfonamide

A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (4-aminomethyl-cyclohexyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone (Compound number 149) (1.95 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=432.1

Example E19 N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-(1-methanesulfonyl-piperidin-4-yl)-acetamide

A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride from Example E17 (2.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=557.4

Example E20 2-(1-Acetyl-piperidin-4-yl)-N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-acetamide

A solution of acetyl chloride (0.39 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride from Example E17 (2.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=521.5

Example E21 1-Isobutyl-piperidine-4-carboxylic acid [4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-amide

A solution of isobutyraldehyde (0.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of piperidine-4-carboxylic acid [4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-amide hydrochloride (Compound number 238) (2.43 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=507.4

Example E22 N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-3-(1-hexyl-piperidin-4-yl)-propionamide

A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 237) (2.57 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=597.6/599.6

Example E23 4-({[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-carbamoyl}-methyl)-piperidine-1-carboxylic acid 4-nitro-benzyl ester

A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride from Example E17 (2.58 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=658.5

Example E24 4-(3,3-Dimethyl-butyl)-piperazine-1-carboxylic acid [4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-amide

DIEA (0.30 ml, 1.7 mmol) and 1,1′-carbonyldiimidazole (39 mg, 0.24 mmol) were added to a solution of (4-aminomethyl-cyclohexyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride (Compound number 149) (78 mg, 0.20 mmol) in DMF (4.0 ml) and the mixture was stirred at room temperature for 2 h. 1-(3,3-Dimethyl-butyl)-piperazine dihydrochloride from Example E4 (56 mg, 0.23 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc, washed with brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 10% methanol:90% dichloromethane) to give a white solid identified as the title compound (32 mg, 29%).

Example E25 3-Chloro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene Example E25.1 N-(4-Chloro-2-hydroxy-phenyl)-benzamide

2-Amino-5-chlorophenol (1.45 g, 10 mmol) was dissolved in EtOAc (30 ml) and water (20 ml). Sodium bicarbonate (1.25 g, 15 mmol) then benzoyl chloride (1.42 g, 10 mmol) were added and the mixture was stirred at room temperature for 1 h. The layers were partitioned and the organic layer was washed with brine, dried and concentrated in vacuo. The residue was triturated with diethyl ether to yield the title compound (2.05 g, 82%).

Example E25.2 (3-Chloro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-phenyl-methanone

N-(4-Chloro-2-hydroxy-phenyl)-benzamide from Example E25.1 (1.0 g, 4 mmol) was dissolved in acetonitrile (10 ml) and dichloromethane (15 ml). 1,3-Dibromopropane (3.26 g, 16 mmol), aliquat 336 (170 mg, 0.4 mmol) and sodium hydroxide (750 mg, 16 mmol) were added and the mixture was heated at 60° C. for 3 h. The solid was filtered off and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% EtOAc:70% hexane) to yield the title compound (783 mg, 83%).

Example E25.3 3-Chloro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene

(3-Chloro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-phenyl-methanone from Example E25.2 (783 mg, 2.7 mmol) was dissolved in dioxan (10 ml) and 6M HCl aqueous solution (50 ml) was added. The mixture was heated at reflux for 20 h then concentrated in vacuo and azeotroped with toluene. The residue was dissolved in diethyl ether and water, basified with NaHCO3 and the layers were partitioned. The organic layer was washed with brine, dried and concentrated in vacuo to yield the title compound (280 mg, 47%).

Example E26 N-Cyclohexyl-N′-methyl-benzene-1,2-diamine Example E26.1 Cyclohexyl-(2-nitro-phenyl)-amine

A mixture of 2-fluoronitrobenzene (5.0 g, 35.4 mmol), cyclohexylamine (4.5 ml, 39.0 mmol) and potassium carbonate (17.1 g, 124 mmol) in acetonitrile (100 ml) was heated at reflux for 2 days. The mixture was diluted with EtOAC, washed with water then brine, dried and partially concentrated in vacuo. The solid which precipitated was collected and washed with hexane to yield the title compound (6.7 g, 86%).

Example E26.2 N-Cyclohexyl-benzene-1,2-diamine

Cyclohexyl-(2-nitro-phenyl)-amine from Example E26.1 (3.0 g, 13.6 mmol) was dissolved in methanol (100 ml) and tin (II) chloride (12.9 g, 68.1 mmol) was added. The mixture was stirred for 20 h at room temperature then heated at reflux for 18 h and concentrated in vacuo. The residue was placed in EtOAC (100 ml), cooled down to 0° C. and pH was adjusted to 14 with conc. NH3. The precipitate was filtered off and washed with EtOAc. The filtrate was washed with 2M NH3, water then brine, dried and concentrated in vacuo to yield the title compound (2.25 g, 86%).

Example E26.3 N-Cyclohexyl-N′-methyl-benzene-1,2-diamine

Potassium carbonate (2.45 g, 17.7 mmol) and iodomethane (0.81 ml, 13.0 mmol) were added to a solution of N-cyclohexyl-benzene-1,2-diamine from Example E26.2 (2.25 g, 11.8 mmol) in DMF (10 ml). The mixture was stirred for 6 h at room temperature then poured into water and extracted with EtOAc. The organic layer was washed with water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% EtOAc:95% hexane) to yield the title compound (950 mg, 39%).

Example E27 3-Fluoro-4-hydroxy-benzoic acid ethyl ester

A solution of 3-fluoro-4-hydroxy-benzoic acid (5.16 g, 33.1 mmol) in ethanol (100 ml) was treated with conc. sulphuric acid (5 ml), and the mixture heated at reflux for 4 days. The volatiles were removed in vacuo, and the aqueous residue was basified with saturated NaHCO3 and extracted twice with diethyl ether. The combined organic extracts were dried and concentrated in vacuo to yield the title compound (5.16 g, 85%).

Example E28 2-Chloro-4-hydroxy-benzoic acid ethyl ester

A solution of 2-chloro-4-hydroxy-benzonitrile (5.0 g, 32.6 mmol) in ethanol (125 ml) was treated with conc. sulphuric acid (25 ml) and the mixture heated at reflux for 3 days. Conc. sulphuric acid (25 ml) was added and the mixture was heated at reflux for another 2 days. The volatiles were removed in vacuo, and the aqueous residue was basified with saturated NaHCO3 and extracted 4 times with diethyl ether. The combined organic extracts were dried and concentrated in vacuo to yield the title compound (2.5 g, 38%).

Example E29 4-Hydroxy-3-methyl-benzoic acid methyl ester

4-Amino-3-methyl-benzoic acid methyl ester (5.25 g, 32.0 mmol) was treated with a 35% solution of sulphuric acid (50 ml) and the mixture was stirred and heated until dissolution then cooled to 0° C. Sodium nitrite (2.82 g, 41.6 mmol) in water (50 ml) was added dropwise and the mixture was stirred for 5 min at 0° C. Urea was added to destroy the excess nitrite. Copper nitrate (121 g, 320 mmol) in water (11) was added then copper oxide (4.25 g, 32.0 mmol). The mixture was warmed up to room temperature over 30 min and extracted with EtOAc (×3). The organics were combined, washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% EtOAc:70% hexane) to yield the title compound (2.2 g, 42%).

Example E30 4-(3-Carboxy-propyl)-3-methyl-benzoic acid methyl ester Example E30.1 4-((E)-2-tert-Butoxycarbonyl-vinyl)-3-methyl-benzoic acid methyl ester

Tetrakis(triphenylphosphine)palladium (0) (5.0 g, 4.33 mmol) was added to a stirred solution of methyl 4-bromo-3-methylbenzoate (9.93 g, 43.3 mmol), tert-butyl acrylate (50 ml, 341.3 mmol) and sodium acetate (35.8 g, 436.4 mmol) in DMA (350 ml). The mixture was heated at 140° C. for 5 h, filtered through Celite® filter agent and the filtrate was concentrated in vacuo. The residue was redissolved in EtOAc, washed with 0.3M KHSO4 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 15% EtOAc:85% hexane to 20% EtOAc:80% hexane) to yield the title compound (4.81 g, 40%).

Example E30.2 4-(2-tert-Butoxycarbonyl-ethyl)-3-methyl-benzoic acid methyl ester

4-((E)-2-tert-Butoxycarbonyl-vinyl)-3-methyl-benzoic acid methyl ester from Example E30.1 (4.00 g, 14.5 mmol) was dissolved in methanol (100 ml) and hydrogenated over 10% Pd/C catalyst (480 mg) for 5 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to yield the title compound (3.41 g, 84%).

Example E30.3 4-(2-Carboxy-ethyl)-3-methyl-benzoic acid methyl ester

Trifluoroacetic acid (40 ml) was added slowly to a stirred solution of 4-(2-tert-butoxycarbonyl-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.2 (4.9 g, 17.6 mmol) in dichloromethane (80 ml) at room temperature. The mixture was stirred for 2 h then concentrated in vacuo and azeotroped with dichloromethane. The residue was recrystallised in EtOAc to yield the title compound (2.77 g, 71%).

Example E30.4 4-(3-Carboxy-propyl)-3-methyl-benzoic acid methyl ester

4-(2-Carboxy-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.3 (500 mg, 2.25 mmol) was dissolved in dry dichloromethane (10 ml) and a few drops of DMF. Oxalyl chloride (0.393 ml, 4.5 mmol) was added dropwise and the mixture was stirred for 1 h at room temperature. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in acetonitrile (20 ml) and cooled to 0° C. A solution of 2M (trimethylsilyl)diazomethane in hexanes (2.25 ml, 4.5 mmol) was added dropwise and the reaction mixture was stirred for 5 h at 0° C. then 20 h at room temperature. Ethyl acetate then 10% citric acid solution were added and the layers were partitioned. The organic layer was washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% ethyl acetate:50% cyclohexane). The product obtained was dissolved in a mixture of acetonitrile and water. A solution of silver benzoate (103 mg, 0.45 mmol) in triethylamine (1.25 ml, 9 mmol) was added gradually while the mixture was sonicated in an ultrasound bath. After 30 min at room temperature, solvents were removed in vacuo. Ethyl acetate and 10% aqueous citric acid solution were added and the layers were partitioned. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% cyclohexane) to yield the title compound (378 mg, 71%).

Example E31 4-(4-Methoxycarbonyl-butyl)-3-methyl-benzoic acid Example E31.1 4-Bromo-3-methyl-benzoic acid tert-butyl ester

4-Bromo-3-methyl-benzoic acid (2.06 g, 9.6 mmol) and thionyl chloride (2.2 ml, 30.2 mmol) in toluene (50 ml) were heated at reflux for 2 h then concentrated in vacuo and azeotroped with toluene. The residue was dissolved in THF (100 ml) and triethylamine (2.8 ml, 20.1 mmol), cooled down to 0° C. and lithium tert-butoxide (1.24 g, 15.5 mmol) was added portionwise. The mixture was stirred for 18 h at room temperature then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M HCl, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% EtOAc:95% pet. ether) to yield the title compound (1.86 g, 71%).

Example E31.2 4-((1E,3E)-4-Methoxycarbonyl-buta-1,3-dienyl)-3-methyl-benzoic acid tert-butyl ester

Tetrakis(triphenylphosphine)palladium (0) (852 mg, 0.7 mol) was added to a stirred solution of 4-bromo-3-methyl-benzoic acid tert-butyl ester from Example E31.1 (1.86 g, 6.8 mmol), 1-acetoxy-1,3-butadiene (7.5 ml, 64.5 mmol) and sodium acetate (5.69 g, 69.4 mmol) in DMA (75 ml). The mixture was heated at 140° C. for 3 h, filtered through Celite® filter agent and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% pet. ether) to yield the title compound (1.54 g, 74%).

Example E31.3 4-(4-Methoxycarbonyl-butyl)-3-methyl-benzoic acid tert-butyl ester

4-((1E,3E)-4-Methoxycarbonyl-buta-1,3-dienyl)-3-methyl-benzoic acid tert-butyl ester from Example E31.2 (1.54 g, 5.1 mmol) was dissolved in methanol (40 ml) and hydrogenated over 10% Pd/C catalyst (200 mg) for 5 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to yield the title compound (1.43 g, 92%).

Example E31.4 4-(4-Methoxycarbonyl-butyl)-3-methyl-benzoic acid

Trifluoroacetic acid (20 ml) was added to a solution of 4-(4-methoxycarbonyl-butyl)-3-methyl-benzoic acid tert-butyl ester from Example E31.3 (1.43 g, 4.7 mmol) in dichloromethane (40 ml) and the mixture was stirred for 2 h at room temperature. Solvents were concentrated in vacuo and azeotroped with dichloromethane to yield the title compound (1.07 g, 92%).

Example E32 4-Carboxymethyl-3-methyl-benzoic acid methyl ester Example E32.1 4-tert-Butoxycarbonylmethyl-3-methyl-benzoic acid methyl ester

Copper (II) fluoride (4.08 g, 40.1 mmol) and bis-[tri-(o-tolyl)phosphine]palladium dichloride (473 mg, 0.6 mmol) were added to a solution of methyl 4-bromo-3-methyl benzoate (4.60 g, 20.1 mmol) in THF (30 ml). The mixture was heated at reflux before silyl ketene acetal (18.5 g, 80.3 mmol) was added. The mixture was heated at reflux for 2 days then diluted with Et2O. Aqueous NH4Cl solution (250 ml) was added and the mixture was stirred for 30 min at room temperature. The layers were partitioned and the aqueous layer extracted twice with Et2O. The organics were combined, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% EtOAc:95% hexane) to yield the title compound (2.84 g, 53%).

Example E32.2 4-Carboxymethyl-3-methyl-benzoic acid methyl ester

Trifluoroacetic acid (15 ml) was added to a solution of 4-tert-butoxycarbonylmethyl-3-methyl-benzoic acid methyl ester from Example E32.1 (2.84 g, 10.7 mmol) in dichloromethane (15 ml). The mixture was stirred for 90 min at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was recrystallised from EtOAc and hexane to yield the title compound (1.81 g, 81%).

Example E33 4-[1,3]-Dioxolan-2-yl-piperidine Example E33.1 4-Hydroxymethyl-piperidine-1-carboxylic acid benzyl ester

4-Piperidinemethanol (5.0 g, 43 mmol) was dissolved in dichloromethane (100 ml) and triethylamine (12 ml, 86 mmol) at 0° C. Benzylchloroformate (6.8 ml, 47.3 mmol) was added and the mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was redissolved in EtOAc, washed with 1M KHSO4, water then brine, dried and concentrated in vacuo to yield the title compound (8.33 g, 77%).

Example E33.2 4-Formyl-piperidine-1-carboxylic acid benzyl ester

Dess-Martin reagent (17 g, 39.6 mmol) was added portionwise to a solution of 4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester from Example E33.1 (8.33 g, 33 mmol) in dichloromethane (100 ml) at room temperature. The mixture was stirred for 3 h under an inert atmosphere then diluted with chloroform and water and the layers were partitioned. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 40% EtOAc:60% hexane) to yield the title compound (5.5 g, 66%).

Example E33.3 4-[1,3]Dioxolan-2-yl-piperidine-1-carboxylic acid benzyl ester

Ethylene glycol (5 ml) and a catalytic amount of p-toluenesulfonic acid were added to 4-formyl-piperidine-1-carboxylic acid benzyl ester from Example E33.2 (5.6 g, 22.6 mmol) in toluene (100 ml) and the mixture was heated at reflux under Dean and Stark conditions for 2.5 h. Solvents were removed in vacuo and the residue was redissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% pet. ether) to yield the title compound (5.14 g, 78%).

Example E33.4 4-[1,3]Dioxolan-2-yl-piperidine

4-[1,3]Dioxolan-2-yl-piperidine-1-carboxylic acid benzyl ester from Example E33.3 (5.14 g, 17.7 mmol) was dissolved in methanol (100 ml) and hydrogenated over 10% Pd/C catalyst (551 mg) for 4 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to yield the title compound (2.84 g, 100%).

Example E34 4-(3-Hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester

A solution of piperazine-1-carboxylic acid tert-butyl ester (26.5 g, 142 mmol) in acetone (300 ml) at room temperature was treated with 3-bromo-propan-1-ol (14.5 ml, 156.2 mmol), potassium carbonate (50 g, 361.8 mmol) and potassium iodide (2.4 g, 14.2 mmol), and the mixture was heated at reflux for 18 h then allowed to cool to room temperature. The suspension was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (27.7 g, 80%).

Example E35 1-Cyclopropylmethyl-imidazolidine ditrifluoroacetate Example E35.1 [2-(Cyclopropylmethyl-amino)-ethyl]-carbamic acid tert-butyl ester

Potassium hydrogen carbonate (220 mg, 2.2 mmol) and (bromoethyl)cyclopropane (270 mg, 2.0 mmol) were added to a solution of tert-butyl-N-(2-aminoethyl)carbamate (320 mg, 2.0 mmol) in THF (10 ml). The mixture was heated at 66° C. for 20 h and solvents were concentrated in vacuo. The residue was dissolved in chloroform, washed with water, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% triethylamine:4% methanol:95% chloroform) to yield the title compound (130 mg, 30%).

Example E35.2 1-Cyclopropylmethyl-imidazolidine ditrifluoroacetate

Trifluoroacetic acid (5 ml) was added to a solution of [2-(cyclopropylmethyl-amino)-ethyl]-carbamic acid tert-butyl ester from Example E35.1 (180 mg, 0.84 mmol) in dichloromethane (3 ml) and the mixture was stirred for 75 min at room temperature. Solvents were removed in vacuo and azeotroped with toluene. The residue was placed in water (10 ml) and formaldehyde (37% w/w solution, 0.10 ml, 1.36 mmol) was added. The mixture was stirred for 6 days at room temperature, concentrated in vacuo, azeotroped with toluene then pet. ether to yield the title compound (255 mg, 86%).

Example E36 2-piperazin-1-yl-1-p-tolyl-ethanone dihydrochloride Example E36.1 4-(2-Oxo-2-p-tolyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester

2-Bromo-4-methylacetophenone (572 mg, 2.68 mmol) was added to a solution of piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.68 mmol) in dichloromethane (5 ml) and triethylamine (0.45 ml, 3.22 mmol). The mixture was stirred for 3 days at room temperature and solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 40% hexane:60% EtOAc) to yield the title compound (661 mg, 77%).

Example E36.2 2-piperazin-1-yl-1-p-tolyl-ethanone dihydrochloride

4-(2-Oxo-2-p-tolyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E36.1 (661 mg, 2.08 mmol) was dissolved in 4M HCl solution in dioxan (25 ml) at 0° C. and the mixture was stirred for 45 min at room temperature. Solvents were concentrated in vacuo and azeotroped with diethyl ether to yield the title compound (536 mg, 88%).

Example E37 2-Bromo-1-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-ethanone

Bromoacetyl bromide (0.52 ml, 6.0 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperazine hydrochloride from Example E4 (1.5 g, 5.7 mmol) in dichloromethane (20 ml) and triethylamine (3.57 ml, 25.6 mmol) at 0° C. The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (220 mg, 13%).

Example E38 Cyclopropyl-piperidin-4-ylmethyl-carbamic acid tert-butyl ester Example E38.1 4-Cyclopropylaminomethyl-piperidine-1-carboxylic acid benzyl ester

Cyclopropylamine (1.4 g, 24.4 mmol) and acetic acid (0.5 ml) were added to a solution of 4-formyl-piperidine-1-carboxylic acid benzyl ester from Example E33.2 (5.5 g, 22.2 mmol) in methanol (49.5 ml) and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (1.84 g, 28.9 mmol) was added and the mixture was stirred for 20 h at room temperature under an inert atmosphere. Solvents were removed in vacuo and azeotroped with toluene. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield the title compound (3.0 g, 47%).

Example E38.2 4-[(tert-Butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidine-1-carboxylic acid benzyl ester

DMAP (127 mg, 1.04 mmol) and di-tert-butyl dicarbonate (3.4 g, 12.5 mmol) were added to a solution of 4-cyclopropylaminomethyl-piperidine-1-carboxylic acid benzyl ester from Example E38.1 (3.0 g, 10.4 mmol) in dichloromethane (50 ml) and triethylamine (to pH9). The mixture was stirred for 20 h at room temperature then concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 40% EtOAc:60% hexane) to yield the title compound (3.67 g, 92%).

Example E38.3 Cyclopropyl-piperidin-4-ylmethyl-carbamic acid tert-butyl ester

4-[(tert-Butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidine-1-carboxylic acid benzyl ester from Example E38.2 (3.67 g, 9.4 mmol) was dissolved in methanol (100 ml) and hydrogenated over 10% Pd/C catalyst (3 g) for 1 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to yield the title compound (2.07 g, 87%).

Example E39 4-[3-(4-Carboxy-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester Example E39.1 4-[3-(4-Ethoxycarbonyl-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester

Triphenylphosphine polystyrene (loading 1.0 mmol/g, 11 g, 11.0 mmol) and DEAD (2.45 g, 11.0 mmol) were added to a solution of 3-fluoro-4-hydroxy-benzoic acid ethyl ester from Example E27 (1.3 g, 7.4 mmol) and 4-(3-hydroxypropyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E34 (1.8 g, 7.4 mmol) in tetrahydrofuran (100 ml) at 0° C. The suspension was allowed to warm to room temperature and stirred for 18 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAC) to yield the title compound (1.7 g, 57%).

Example E39.2 4-[3-(4-Carboxy-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester

A solution of 4-[3-(4-ethoxycarbonyl-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E39.1 (1.7 g, 4.1 mmol) in dioxan (25 ml) was treated with 2N NaOH (3 ml) and the mixture stirred at 50° C. for 18 h. A further aliquot of 2N NaOH was added (2 ml), and stirring continued at 50° C. for 3 h. Solvents were removed in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel (eluant; 1% acetic acid:9% methanol:90% chloroform) to yield the title compound (1.45 g, 92%).

Example E40 4-{2-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-ethoxy}-3-methyl-benzoic acid Example E40.1 4-[2-(4-Methoxycarbonyl-2-methyl-phenoxy)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester

4-(2-Hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.2 mmol) was dissolved in THF (30 ml) and cooled down to 0° C. Polymer-supported triphenylphosphine (2.2 g, 2.2 mmol), DEAD (378 mg, 2.2 mmol) and 4-hydroxy-3-methyl-benzoic acid methyl ester from Example E29 (361 mg, 2.2 mmol) were added and the mixture was stirred for 20 h at room temperature. The resin was filtered off and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (495 mg, 60%).

Example E40.2 3-Methyl-4-(2-piperazin-1-yl-ethoxy)-benzoic acid methyl ester dihydrochloride

4-[2-(4-Methoxycarbonyl-2-methyl-phenoxy)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E40.1 (200 mg, 0.53 mmol) was dissolved in 4M HCl solution in dioxan (5 ml). The mixture was stirred for 30 min at room temperature, concentrated in vacuo and azeotroped with toluene to yield the title compound (185 mg, 100%).

Example E40.3 4-{2-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-ethoxy)}-3-methyl-benzoic acid methyl ester

3,3-Dimethylbutyraldehyde (54 mg, 0.53 mmol) was added to a solution of 3-methyl-4-(2-piperazin-1-ylethoxy)-benzoic acid methyl ester dihydrochloride from Example E40.2 (146 mg, 0.42 mmol) in methanol/acetic acid (99:1, v/v, 10 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (42 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3, water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (64 mg, 34%).

Example E40.4 4-{2-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-ethoxy}-3-methyl-benzoic acid

4-{2-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-ethoxy}-3-methyl-benzoic acid methyl ester from Example E40.3 (42 mg, 0.12 mmol) was dissolved in dioxan (5 ml) and 1M NaOH (1 ml) was added. The mixture was heated at reflux for 2 h then solvents were concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3, water then brine, dried and concentrated in vacuo to yield the title compound (40 mg, 100%).

Example E41 4-{2-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-2-oxo-ethoxy}-3-methyl-benzoic acid Example E41.1 4-tert-Butoxycarbonylmethoxy-3-methyl-benzoic acid methyl ester

Potassium carbonate (4.6 g, 33 mmol), potassium iodide (0.25 g, 1.5 mmol) and tert-butylbromoacetate (2.5 ml, 16.5 mmol) were added to a solution of 4-hydroxy-3-methyl-benzoic acid methyl ester from Example E29 (2.5 g, 15 mmol) in acetone (150 ml) and the mixture was heated at reflux for 20 h. The solid was filtered off and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1N KHSO4, water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 15% EtOAc:85% hexane) to yield the title compound (3.8 g, 90%).

Example E41.2 4-Carboxymethoxy-3-methyl-benzoic acid methyl ester

Trifluoroacetic acid (20 ml) was added to a solution of 4-tert-butoxycarbonylmethoxy-3-methyl-benzoic acid methyl ester from Example E41.1 (3.8 g, 13.6 mmol) in dichloromethane (40 ml) and the mixture was stirred for 1 h at room temperature. Volatiles were removed in vacuo and azeotroped with dichloromethane to yield the title compound (3.04 g, 100%).

Example E41.3 4-{2-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-2-oxo-ethoxy}-3-methyl-benzoic acid methyl ester

WSCD (5.14 g, 27.2 mmol) and DMAP (1.64 g, 13.6 mmol) were added to a solution of 4-carboxymethoxy-3-methyl-benzoic acid methyl ester from Example E41.2 (3.04 g, 13.6 mmol) in dichloromethane (100 ml) and triethylamine (5 ml). The mixture was stirred for 1 h at room temperature then 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (3.67 g, 14.9 mmol) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (2.8 g, 55%).

Example E41.4 4-{2-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-2-oxo-ethoxy}-3-methyl-benzoic acid

1M Boron tribromide solution (2.66 ml, 2.66 mmol) was added dropwise to a solution of 4-{2-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-2-oxo-ethoxy}-3-methyl-benzoic acid methyl ester from Example E41.3 (500 mg, 1.33 mmol) in dichloromethane (20 ml) at 0° C. under an inert atmosphere. The mixture was stirred for 20 h at room temperature then cooled down to 0° C. 1M Boron tribromide solution (1.33 ml, 1.33 mmol) was added and the mixture was stirred for 2 h at room temperature. Solvents were removed in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel (eluant; 1% acetic acid:5% methanol:94% chloroform) to yield the title compound (350 mg, 72%).

Example E41a 4-(2-Bromo-acetyl)-piperazine-1-carboxylic acid tert-butyl ester

A solution of bromoacetyl bromide (8.5 ml, 97 mmol) in DCM (250 ml) at 0° C. was treated dropwise with a solution of 1-Boc-piperazine (15.9, 85.3 mmol) and triethylamine (18.0 ml, 130 mmol) in DCM (150 ml). After addition was complete, the mixture was stirred at room temperature for 4 h. The solution was washed with ice-cold 1M HCl, sat. aq. NaHCO3, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% cyclohexane to 50% EtOAc:50% cyclohexane) to yield the title compound (15.7 g, 60.0%).

Example E41b 2-Chloro-4-hydroxy-benzoic acid methyl ester Example E41b.1 4-Amino-2-chloro-benzoic acid methyl ester

A solution of 4-Amino-2-chloro-benzoic acid (5.3 g, 31 mmol) in methanol (100 ml) was treated with acetyl chloride (5 ml) and then heated at reflux for 16 hours. The solvents were evaporated in vacuo. The residue was dissolved in EtOAc, washed with saturated sodium hydrogen carbonate, dried and concentrated in vacuo to yield the title compound as a purple solid, 5.45 g, 95%.

Example E41b.2 2-Chloro-4-hydroxy-benzoic acid

4-Amino-2-chloro-benzoic acid methyl ester from Example E41b.1 (5.45 g, 29.4 mmol) was treated with a 35% solution of sulphuric acid (120 ml) and the mixture was stirred and heated until dissolution then cooled to 0° C. Sodium nitrite (4.30 g, 62.5 mmol) in water (25 ml) was added dropwise and the mixture was stirred for 15 min at 0° C. Urea was added to destroy the excess nitrite. Copper nitrate (200 mg, 0.83 mmol) was added and heated to 90° C. The reaction mixture was cooled to room temperature, extracted into ethyl acetate ×3, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% EtOAc:70% hexane to 50% EtOAc:49% hexane:1% AcOH) to yield the title compound (3.7 g, 73%).

Example E41b.3 2-Chloro-4-hydroxy-benzoic acid methyl ester

A solution of 2-chloro-4-hydroxy-benzoic acid (3.70 g, 21.4 mmol)) in methanol (50 ml) was treated with thionyl chloride (2.4 ml, 32 mmol) dropwise and stirred for 24 hours and the solvents were removed in vacuo. The residue was dissolved in ethyl acetate and washed with sat. sodium hydrogen carbonate, dried and solvents were removed in vacuo. The residue was purified by column chromatography on silica gel (eluant with 30% EtOAc:70% cyclohexane) to yield the desired product as a yellow solid, 3.68 g, 92%.

Example E41c 4-[2-(4-Carboxy-3-chloro-phenoxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester Example E41c.1 4-[2-(3-Chloro-4-methoxycarbonyl-phenoxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester

2-Chloro-4-hydroxy-benzoic acid methyl ester from example E41b (2.0 g, 10.9 mmol) and 4-(2-Bromo-acetyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E41a (3.68 g, 12.0 mmol) in acetonitrile (30 ml) were treated with potassium carbonate (1.6 g, 11.5 mmol), and the mixture heated at reflux 18 h. before the solvents were removed in vacuo. The residue was adsorbed onto silica gel and purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% cyclohexane to 50% EtOAc:50% cyclohexane to 70% EtOAc:30% cyclohexane) to yield the title compound (4.5 g, 100%).

Example E41c.2 4-[2-(4-Carboxy-3-chloro-phenoxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester

A solution of 4-[2-(3-Chloro-4-methoxycarbonyl-phenoxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E41c.1 (4.5 g, 10.8 mmol) in THF at 0° C. was treated with potassium trimethylsilanolate (1.6 g, 10.9 mmol), and the mixture stirred at room temperature for 18 h. A further 1.6 g (10.9 mmol) potassium silanolate was added, and stirring continued at room temperature for 2 h. A further 1.6 g (10.9 mmol) potassium silanolate was added, and the mixture was stirred at 45° C. for 2 h. The mixture was then diluted with water and THF was removed in vacuo. The residue was washed with ether, cooled in an ice-bath and adjusted to pH5 with solid KHSO4 whereupon it was extracted with CHCl3 and CHCl3/isopropanol (90:10 v/v). The combined organics were dried and solvents were removed in vacuo to yield the title compound (3.7 g, 85%).

Example E42 4-(3-tert-Butoxycarbonyl-propoxy)-3-methyl-benzoic acid Example E42.1 4-Bromo-butyric acid tert-butyl ester

1M Boron tribromide (39 ml, 39 mmol) was added to a solution of butyrolactone (3 ml, 39 mmol) in dichloromethane (30 ml). The mixture was stirred for 20 h at room temperature then quenched with an excess of tert-butylalcohol. The mixture was stirred for 2 h at room temperature, diluted with dichloromethane, washed with saturated NaHCO3, saturated Na2S2O3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 5% EtOAc:95% hexane) to yield the title compound (3 g, 34%).

Example E42.2 4-(3-tert-Butoxycarbonyl-propoxy)-3-methyl-benzoic acid methyl ester

Potassium carbonate (580 mg, 4.20 mmol) and potassium iodide (72 mg, 0.43 mmol) were added to a solution of 4-hydroxy-3-methyl-benzoic acid methyl ester from Example E29 (293 mg, 1.76 mmol) and 4-bromo-butyric acid tert-butyl ester from Example E42.1 (397 mg, 1.78 mmol) in acetone (50 ml). The mixture was heated at reflux for 18 h then the solid was filtered off and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc, washed with water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% pet. ether) to yield the title compound (414 mg, 76%).

Example E42.3 4-(3-tert-Butoxycarbonyl-propoxy)-3-methyl-benzoic acid

Lithium hydroxide monohydrate (137 mg, 3.26 mmol) was added to a solution of 4-(3-tert-butoxycarbonyl-propoxy)-3-methyl-benzoic acid methyl ester from Example E42.2 (414 mg, 1.34 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 48 h at room temperature and concentrated in vacuo. The residue was dissolved in chloroform, acidified with 1M HCl then washed with brine, dried and concentrated in vacuo to yield the title compound (275 mg, 70%).

Example E43 4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid Example E43.1 4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid methyl ester

HBTU (910 mg, 2.4 mmol) was added to a solution of 4-(3-carboxy-propyl)-3-methyl-benzoic acid methyl ester from Example E30 (378 mg, 1.6 mmol) and 1-(3,3-dimethyl-butyl)-piperazine hydrochloride from Example E4 (467 mg, 1.9 mmol) in dichloromethane (15 ml) and DIEA (0.836 ml, 4.8 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 5% methanol:95% dichloromethane) to yield the title compound (582 mg, 94%).

Example E43.2 4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid

Lithium hydroxide monohydrate (108 mg, 2.6 mmol) was added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid methyl ester from Example E43.1 (500 mg, 1.3 mmol) in THF (12 ml) and water (6 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% acetic acid:4% methanol:94% dichloromethane) then recrystallised from chloroform and pet. ether to yield the title compound (439 mg, 91%).

Example E44 4-{3-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid Example E44.1 4-{3-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid methyl ester

Oxalyl chloride (2.6 ml, 30 mmol) was added slowly to a solution of 4-(2-carboxy-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.3 (5.33 g, 24 mmol) in dichloromethane (60 ml) and few drops of DMF at 0° C. The mixture was stirred for 2 h at room temperature then concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (30 ml) and added to a solution of 1-(3,3-dimethyl-butyl)-piperazine hydrochloride from Example E4 (6.3 g, 26 mmol) in dichloromethane (45 ml) and DIEA (17 ml, 96 mmol) at 0° C. The mixture was stirred for 1 h at room temperature then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (8.5 g, 96%).

Example E44.2 4-{3-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid

Lithium hydroxide monohydrate (2.4 g, 56.7 mmol) was added to a solution of 4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid methyl ester from Example E44.1 (8.5 g, 22.7 mmol) in THF (200 ml) and water (100 ml). The mixture was stirred for 24 h at room temperature then solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% acetic acid:4% methanol:94% dichloromethane) to yield the title compound (8.1 g, 99%).

Example E45 3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid Example E45.1 4-((E)-2-tert-Butoxycarbonyl-vinyl)-3-methyl-benzoic acid

Lithium hydroxide monohydrate (384 mg, 9.2 mmol) was added to a solution of 4-((E)-2-tert-butoxycarbonyl-vinyl)-3-methyl-benzoic acid methyl ester from Example E30.1 (1.27 g, 4.6 mmol) in THF (50 ml) and water (20 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was dissolved in EtOAc, washed with 1M KHSO4, water then brine, dried and concentrated in vacuo to yield the title compound (1.1 g, 92%).

Example E45.2 (E)-3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-acrylic acid tert-butyl ester

4-((E)-2-tert-Butoxycarbonyl-vinyl)-3-methyl-benzoic acid from Example E45.1 (1.1 g, 4.2 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (720 mg, 3.6 mmol) were dissolved in dichloromethane (50 ml) and triethylamine (0.75 ml). DMAP (4.45 g, 3.6 mmol) and WSCD (1.36 g, 7.1 mmol) were added and the mixture was heated at reflux for 2 days. The solution was diluted with dichloromethane, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (1.35 g, 82%).

Example E45.3 3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid tert-butyl ester

(E)-3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-acrylic acid tert-butyl ester from Example E45.2 (436 mg, 0.99 mmol) was dissolved in methanol (40 ml) and hydrogenated over 10% Pd/C catalyst (91 mg) for 5 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo and azeotroped with dichloromethane to yield the title compound (426 mg, 96%).

Example E45.4 3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid

Trifluoroacetic acid (5 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid tert-butyl ester from Example E45.3 (413 mg, 0.92 mmol) in dichloromethane (10 ml) and the mixture was stirred for 45 min at room temperature. Solvents were removed in vacuo and azeotroped with dichloromethane. The residue was crystallised with MeOH/Et2O to yield the title compound (322 mg, 90%).

Example E46 (E)-3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-acrylic acid

Trifluoroacetic acid (5 ml) was added to a solution of (E)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-acrylic acid tert-butyl ester from Example E45.2 (338 mg, 0.76 mmol) in dichloromethane (10 ml) and the mixture was stirred for 45 min at room temperature. Solvents were removed in vacuo and azeotroped with dichloromethane to yield the title compound (337 mg, 80%).

Example E47 3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-1-piperazin-1-yl-propan-1-one Example E47.1 4-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperazine-1-carboxylic acid tert-butyl ester

PyBroP (1.54 g, 3.3 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (850 mg, 2.25 mmol) and DMAP (275 mg, 2.25 mmol) in dichloromethane (20 ml) and DIEA (0.90 ml, 5.2 mmol). The mixture was stirred for 15 mins at room temperature then 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (450 mg, 2.25 mmol) was added. The mixture was heated at reflux for 18 h, diluted with dichloromethane, washed with 0.3M KHSO4 solution then saturated NaHCO3, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% EtOAc) to yield the title compound (1.09 g, 87%).

Example E47.2 3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-1-piperazin-1-yl-propan-1-one

4-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperazine-1-carboxylic acid tert-butyl ester from Example E47.1 (1.09 g, 1.95 mmol) was dissolved in methanol (20 ml) and 4M HCl/dioxan solution (20 ml) was added. The mixture was stirred for 3 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in methanol (30 ml) and ammonia (5 ml) then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 0.5% 35% ammonia:4.5% methanol:95% dichloromethane to 1% 35% ammonia:9% methanol:90% dichloromethane) to yield the title compound (759 mg, 73%).

Example E48 {4-[3-(4-Cyclopropyl-piperazin-1-yl)-propoxy]-3-fluorophenyl}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone Example E48.1 4-(3-Bromo-propoxy)-3-fluoro-benzoic acid ethyl ester

1,3-Dibromopropane (2.2 g, 11.0 mmol), potassium carbonate (1.86 g, 13.6 mmol) and potassium iodide (90 mg, 0.5 mmol) were added to 3-fluoro-4-hydroxy-benzoic acid ethyl ester from Example E27 (1.0 g, 5.4 mmol) in acetone (25 ml) and the mixture was heated at reflux for 20 h. The solid was filtered off and washed with EtOAc. The filtrate was concentrated in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% hexane) to yield the title compound (1.18 g, 71%).

Example E48.2 4-[3-(4-Cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-benzoic acid ethyl ester

1-Cyclopropyl-piperazine dihydrochloride (642 mg, 3.2 mmol, according to the procedure described by G. S. Poindexter, M. A. Bruce, K. L. Le Boulluec, I. Monkovic, Tet. Lett., 35(44), 7331-7334, 1994), potassium carbonate (2.1 g, 15.2 mmol) and potassium iodide (50 mg, 0.3 mmol) were added to 4-(3-bromo-propoxy)-3-fluorobenzoic acid ethyl ester from Example E48.1 (1.2 g, 3.9 mmol) in acetone (25 ml). The mixture was heated at reflux for 20 h. The solid was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc then 1% 35% ammonia:9% methanol:90% dichloromethane) to yield the title compound (1.0 g, 89%).

Example E48.3 4-[3-(4-Cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-benzoic acid

4-[3-(4-Cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-benzoic acid ethyl ester from Example E48.2 (1.0 g, 2.9 mmol) was dissolved in dioxan (10 ml) and 2N NaOH solution (3 ml, 6.0 mmol) was added. The mixture was heated at 60° C. for 18 h then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:19% methanol:80% dichloromethane) to yield the title compound (920 mg, 100%).

Example E48.4 {4-[3-(4-Cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-phenyl}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone

HBTU (325 mg, 0.9 mmol) and 4M HCl in dioxan (0.45 ml, 1.8 mmol) were added to a solution of 4-[3-(4-cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-benzoic acid from Example E48.3 (230 mg, 0.7 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 30 min. 3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E65 (186 mg, 0.9 mmol) and DIEA (pH=9) were added and the mixture was stirred at room temperature for 18 h. The mixture was heated at 60° C. for 3 h then HBTU (300 mg, 0.8 mmol) was added. The mixture was heated at 60° C. for 2 days then solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in EtOAc, washed with saturated Na—HCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a brown solid identified as the title compound (55 mg, 15%).

Example E49 [3-Fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone dihydrochloride Example E49.1 4-{3-[2-Fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester

A solution of 4-[3-(4-carboxy-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E39 (865 mg, 2.3 mmol) in dichloromethane (50 ml) was treated with triethylamine (to pH9), WSCD (865 mg, 4.5 mmol) and DMAP (276 mg, 2.3 mmol), and the mixture was stirred at room temperature for 10 min. 3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (541 mg, 2.7 mmol) was added. The mixture was heated at reflux for 18 h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3 then brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield the title compound (615 mg, 48%).

Example E49.2 [3-Fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone dihydrochloride

A solution of 4-{3-[2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester from Example E49.1 (615 mg, 1.09 mmol) in methanol (2 ml) at 0° C. was treated with 4N HCl in dioxan (5 ml). The solution was allowed to warm to room temperature and stirred for 1 h. Solvents were removed in vacuo to give a white foam identified as the title compound (585 mg, 100%).

Example E50 (4-{3-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluoro-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone bis(trifluoroacetate)

3,3-Dimethylbutyraldehyde (120 mg, 1.20 mmol) and triethylamine (to pH9) were added to a solution of [3-fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone dihydrochloride from Example E49 (585 mg, 1.09 mmol) in methanol/acetic acid (99:1, v/v, 20 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (103 mg, 1.30 mmol) was added and the mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield (4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluorophenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone, which was lyophilised from aqueous trifluoroacetic acid to give a white solid identified as the title compound (700 mg, 83%).

Example E51 (3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-{4-[3-(1-isobutyl-piperidin-4-yl)-propoxy]-3-methyl-phenyl}-methanone

A solution of isobutyraldehyde (0.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of (3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[3-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-methanone hydrochloride (2.6 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=530.5

Example E52 (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-{2-fluoro-4-[3-(4-hexyl-piperazin-1-yl)-propoxy]-phenyl}-methanone

A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of (6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[2-fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride from Example E5a (2.85 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=583.6

Example E53 1-(4-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-propyl}-piperazin-1-yl)-ethanone

A solution of acetyl chloride (0.39 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)=[3-methyl-4-(3-piperazin-1-yl-propoxy)-phenyl]-methasone dihydrochloride (Compound number 408) (2.67 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=503.2

Example E54 {4-[3-(4-Methanesulfonyl-piperazin-1-yl)-propoxy]-3-methyl-phenyl}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone

A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[3-methyl-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride (Compound number 408) (2.67 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=539.2

Example E55 1-(4-[1,3]Dioxolan-2-yl-piperidin-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propan-1-one

HBTU (327 mg, 0.86 mmol) was added to a solution of 4-[1,3]dioxolan-2-yl-piperidine from Example E33 (143 mg, 0.91 mmol) and 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (320 mg, 0.82 mmol) in dichloromethane (20 ml) and DIEA (0.7 ml, 4.02 mmol) and the mixture was stirred for 20 h at room temperature. Dichloromethane was added and the solution was washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 4% methanol:96% dichloromethane to 8% methanol:92% dichloromethane) to give a white solid identified as the title compound (359 mg, 83%).

Example E56 1-[4-(Furan-2-carbonyl)-piperazin-1-yl]-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propan-1-one

A solution of HBTU (1.90 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (1.95 mg, 0.005 mmol) in DMF (0.05 ml) and DIEA (0.0022 ml). The mixture was stirred at room temperature for 30 min then a solution of 1-(2-furoyl)piperazine (0.90 mg, 0.005 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 18 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=553.4

Example E57 (E)-3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-1-[4-(2-piperidin-1-yl-ethyl)-piperazin-1-yl]-propenone

A solution of HBTU (1.90 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of(E)-3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-acrylic acid from Example E46 (1.95 mg, 0.005 mmol) in DMF (0.05 ml) and DIEA (0.0022 ml). The mixture was stirred at room temperature for 30 min then a solution of 1-(2-Piperidin-1-yl-ethyl)-piperazine (0.99 mg, 0.005 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 18 h at room temperature then solvents were removed in vacuo to yield the title compound.

Example E58 1-{4-[(Butyl-methyl-amino)-methyl]-piperidin-1-yl}-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propan-1-one Example E58.1 1-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidine-4-carbaldehyde

Pyridinium p-toluenesulfonate (85 mg, 0.34 mmol) was added to a solution of 1-(4-[1,3]dioxolan-2-yl-piperidin-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propan-1-one from Example E55 (614 mg, 1.16 mmol) in acetone (20 ml) and water (20 ml). The mixture was heated at reflux for 7 days then solvents were removed in vacuo. The residue was redissolved in EtOAc, washed with 0.3M KHSO4 then brine, dried, concentrated in vacuo then crystallised with chloroform and pet. ether to yield the title compound (451 mg, 80%).

Example E58.2 1-{4-[(Butyl-methyl-amino)-methyl]-piperidin-1-yl}-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propan-1-one

A solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidine-4-carbaldehyde from Example E58.1 (2.43 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of butyl-methyl-amine (0.43 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and the mixture was heated at 50° C. for 3 h then stirred at room temperature for 2 days. A solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added and the mixture was stirred for 20 h at room temperature. Solvents were removed in vacuo to yield the title compound. MS: (ESI)+: [M+H]+=557.6

Example E59 3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-1-[4-(2-morpholin-4-yl-ethylamino)-piperidin-1-yl]-propan-1-one

A solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-one (Compound number 701) (2.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of 2-morpholin-4-yl-ethylamine (0.65 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and the mixture was heated at 50° C. for 3 h then stirred at room temperature for 2 days. A solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added and the mixture was stirred for 20 h at room temperature. Solvents were removed in vacuo to yield the title compound. MS: (ESI)+: [M+H]+=586.6

Example E60 1-(4-Hexyl-piperazin-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propan-1-one

A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-1-piperazin-1-yl-propan-1-one from Example E47 (2.29 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=543.4

Example E61 3-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-1-(4-propyl-piperazin-1-yl)-propan-1-one

A solution of propionaldehyde (0.29 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of 3-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-1-piperazin-1-yl-propan-1-one (2.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=515.5

Example E62 1-(4-Acetyl-piperazin-1-yl)-3-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-propan-1-one

A solution of acetyl chloride (0.39 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of 3-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-1-piperazin-1-yl-propan-1-one (2.47 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 20 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=535.5

Example E63 3-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-1-(4-methanesulfonyl-piperazin-1-yl)-propan-1-one

A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of 3-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-1-piperazin-1-yl-propan-1-one (2.36 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 20 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=551.3

Example E64 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-butan-1-one

4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid from Example E43 (139 mg, 0.37 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (75 mg, 0.37 mmol) were dissolved in dichloromethane (5 ml) and DIEA (0.195 ml, 1.11 mmol). WSCD (93 mg, 0.48 mmol) and DMAP (9 mg, 0.07 mmol) were added and the mixture was heated at reflux for 3 days, then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (11 mg, 5%).

Example E65 N-Benzyl-3-[4-(2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-propionamide Example E65.1 4-((E)-2-Methoxycarbonyl-vinyl)-benzoic acid

Sodium hydride (60% dispersion in oil, 1.46 g, 36.6 mmol) was added to a solution of 4-formylbenzoic acid (5.0 g, 33.3 mmol) in toluene (200 ml) and the mixture was stirred for 2 h at room temperature. Methyl (triphenyl-phosphoranylidene)acetate (11.69 g, 35.0 mmol) was added and the mixture was heated at reflux for 20 h. Solvents were removed in vacuo and the residue was redissolved in dichloromethane and 1M NaHCO3. The layers were partitioned and the aqueous layer was acidified with 1M HCl solution then extracted with chloroform. The organic layer was dried and concentrated in vacuo to yield the title compound (3.65 g, 53%).

Example E65.2 (E)-3-[4-(2,3,4,5-Tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-acrylic acid methyl ester

WSCD (1.17 g, 6.16 mmol) was added to a solution of 4-((E)-2-methoxycarbonyl-vinyl)-benzoic acid from Example E65.1 (740 mg, 3.59 mmol), 2,3,4,5-tetrahydro-1H-benzo[b]azepine (445 mg, 3.02 mmol) and DMAP (370 mg, 3.02 mmol) in dichloromethane (40 ml) and triethylamine (0.7 ml, 5.02 mmol). The mixture was heated at reflux for 42 h then solvents were concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M KHSO4 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% EtOAc:70% pet. ether) to yield the title compound (484 mg, 48%).

Example E65.3 3-[4-(2,3,4,5-Tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-propionic acid methyl ester

(E)-3-[4-(2,3,4,5-Tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-acrylic acid methyl ester from Example E65.2 (485 mg, 1.44 mmol) was dissolved in methanol (60 ml) and hydrogenated over 10% Pd/C catalyst (214 mg) for 2 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to yield the title compound (415 mg, 85%).

Example E65.4 3-[4-(2,3,4,5-Tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-propionic acid

Lithium hydroxide monohydrate (114 mg, 2.72 mmol) was added to a solution of 3-[4-(2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-propionic acid methyl ester from Example E65.3 (415 mg, 1.23 mmol) in water (5 ml) and dioxan (20 ml). The mixture was stirred for 18 h at room temperature then concentrated in vacuo. The residue was dissolved in chloroform, washed with 1M HCl solution then brine, dried and concentrated in vacuo to yield the title compound (241 mg, 61%).

Example E65.5 N-Benzyl-3-[4-(2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-propionamide

A mixture of 3-[4-(2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-propionic acid from Example E65.4 (57 mg, 0.18 mmol) and thionyl chloride (0.2 ml, 2.74 mmol) in dichloromethane (6 ml) was heated at reflux for 2 h then volatiles were removed in vacuo. The residue was dissolved in dichloromethane (8 ml) then benzylamine (0.022 ml, 0.20 mmol) and triethylamine (0.05 ml, 0.36 mmol) were added. The mixture was stirred for 3 h at room temperature then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% pet. ether:70% EtOAc) to give a white fluffy solid identified as the title compound (36.5 mg, 50%).

Example E66 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-3-[2-methyl-4-(2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-phenyl]-propan-1-one

Oxalyl chloride (0.049 ml, 0.55 mmol) was added slowly to a solution of 4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid from Example E44 (100 mg, 0.28 mmol) in dichloromethane (10 ml) and few drops of DMF. The mixture was stirred for 1 h at room temperature then concentrated in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (10 ml) and DIEA (0.144 ml, 0.84 mmol) then 2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene from Example E5 (55 mg, 0.28 mmol) was added. The mixture was stirred for 20 h at room temperature then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white fluffy solid identified as the title compound (42 mg, 28%).

Example E67 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-3-[2-methyl-4-(6-methyl-3,4-dihydro-2E-quinoline-1-carbonyl)-phenyl]-propan-1-one

DMAP (51 mg, 0.42 mmol) and WSCD (161 mg, 0.84 mmol) were added to a solution of 4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid from Example E44 (150 mg, 0.42 mmol) in dichloromethane (10 ml) and triethylamine (0.176 ml, 1.26 mmol) and the mixture was stirred for 30 min at room temperature. 6-Methyl-1,2,3,4-tetrahydro-quinoline (67 mg, 0.46 mmol) was added and the mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was redissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (12 mg, 6%).

Example E68 (4-{3-[1-(3,3-Dimethyl-butyl)-piperidin-4-yl]-propoxy}-3-methyl-phenyl)-(3-methyl-4,10-dihydro-3E-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone Example E68.1 4-(3-Hydroxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester

4-(2-Carboxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.9 mmol, according to the procedure described in J. Med. Chem., 41(14), 2492, 1998) was dissolved in THF (50 ml) and cooled down to 0° C. 2M Borane solution in THF (3.9 ml, 7.8 mmol) was added slowly and the mixture was stirred for 20 h at room temperature. Water was added and solvents were concentrated in vacuo. The residue was dissolved in EtOAC, basified with NaHCO3, washed with brine, dried and concentrated in vacuo to yield the title compound (938 mg, 99%).

Example E68.2 4-[3-(4-Methoxycarbonyl-2-methyl-phenoxy)-propyl]-piperidine-1-carboxylic acid tert-butyl ester

4-(3-Hydroxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester from Example E68.1 (400 mg, 1.64 mmol) and 4-hydroxy-3-methyl-benzoic acid methyl ester from Example E29 (274 mg, 1.64 mmol) were dissolved in THF (30 ml) and cooled down to 0° C. Polymer-supported triphenylphosphine (1.7 g, 2.46 mmol) then DEAD (0.387 ml, 2.46 mmol) were added and the mixture was heated at reflux for 20 h. The resin was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 20% EtOAC:80% cyclohexane) to yield the title compound (340 mg, 53%).

Example E68.3 4-[3-(4-Carboxy-2-methyl-phenoxy)-propyl]-piperidine-1-carboxylic acid tert-butyl ester

2M NaOH solution (1.25 ml, 2.5 mmol) was added to 4-[3-(4-methoxycarbonyl-2-methyl-phenoxy)-propyl]-piperidine-1-carboxylic acid tert-butyl ester from Example E68.2 (340 mg, 0.87 mmol) in dioxan (10 ml) and the mixture was heated at 60° C. for 20 h. 2M NaOH solution (5 ml, 10 mmol) was added and the mixture was heated at 60° C. for 20 h then concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 1% acetic acid:9% methanol:90% dichloromethane) to yield the title compound (303 mg, 92%).

Example E68.4 4-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-propyl}-piperidine-1-carboxylic acid tert-butyl ester

PyBroP (224 mg, 0.48 mmol) and DMAP (39 mg, 0.32 mmol) were added to a solution of 4-[3-(4-carboxy-2-methyl-phenoxy)-propyl]-piperidine-1-carboxylic acid tert-butyl ester from Example E68.3 (120 mg, 0.32 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (70 mg, 0.35 mmol) in dichloromethane (5 ml) and DIEA (0.111 ml, 0.64 mmol). The mixture was heated at reflux for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to yield the title compound (71 mg, 40%).

Example E68.5 (3-Methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[3-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-methanone hydrochloride

4M HCl solution in dioxan (1 ml) was added to a solution of 4-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-propyl}-piperidine-1-carboxylic acid tert-butyl ester from Example E68.4 (71 mg, 0.13 mmol) in methanol (3 ml). The mixture was stirred for 20 h at room temperature then solvents were concentrated in vacuo. The residue was triturated with diethyl ether to yield the title compound (61 mg, 97%).

Example E68.6 (4-{3-[1-(3,3-Dimethyl-butyl)-piperidin-4-yl]-propoxy}-3-methyl-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone

Acetic acid (0.05 ml) and 3,3-dimethylbutyraldehyde (0.024 ml, 0.19 mmol) were added to a solution of (3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[3-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-methanone hydrochloride from Example E68.5 (60 mg, 0.12 mmol) in methanol (2.45 ml) and triethylamine (0.026 ml, 0.19 mmol). The mixture was stirred at room temperature for 1 h then sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added. The mixture was stirred at room temperature for 18 h, diluted with dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white fluffy solid identified as the title compound (33 mg, 48%).

Example E69 (4-{3-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluoro-phenyl)-(2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone Example E69.1 4-{3-[4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-fluoro-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester

4-[3-(4-Carboxy-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E39 (130 mg, 0.34 mmol) was dissolved in dichloromethane (5 ml) and a few drops of DMF. Oxalyl chloride (0.059 ml, 0.68 mmol) was added slowly and the mixture was stirred, for 30 min at room temperature. Solvents were concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (5 ml) and 1-benzyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene from Example E5a (100 mg, 0.34 mmol) then DIEA (0.176 ml, 1.02 mmol) were added. The mixture was stirred for 2 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to yield the title compound (110 mg, 50%).

Example E69.2 (1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[3-fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride

4-{3-[4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-fluoro-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester from Example E69.1 (110 mg, 0.17 mmol) was dissolved in methanol (5 ml) and 4M HCl in dioxan (2 ml) was added. The mixture was stirred for 20 h at room temperature then concentrated in vacuo to yield the title compound (105 mg, 100%).

Example E69.3 (1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluoro-phenyl)-methanone

(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[3-fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride from Example E69.2 (105 mg, 0.17 mmol) was dissolved in methanol (2.45 ml) and triethylamine (0.07 ml, 0.50 mmol). Acetic acid (0.05 ml) then 3,3-dimethylbutyraldehyde (0.032 ml, 0.25 mmol) were added and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (16 mg, 0.25 mmol) was added and the mixture was stirred for 3 h at room temperature then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (102 mg, 95%).

Example E69.4 (4-{3-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluoro-phenyl)-(2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone

(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluoro-phenyl)-methanone from Example E69.3 (90 mg, 0.14 mmol) was dissolved in methanol (5 ml) and acetic acid (1 ml) and hydrogenated over 20 wt. % palladium hydroxide catalyst (90 mg) for 8 h. The mixture was filtered through Celite® filter agent and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (39 mg, 51%).

Example E70 (4-{3-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-methyl-phenyl)-(2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone Example E70.1 4-{3-[4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester

4-[3-(4-Carboxy-2-methyl-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester (350 mg, 0.92 mmol) was dissolved in dichloromethane (5 ml) and a few drops of DMF. Oxalyl chloride (0.162 ml, 1.84 mmol) was added slowly and the mixture was stirred for 30 min at room temperature. Solvents were concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (10 ml) and 1-benzyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene from Example E5a (268 mg, 0.92 mmol) then DIEA (0.48 ml, 2.77 mmol) were added. The mixture was stirred for 2 days at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to yield the title compound (230 mg, 38%).

Example E70.2 (1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[3-methyl-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride

4-{3-[4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester from Example E70.1 (230 mg, 0.35 mmol) was dissolved in methanol (5 ml) and 4M HCl in dioxan (2 ml) was added. The mixture was stirred for 2 h at room temperature then concentrated in vacuo and triturated with diethyl ether to yield the title compound (215 mg, 98%).

Example E70.3 (1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-methyl-phenyl)-methanone

(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[3-methyl-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride from Example E70.2 (100 mg, 0.16 mmol) was dissolved in methanol (2.45 ml) and triethylamine (0.068 ml, 0.48 mmol). Acetic acid (0.05 ml) then 3,3-dimethylbutyraldehyde (0.031 ml, 0.24 mmol) were added and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (16 mg, 0.24 mmol) was added and the mixture was stirred for 20 h at room temperature then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to yield the title compound (98 mg, 96%).

Example E70.4 (4-{3-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-methyl-phenyl)-(2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone

(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-methyl-phenyl)-methanone from Example E70.3 (98 mg, 0.15 mmol) was dissolved in methanol (5 ml) and acetic acid (1 ml) and hydrogenated over 20 wt. % palladium hydroxide catalyst (98 mg) for 8 h. The mixture was filtered through glass-fibre paper and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (17 mg, 20%).

Example E71

N-(4-Chloro-phenyl)-4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluoro-N-methyl-benzamide

Example E71.1 4-(3-{4-[(4-Chloro-phenyl)-methyl-carbamoyl]-2-fluoro-phenoxy}-propyl)-piperazine-1-carboxylic acid tert-butyl ester

PyBroP (606 mg, 1.3 mmol) was added to a solution of 4-[3-(4-carboxy-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E39 (382 mg, 1.0 mmol) in dichloromethane (20 ml) and DIEA (to pH9). The mixture was stirred for 1 h at room temperature then (4-chloro-phenyl)-methyl amine (156 mg, 1.1 mmol) was added. The mixture was stirred for 2 days at room temperature then solvents were concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (210 mg, 41%).

Example E71.2 N-(4-Chloro-phenyl)-3-fluoro-N-methyl-4-(3-piperazin-1-yl-propoxy)-benzamide dihydrochloride

4-(3-{4-[(4-Chloro-phenyl)-methyl-carbamoyl]-2-fluoro-phenoxy}-propyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E71.1 (210 mg, 0.4 mmol) was dissolved in 4M HCl in dioxan (5 ml) and stirred for 1 h at room temperature. Solvents were concentrated in vacuo and azeotroped with toluene to yield the title compound (184 mg, 100%).

Example E71.3 N-(4-Chloro-phenyl)-4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluoro-N-methyl-benzamide

N-(4-Chloro-phenyl)-3-fluoro-N-methyl-4-(3-piperazin-1-yl-propoxy)-benzamide dihydrochloride from Example E71.2 (184 mg, 0.4 mmol) was dissolved in methanol (4.95 ml) and triethylamine (0.167 ml, 1.2 mmol). Acetic acid (0.05 ml) then 3,3-dimethylbutyraldehyde (46 mg, 0.44 mmol) were added and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (31 mg, 0.5 mmol) was added and the mixture was stirred for 20 h at room temperature then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to give a white foam identified as the title compound (77 mg, 37%).

Example E72 (4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-butoxy}-3-fluoro-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone Example E72.1 4-(4-Bromo-butoxy)-3-fluoro-benzoic acid ethyl ester

1,4-Dibromobutane (2.34 g, 10.8 mmol), potassium carbonate (1.86 g, 13.5 mmol) and potassium iodide (90 mg, 0.5 mmol) were added to a solution of 3-fluoro-4-hydroxy-benzoic acid ethyl ester from Example E27 (1.0 g, 5.4 mmol) in acetone (25 ml) and the mixture was heated at reflux for 20 h. The solid was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 15% EtOAc:85% hexane) to yield the title compound (1.38 g, 80%).

Example E72.2 4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-butoxy}-3-fluoro-benzoic acid ethyl ester

1-(3,3-Dimethyl-butyl)-piperazine hydrochloride from Example E4 (874 mg, 3.7 mmol), potassium carbonate (2.5 g, 18.0 mmol) and potassium iodide (60 mg, 0.4 mmol) were added to a solution of 4-(4-bromo-butoxy)-3-fluoro-benzoic acid ethyl ester from Example E72.1 (1.4 g, 4.4 mmol) in acetone (35 ml) and the mixture was heated at reflux for 20 h. The solid was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc to 1% 35% ammonia:10% methanol:89% EtOAc) to yield the title compound (1.35 g, 90%).

Example E72.3 4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-butoxy}-3-fluoro-benzoic acid

Sodium hydroxide (0.5 g, 13.2 mmol) and water (5 ml) were added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-butoxy}-3-fluoro-benzoic acid ethyl ester from Example E72.2 (1.35 g, 3.3 mmol) in dioxan (20 ml). The mixture was stirred for 1 h at room temperature then heated at 60° C. for 20 h. Solvents were concentrated in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:19% methanol:80% chloroform) to yield the title compound (0.85 g, 67%).

Example E72.4 (4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-butoxy}-3-fluoro-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone

A mixture of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-butoxy}-3-fluoro-benzoic acid from Example E72.3 (190 mg, 0.5 mmol) and thionyl chloride (2 ml) in dichloromethane (5 ml) was heated at reflux for 1 h. Solvents were concentrated in vacuo and the residue was dissolved in dichloromethane (10 ml). 3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (110 mg, 0.55 mmol) and DIEA (to pH9) were added. The mixture was stirred at room temperature for 2 days and concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a colourless oil identified as the title compound (48 mg, 17%).

Example E73 (4-{2-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-ethoxy}-3-methyl-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone

WSCD (58 mg, 0.30 mmol) and DMAP (20 mg, 0.15 mmol) were added to a solution of 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (37 mg, 0.20 mmol) and 4-{2-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-ethoxy}-3-methyl-benzoic acid from Example E40 (53 mg, 0.15 mmol) in dichloromethane (5 ml) and triethylamine (to pH9). The mixture was heated at reflux for 2 days then concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% chloroform) to give an off-white solid identified as the title compound (3.5 mg, 4%).

Example E74 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-2-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-ethanone

Oxalyl chloride (42 mg, 0.34 mmol) and 2 drops of DMF were added to a solution of 4-{2-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-2-oxo-ethoxy}-3-methyl-benzoic acid from Example E41 (100 mg, 0.28 mmol) in dichloromethane (5 ml) at 0° C. The mixture was stirred for 1 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (5 ml) and a solution of 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (61 mg, 0.31 mmol) in dichloromethane (1 ml) and triethylamine (to pH9) was added. The mixture was stirred for 2 days at room temperature then concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified twice by flash chromatography on silica gel (eluant; 5% methanol:95% chloroform to 10% methanol:90% chloroform then 5% methanol:95% EtOAc to 10% methanol:90% EtOAc) to give a white solid identified as the title compound (25 mg, 17%).

Example E75 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-2-[4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-ethanone Example E75.1 (4-Benzyloxy-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone

Oxalyl chloride (0.41 ml, 4.7 mmol) and a few drops of DMF were added to a solution of 4-(benzyloxy)benzoic acid (855 mg, 3.7 mmol) in dichloromethane (15 ml). The mixture was stirred for 2 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (10 ml) and a solution of 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (500 mg, 2.5 mmol) in dichloromethane (10 ml) and triethylamine (0.87 ml, 6.2 mmol) was added. The mixture was stirred for 20 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc to 3% methanol:97% EtOAc) to yield the title compound (820 mg, 80%).

Example E75.2 (4-Hydroxy-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone

(4-Benzyloxy-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone from Example E75.1 (800 mg, 1.95 mmol) was dissolved in methanol (100 ml) and hydrogenated over 10% Pd/C catalyst (400 mg) for 7 h. The mixture was filtered through Celite® filter agent, washed with chloroform and methanol and the filtrate was concentrated in vacuo to yield the title compound (140 mg, 22%).

Example E75.3 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-2-[4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-ethanone

Potassium carbonate (104 mg, 0.76 mmol) was added to a mixture of 2-bromo-1-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-ethanone from Example E37 (110 mg, 0.38 mmol) and (4-hydroxy-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone from Example E75.2 (90 mg, 0.28 mmol) in acetonitrile (5 ml). The mixture was heated at reflux for 20 h then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with 5% KHCO3 solution, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (21 mg, 11%).

Example E76 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-butan-1-one Example E76.1 4-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-butyric acid tert-butyl ester

WSCD (391 mg, 2.06 mmol) and DMAP (133 mg, 1.09 mmol) were added to a solution of 4-(3-tert-butoxycarbonyl-propoxy)-3-methyl-benzoic acid from Example E42 (275 mg, 0.94 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (191 mg, 0.95 mmol) in dichloromethane (30 ml) and triethylamine (0.28 ml, 2.01 mmol). The mixture was heated at reflux for 72 h, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (80 mg, 18%).

Example E76.2 4-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-butyric acid

Trifluoroacetic acid (5 ml) was added to a solution of 4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-butyric acid tert-butyl ester from Example E76.1 (80 mg, 0.17 mmol) in dichloromethane (10 ml). The mixture was stirred for 2 h at room temperature, concentrated in vacuo and azeotroped with dichloromethane to yield the title compound (71 mg, 100%).

Example E76.3 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-butan-1-one

HBTU (101 mg, 0.27 mmol) was added to a solution of 4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-butyric acid from E76.2 (71 mg, 0.17 mmol) and 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (54 mg, 0.22 mmol) in dichloromethane (10 ml) and DIEA (0.15 ml, 0.86 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 6% methanol:94% dichloromethane) to give a white powder identified as the title compound (52 mg, 53%).

Example E77 3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid piperidin-4-ylmethyl ester Example E77.1 4-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyloxymethyl}-piperidine-1-carboxylic acid benzyl ester

WSCD (107 mg, 0.54 mmol) and DMAP (33 mg, 0.27 mmol) were added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (106 mg, 0.27 mmol) and 4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (81 mg, 0.32 mmol) in dichloromethane (5 ml) and DIEA (0.095 ml, 0.54 mmol). The mixture was stirred for 3 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (44 mg, 26%).

Example E77.2 3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid piperidin-4-ylmethyl ester

4-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyloxymethyl}-piperidine-1-carboxylic acid benzyl ester from Example E77.1 (44 mg, 0.07 mmol) was dissolved in methanol (5 ml) and hydrogenated over 10% Pd/C catalyst (5 mg) for 2 h. The mixture was filtered through Celite® filter agent and the filtrate concentrated in vacuo to give a white powder identified as the title compound (34 mg, 98%).

Example E78 Methyl (3-chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy)acetate

Diisopropylethylamine (2.1 ml, 12.0 mmol), dimethylamino-pyridine (0.74 g, 6.0 mmol), PyBroP® (4.20 g, 9.0 mmol) and 3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene from Example E2 (1.28 g, 6.0 mmol) were added to a solution of tert-butyl 4-(2-(4-carboxy-3-chloro-phenoxy)-acetyl)-piperazine-1-carboxylate from Example E41c (2.39 g, 6.0 mmol) in dichloromethane (50 ml) and the mixture was heated at reflux for 20 h. The reaction mixture was cooled, diluted with dichloromethane (50 ml), washed with saturated aqueous sodium hydrogen carbonate, dried and concentrated in vacuo. The residue was dissolved in methanol (150 ml) and treated with a 4M solution of hydrogen chloride in dioxan (50 ml), with cooling in an ice bath. The solution was stirred at room temperature for 16 h. The reaction mixture was evaporated and the residue taken up in water and washed with chloroform. The aqueous was treated with solid sodium hydrogen carbonate until basic pH, extracted into chloroform, dried and evaporated. The residue was purified by flash chromatography on silica gel (eluant; EtOAc followed by a 2% to 10% methanol:98% to 90% EtOAc gradient) to yield a white solid identified as the title compound (0.53 g, 20%).

Example E79 1-(4-Hydroxymethyl-piperidin-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propan-1-one

Sodium borohydride (12 mg, 0.32 mmol) was added to a solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidine-4-carbaldehyde from Example E58.1 (74 mg, 0.15 mmol) in methanol (6 ml). The mixture was stirred for 1 h at room temperature, acidified with 1M HCl and concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was crystallised from chloroform and pet. ether to give a white powder identified as the title compound (28 mg, 38%).

Example E80 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-propan-1-one Example E80.1 3-[4-(3,4-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-propionic acid tert-butyl ester

Sodium hydride (14 mg, 0.34 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid tert-butyl ester from Example E45 (125 mg, 0.28 mmol) in DMF (2 ml) at 0° C. The mixture was stirred for 20 min at room temperature then cooled down to 0° C. Methyl iodide (0.09 ml, 1.4 mmol) was added and the mixture was stirred for 20 h at room temperature. EtOAc was added and the mixture was washed with 0.3M KHSO4 then brine, dried, concentrated in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (46 mg, 36%).

Example E80.2 3-[4-(3,4-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-propionic acid

Trifluoroacetic acid (2 ml) was added to 3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-propionic acid tert-butyl ester from Example E80.1 (46 mg, 0.10 mmol) in dichloromethane (5 ml). The mixture was stirred for 2 h at room temperature then concentrated in vacuo to yield the title compound (40 mg, 100%).

Example E80.3 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-propan-1-one

Oxalyl chloride (0.018 ml, 0.20 mmol) was added to a solution of 3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-propionic acid from Example E80.2 (40 mg, 0.10 mmol) in dichloromethane (5 ml) and a few drops of DMF. The mixture was stirred for 1 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (5 ml) and 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (30 mg, 0.12 mmol) and DIEA (0.052 ml, 0.30 mmol) were added. The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (36 mg, 65%).

Example E81 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-[2-methyl-4-(2,3,4,5-tetrahydro-benzo[e][1,4]diazepine-1-carbonyl)-phenyl]-butan-1-one Example E81.1 1-(4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester

WSCD (58 mg, 0.30 mmol) and DMAP (18 mg, 0.15 mmol) were added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid from Example E43 (55 mg, 0.15 mmol) and 1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (73 mg, 0.30 mmol) in dichloromethane (3 ml) and DIEA (0.052 ml, 0.30 mmol). The mixture was heated at reflux for 5 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to yield the title compound (25 mg, 28%).

Example E81.2 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-[2-methyl-4-(2,3,4,5-tetrahydro-benzo[e][1,4]diazepine-1-carbonyl)-phenyl]-butan-1-one

1-(4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester from Example E81.1 (25 mg, 0.04 mmol) was dissolved in methanol (2 ml) and 4M HCl in dioxan (2 ml) was added. The mixture was stirred for 1 h at room temperature then concentrated in vacuo to give a white powder identified as the title compound (6 mg, 28%). (ESI)+: [M+H]+=505.5

Example E82 4-[4-(7,8-Dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carbonyl)-2-methyl-phenyl]-1-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-butan-1-one

WSCD (58 mg, 0.30 mmol) and DMAP (18 mg, 0.15 mmol) were added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid from Example E43 (55 mg, 0.15 mmol) and 6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (44 mg, 0.30 mmol) in dichloromethane (3 ml) and DIEA (0.052 ml, 0.30 mmol). The mixture was heated at reflux for 5 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (6 mg, 10%).

Example E83 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-pentan-1-one Example E83.1 5-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-pentanoic acid methyl ester

WSCD (822 mg, 4.3=01) and DMAP (273 mg, 2.2 mmol) were added to a solution of 4-(4-methoxycarbonyl-butyl)-3-methyl-benzoic acid from Example E31 (571 mg, 2.3 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (424 mg, 2.1 mmol) in dichloromethane (50 ml) and triethylamine (0.6 ml, 4.3 mmol). The mixture was heated at reflux for 72 h, diluted with dichloromethane, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc to 5% triethyamine:95% EtOAc) to yield the title compound (424 mg, 46%).

Example E83.2 5-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-pentanoic acid

Lithium hydroxide monohydrate (120 mg, 2.86 mmol) was added to a solution of 5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-pentanoic acid methyl ester from Example E83.1 (410 mg, 0.95 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 24 h at room temperature and concentrated in vacuo. The residue was acidified with 1M HCl and extracted with chloroform. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 3% acetic acid:7% methanol:90% chloroform) to yield the title compound (105 mg, 26%).

Example E83.3 1-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-pentan-1-one

HBTU (104 mg, 0.27 mmol) was added to a solution of 5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-pentanoic acid from E83.2 (105 mg, 0.25 mmol) and 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (69 mg, 0.28 mmol) in DMF (10 ml) and DIEA (0.2 ml, 1.15 mmol). The mixture was stirred for 24 h at room temperature then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 4% methanol:96% dichloromethane to 8% methanol:92% dichloromethane) to give a white solid identified as the title compound (88 mg, 62%).

Example E84 1-(4-Hydroxy-piperidin-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propan-1-one

Sodium borohydride (4 mg, 0.1 mmol) was added to a solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-one (Compound number 701) (50 mg, 0.11 mmol) in methanol/acetic acid (99:1, v/v, 100 ml) and the mixture was stirred at room temperature for 1 h. Sodium borohydride (4 mg, 0.11 mmol) was added again and the mixture was stirred for 1 h at room temperature then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to give a white powder identified as the title compound (28 mg, 56%).

Example E85 1-(4-Cyclobutylmethyl-piperazin-1-yl)-2-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-ethanone Example E85.1 4-[2-(4-Cyclobutylmethyl-piperazin-1-yl)-2-oxo-ethyl]-3-methyl-benzoic acid methyl ester

Oxalyl chloride (0.36 ml, 3.3 mmol) was added to a solution of 4-carboxymethyl-3-methyl-benzoic acid methyl ester from Example E32 (687 mg, 3.3 mmol) in dichloromethane (20 ml) and few drops of DMF. The mixture was stirred for 3 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (10 ml) and added to a solution of 1-cyclobutylmethyl-piperazine dihydrochloride (750 mg, 3.3 mmol) in dichloromethane (10 ml) and DIEA (1.73 ml, 9.9 mmol) at 0° C. The mixture was stirred for 20 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 3% methanol:97% dichloromethane) to yield the title compound (528 mg, 46%).

Example E85.2 4-[2-(4-Cyclobutylmethyl-piperazin-1-yl)-2-oxo-ethyl]-3-methyl-benzoic acid

Lithium hydroxide monohydrate (122 mg, 2.9 mmol) was added to a solution of 4-[2-(4-cyclobutylmethyl-piperazin-1-yl)-2-oxo-ethyl]-3-methyl-benzoic acid methyl ester from Example E85.1 (500 mg, 1.4 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 20 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 3% acetic acid:7% methanol:90% chloroform) to yield the title compound (300 mg, 63%).

Example E85.3 1-(4-Cyclobutylmethyl-piperazin-1-yl)-2-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-ethanone

WSCD (76 mg, 0.39 mmol) and DMAP (7 mg, 0.06 mmol) were added to a solution of 4-[2-(4-cyclobutylmethyl-piperazin-1-yl)-2-oxo-ethyl]-3-methyl-benzoic acid from Example E85.2 (100 mg, 0.30 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (61 mg, 0.30 mmol) in dichloromethane (20 ml) and DIEA (0.16 ml, 0.91 mmol). The mixture was heated at reflux for 20 h and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 4% methanol:96% dichloromethane to 6% methanol:94% dichloromethane to 1% 35% ammonia:7% methanol:92% dichloromethane) to give an off-white solid identified as the title compound (50 mg, 32%).

Example E86 1-(4-Cyclopropylaminomethyl-piperidin-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propan-1-one Example E86.1 4-(3-{4-[(tert-Butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic acid methyl ester

Oxalyl chloride (1.26 ml, 14.4 mmol) was added to a solution of 4-(2-carboxy-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.3 (1.60 g, 7.2 mmol) in dichloromethane (50 ml) and few drops of DMF. The mixture was stirred for 1 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (50 ml) and DIEA (2.5 ml, 14.4 mmol) and cyclopropyl-piperidin-4-ylmethyl-carbamic acid tert-butyl ester from Example E38 (1.83 g, 7.2 mmol) in dichloromethane (5 ml) was added. The mixture was stirred for 2 h at room temperature, diluted with dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% cyclohexane) to yield the title compound (1.42 g, 43%).

Example E86.2 4-(3-{4-[(tert-Butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic acid

Lithium hydroxide monohydrate (142 mg, 3.4 mmol) was added to a solution of 4-(3-{4-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic acid methyl ester from Example E86.1 (1.41 g, 3.1 mmol) in THF (20 ml) and water (2 ml). The mixture was stirred for 16 h at room temperature then 1M NaOH solution (5 ml) was added. The mixture was heated at 60° C. for 3 h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M HCl then brine, dried and concentrated in vacuo to yield the title compound (1.25 g, 91%).

Example E86.3 Cyclopropyl-(1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester

WSCD (1.08 g, 5.6 mmol) and DMAP (343 mg, 2.8 mmol) were added to a solution of 4-(3-{4-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic acid from Example E86.2 (1.25 g, 2.8 mmol) in dichloromethane (100 ml) and triethylamine (0.783 ml, 5.6 mmol). The mixture was stirred for 1 h at room temperature then 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (676 mg, 3.4 mmol) was added. The mixture was heated at reflux for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% methanol:98% EtOAc to 5% methanol:95% EtOAc) to yield the title compound (1.1 g, 62%).

Example E86.4 1-(4-Cyclopropylaminomethyl-piperidin-1-yl)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propan-1-one

Cyclopropyl-(1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester from Example E86.3 (220 mg, 0.35 mmol) was dissolved in methanol (5 ml) and 4M HCl solution in dioxan (5 ml) was added. The mixture was stirred for 2 h at room temperature then concentrated in vacuo to give an off-white solid identified as the title compound (189 mg, 95%).

Example E87 N-Cyclopropyl-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-N-piperidin-4-ylmethyl-propionamide hydrochloride Example E87.1 4-[(Cyclopropyl-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester

PyBroP (238 mg, 0.51 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (200 mg, 0.51 mmol) and 4-cyclopropylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.51 mmol) in dichloromethane (10 ml) and DIEA (0.18 ml, 1.02 mmol). The mixture was stirred for 4 days at room temperature, diluted with EtOAc, washed with 5% KHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (235 mg, 73%).

Example E87.2 N-Cyclopropyl-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-N-piperidin-4-ylmethyl-propionamide hydrochloride

4-[(Cyclopropyl-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester from Example E87.1 (235 mg, 0.37 mmol) was dissolved in 4M HCl solution in dioxan (5 ml). The mixture was stirred for 1 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in 1M HCl, washed twice with dichloromethane and freeze-dried to give an off-white solid identified as the title compound (82 mg, 39%).

Example E88 1-Methyl-5-(3-methyl-2-nitro-phenylamino)-1H-pyrazole-4-carboxylic acid ethyl ester

Cesium carbonate (35.2 g, 108 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.4 g, 0.7 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.2 g, 0.2 mmol) were added to a solution of ethyl 5-amino-1-methylpyrazole-4-carboxylate (15.3 g, 90 mmol) in dioxan (50 ml) under an inert atmosphere. A solution of 3-bromo-2-nitrotoluene (16.2 g, 75 mmol) in dioxane (10 ml) was added and the mixture was stirred for 30 min at room temperature then heated at reflux for 72 h. The suspension was filtered through Celite® filter agent, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% pet. ether) then recrystallised from EtOAc/pet. ether to yield the title compound (12.5 g, 45%).

Example E89 5-Amino-1-ethyl-1H-pyrazole-4-carboxylic acid ethyl ester

Triethylamine (19.6 ml, 144 mmol) was added cautiously to a solution of ethyl (ethoxymethylene)cyanoacetate (10.1 g, 60 mmol) and ethyl hydrazine oxalate (9.9 g, 66 mmol) in ethanol (200 ml). The mixture was heated at reflux for 24 h then concentrated in vacuo. The residue was redissolved in EtOAc, washed with 5% KHCO3 solution then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 25% pet. ether:75% EtOAc) to yield the title compound (8.8 g, 80%).

Example E90 1-Cyclopropylmethyl-piperidine-4-carboxylic acid 3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide Example E90.1 [3-Fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-carbamic acid tert-butyl ester

A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-fluoro-benzoic acid from Example E2 (1.35 g, 5.0 mmol), 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (1.0 g, 5.0 mmol) and PyBroP (3.03 g, 6.5 mmol) in dichloromethane (25 ml) and DIEA (1.31 ml, 7.5 mmol) was heated at reflux for 18 h. After cooling to room temperature, the mixture was washed with 5% KHCO3, 1M HCl then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (1.25 g, 56%).

Example E90.2 (4-Aminomethyl-2-fluoro-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride

[3-Fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-carbamic acid tert-butyl ester from Example E90.1 (1.25 g, 2.8 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (1.0 g, 97%).

Example E90.3 1-Cyclopropylmethyl-piperidine-4-carboxylic acid 3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide

HBTU (227 mg, 0.6 mmol) was added to a solution of 1-cyclopropylmethyl-piperidine-4-carboxylic acid from Example E15a (99 mg, 0.45 mmol) in DMF (5 ml) and DIEA (to pH9). The mixture was stirred at room temperature for 1 h. (4-Aminomethyl-2-fluoro-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E90.2 (116 mg, 0.3 mmol) was added and the mixture was stirred at room temperature for 18 h. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:19% methanol:80% dichloromethane) to give a white solid identified as the title compound (71.5 mg, 46%).

Example E91

N-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-2-piperidin-4-yl-acetamide hydrochloride

A solution of 4-{[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylcarbamoyl]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (Compound number 1067) (156 mg, 0.27 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (135 mg, 97%).

Example E92 2-[1-(3,3-Dimethyl-butyl)-piperidin-4-yl]-N-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-acetamide

3,3-Dimethylbutyraldehyde (0.048 ml, 0.38 mmol) was added to a solution of N-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-2-piperidin-4-yl-acetamide from Example E91 (130 mg, 0.25 mmol) in methanol/acetic acid (49:1, v/v, 2.5 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride.(24 mg, 0.38 mmol) was added, and the mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated Na—HCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 1.5% 35% ammonia:15% methanol:83.5% dichloromethane) to give a white solid identified as the title compound (107 mg, 75%).

Example E93 1-Propyl-piperidine-4-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide

A solution of propionaldehyde (0.29 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of piperidine-4-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide hydrochloride (Compound number 1109) (2.8 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=521.4

Example E94 N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-2-(1-hexyl-piperidin-4-yl)-acetamide

A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-2-piperidin-4-yl-acetamide hydrochloride (Compound number 1110) (2.82 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=575.7

Example E95 N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-(1-propionyl-piperidin-4-yl)-propionamide

A solution of propionyl chloride (0.46 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 1108) (2.97 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=577:4

Example E96 N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-(1-ethanesulfonyl-piperidin-4-yl)-propionamide

A solution of ethanesulfonyl chloride (0.64 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 1108) (2.97 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=613.4

Example E97 4-{2-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methylbenzylcarbamoyl]-ethyl}-piperidine-1-carboxylic acid 4-nitro-benzyl ester

A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 1108) (2.97 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=700.5, 702.5

Example E98 Propane-1-sulfonic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide Example E98.1 [4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-carbamic acid tert-butyl ester

A mixture of 4-(tert-butoxycarbonylamino-methyl)-3-fluoro-benzoic acid from Example E3 (1.38 g, 5.1 mmol) and 3,6-dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E2 (1.0 g, 4.7 mmol) in dichloromethane (20 ml) at room temperature was treated with DIEA (2.44 ml, 14.0 mmol), DMAP (627 mg, 5.1 mmol) and WSCD (1.16 g, 6.1 mmol). The solution was heated at reflux for 2 days then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (1.29 g, 59%).

Example E98.2 (4-Aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride

[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-carbamic acid tert-butyl ester from Example E98.1 (1.29 g, 2.8 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (1.1 g, 99%).

Example E98.3 Propane-1-sulfonic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide

1-Propanesulfonyl chloride (0.016 ml, 0.14 mmol) was added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E98.2 (50 mg, 0.12 mmol) in dichloromethane (2 ml) and triethylamine (0.038 ml, 0.27 mmol) at room temperature. The mixture was stirred for 1 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (30 mg, 51%).

Example E99 N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-formamide

Formic acid (0.85 ml, 22.5 mmol) and acetic anhydride (1.4 ml, 13.5 mmol) were combined and stirred for 1 h at room temperature. (4-Aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E98.2 (113 mg, 0.3 mmol) was added and the mixture was stirred for 1 h. Water (20 ml) was added and the mixture was stirred for 1 h. It was diluted with chloroform, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to yield a white solid identified as the title compound (48 mg, 40%).

Example E100 Cyclopropanecarboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide

DIEA (0.08 ml, 0.46 mmol) and cyclopropanecarbonyl chloride (0.013 ml, 0.14 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E98.2 (57 mg, 0.14 mmol) in dichloromethane (10 ml) at 0° C. The mixture was stirred for 90 min at room temperature then diluted with dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (33 mg, 54%).

Example E101 Cyclopropanecarboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide Example E101.1 4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzonitrile

A mixture of 4-cyano-3-methyl-benzoic acid from Example E6 (753 mg, 4.7 mmol) and thionyl chloride (1.02 ml, 14.0 mmol) in toluene (50 ml) was heated at reflux for 2 h. After cooling at room temperature, solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (45 ml) and a solution of 3,6-dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E2 (1.0 g, 4.7 mmol) in dichloromethane (5 ml) and triethylamine (1.3 ml, 9.3 mmol) was added slowly. The mixture was stirred at room temperature for 20 h, washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (1.42 g, 85%).

Example E101.2 (4-Aminomethyl-3-methyl-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone

A solution of 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzonitrile from Example E101.1 (1.42 g, 4.0 mmol) in methanol (50 ml),at 0° C. was treated with cobalt(II) chloride hexahydrate (1.90 g, 8.0 mmol). The mixture was stirred for 15 min at room temperature then sodium borohydride (1.51 g, 40.0 mmol) was added portionwise. The reaction mixture was stirred for 2 h then saturated NH4Cl was added. The mixture was stirred for 30 min then the solid was filtered off through Celite® filter agent and the filtrate concentrated in vacuo. The residue was redissolved in EtOAc and saturated NaHCO3. The layers were partitioned and the aqueous layer was extracted further with chloroform. Organics were combined, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 1% 35% ammonia:9% methanol:90% dichloromethane) to yield the title compound (511 mg, 35%).

Example E101.3 Cyclopropanecarboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide

Triethylamine (0.145 ml, 1.04 mmol) and cyclopropanecarbonyl chloride (0.041 ml, 0.45 mmol) were added to a solution of (4-aminomethyl-3-methyl-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone from Example E101.2 (150 mg, 0.41 mmol) in dichloromethane (10 ml) at room temperature. The mixture was stirred for 20 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give an off-white solid identified as the title compound (91 mg, 51%).

Example E102 Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide Example E102.1 [4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-carbamic acid tert-butyl ester

A solution of 4-(tert-butoxycarbonylamino-methyl)-3-fluoro-benzoic acid from Example E3 (568 mg, 2.1 mmol) in dichloromethane (25 ml) at room temperature was treated with DMAP (256 mg, 2.1 mmol), DIEA (1.1 ml, 6.3 mmol) then WSCD (520 mg, 2.7 mmol). The mixture was stirred for 3 h then 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (450 mg, 1.9 mmol) was added. The mixture was stirred for 4 days then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (503 mg, 54%).

Example E102.2 (4-Aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride

[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-carbamic acid tert-butyl ester from Example E102.1 (503 mg, 1.03 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (440 mg, 100%).

Example E102.3 Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide

Cyclopropanecarbonyl chloride (0.045 ml, 0.5 mmol) was added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (210 mg, 0.5 mmol) in dichloromethane (40 ml) and DIEA (0.30 ml, 1.7 mmol) at 0° C. The mixture was stirred for 1 h at room temperature then washed with saturated NaHCO3, brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (134 mg, 59%).

Example E103 N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-propionamide

DIEA (0.27 ml, 1.56 mmol) and propionyl chloride (0.048 ml, 0.55 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (220 mg, 0.52 mmol) in dichloromethane (6 ml) at room temperature. The mixture was stirred for 2 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (129 mg, 56%).

Example E104 N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-butyramide

DIEA (0.135 ml, 0.78 mmol) and butyryl chloride (0.027 ml, 0.27 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (110 mg, 0.26 mmol) in dichloromethane (3 ml) at room temperature. The mixture was stirred for 1 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (77 mg, 65%).

Example E105 N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-isobutyramide

DIEA (0.135 ml, 0.78 mmol) and isobutyryl chloride (0.029 ml, 0.27 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (110 mg, 0.26 mmol) in dichloromethane (3 ml) at room temperature. The mixture was stirred for 1 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (85 mg, 71%).

Example E106 Cyclopropanecarboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide Example E106.1 [2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-carbamic acid tert-butyl ester

A solution of 4-(tert-butoxycarbonylamino-methyl)-3-chloro-benzoic acid from Example E2b (568 mg, 2.0 mmol) in dichloromethane (25 ml) at room temperature was treated with DMAP (244 mg, 2.0 mmol), DIEA (1.0 ml, 6.0 mmol) then WSCD (500 mg, 2.6 mmol). The mixture was stirred for 3 h then 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (430 mg, 1.8 mmol) was added. The mixture was stirred for 4 days then washed with saturated NaHCO3, brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (570 mg, 63%).

Example E106.2 (4-Aminomethyl-3-chloro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride

[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-carbamic acid tert-butyl ester from Example E106.1 (570 mg, 1.13 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (490 mg, 100%).

Example E106.3 Cyclopropanecarboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide

Cyclopropanecarbonyl chloride (0.045 ml, 0.5 mmol) was added to a solution of (4-aminomethyl-3-chloro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E106.2 (220 mg, 0.5 mmol) in dichloromethane (40 ml) and DIEA (0.30 ml, 1.7 mmol) at 0° C. The mixture was stirred for 1 h at room temperature then washed with saturated NaHCO3, brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (135 mg, 57%).

Example E107 N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-butyramide

Butyryl chloride (46 mg, 0.4 mmol) was added to a solution of (4-aminomethyl-3-chloro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E106.2 (161 mg, 0.4 mmol) in dichloromethane (10 ml) and triethylamine (to pH9) at room temperature. The mixture was stirred for 20 h, diluted with EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (110 mg, 58%).

Example E108 N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-isobutyramide

Isobutyryl chloride (46 mg, 0.4 mmol) was added to a solution of (4-aminomethyl-3-chloro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E106.2 (161 mg, 0.4 mmol) in dichloromethane (10 ml) and triethylamine (to pH9) at room temperature. The mixture was stirred for 18 h, diluted with EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (75 mg, 40%).

Example E109 {4-[(Cyclopropylmethyl-amino)-methyl]-3-methyl-phenyl}(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone

Cyclopropanecarboxaldehyde (26 mg, 0.34 mmol) was added to a solution of (4-Aminomethyl-3-methyl-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone (131 mg, 0.38 mmol) in MeOH/AcOH (99:1, 5 ml) and the mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (31 mg, 0.49 mmol) was added and the mixture was stirred at room temperature for 18 h. The solvents were removed in vacuo and the residue was dissolved in EtOAc. The solution was washed with sat. aq. NaHCO3 and brine, then dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane to give a white solid identified as the title compound (70 mg, 51%).

Example E110 [4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamino]-acetic acid methyl ester and Example E111 {[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-methoxycarbonylmethyl-amino}-acetic acid methyl ester

Methyl bromoacetate (0.054 ml, 0.58 mmol) was added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from example E102.2 (107 mg, 0.28 mmol) and DIEA (0.26 ml, 1.53 mmol) in THF (25 ml) and the mixture was stirred at room temperature for 2 h. A further amount of methyl bromoacetate (0.10 ml, 1.11 mmol) was added, and the mixture was stirred overnight at room temperature. The solution was quenched with water and diluted with EtOAc. The organic layer was washed with brine (×3), dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to yield two products. The faster eluting product was isolated as a white solid and identified as E111 (68 mg, 46%).

The slower eluting product was isolated as a white solid and identified as E110 (13 mg, 10%).

Example E112 (6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-{3-fluoro-4-[(2-hydroxy-ethylamino)-methyl]-phenyl}-methanone

Lithium aluminium hydride (14.5 mg, 0.38 mmol) was added to a solution of [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamino]-acetic acid methyl ester from example E110 (58.5 mg, 0.13 mmol) in THF (5 ml), and the mixture was stirred at room temperature for 30 min. Before being quenched with MeOH and extracted with EtOAc. The organic extract was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane then 20% methanol:80% dichloromethane) to give a pale yellow solid identified as the title compound (15 mg, 28%).

Example E113 {[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylcarbamoyl]-methyl}-carbamic acid tert-butyl ester

HBTU (165 mg, 0.44 mmol) was added to a solution of N-(tert-butoxycarbonyl)glycine (65 mg, 0.37 mmol) in DMF (10 ml) and the mixture was stirred for 30 min at room temperature. (4-Aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (100 mg, 0.22 mmol) and DIEA (0.228 ml, 1.31 mmol) were added and the mixture was stirred for 24 h at room temperature. The solution was diluted with EtOAc, washed with water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane then 10% methanol:90% dichloromethane) to give a white solid identified as the title compound (123 mg, 100%).

Example E114 2-Amino-N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-acetamide hydrochloride

{[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylcarbamoyl]-methyl}-carbamic acid tert-butyl ester from Example E113 (120 mg, 0.22 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (95 mg, 83%).

Example E115 4-[(3-Chloro-benzoylamino)-methyl]-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide Example E115.1 N-(4-Chloro-phenyl)-4-cyano-3,N-dimethyl-benzamide

A mixture of 4-cyano-3-methyl-benzoic acid from Example E6 (3.4 g, 21 mmol) and thionyl chloride (10 ml, 137 mmol) in dichloromethane (50 ml) was heated at reflux for 2 h. After cooling at room temperature, solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (50 ml). (4-Chlorophenyl)-methyl amine (3.0 g, 21 mmol) and triethylamine (to pH9) were added and the mixture was stirred at room temperature for 20 h then concentrated in vacuo. The residue was redissolved in EtOAc, washed with 1M KHSO4, water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 35% EtOAc:65% cyclohexane) to yield the title compound (5.1 g, 85%).

Example E115.2 4-Aminomethyl-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide

A solution of N-(4-chloro-phenyl)-4-cyano-3,N-dimethyl-benzamide from Example E115.1 (5.1 g, 17.9 mmol) in methanol (250 ml) was treated with cobalt(II) chloride hexahydrate (8.4 g, 35.8 mmol). The mixture was stirred for 15 min at room temperature then cooled down to 0° C. and sodium borohydride (6.7 g, 179 mmol) was added portionwise. The mixture was stirred for 1 h at room temperature, filtered through Celite® filter agent, washed with methanol and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:10% methanol:89% dichloromethane) to yield the title compound (3.6 g, 70%).

Example E115.3 4-[(3-Chloro-benzoylamino)-methyl]-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide

3-Chlorobenzoyl chloride (61 mg, 0.35=01) and triethylamine (to pH9) were added to a solution of 4-aminomethyl-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide from Example E115.2 (100 mg, 0.35 mmol) in dichloromethane (5 ml) at room temperature. The mixture was stirred for 1 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (101 mg, 69%).

Example E116 1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-[(4-chloro-phenyl)-methyl-carbamoyl]-2-methyl-benzylamide

PyBroP (212 mg, 0.45 mmol) and 1-cyclopropylmethyl-piperidine-4-carboxylic acid from Example E15a (76 mg, 0.42 mmol) were added to a solution of 4-aminomethyl-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide from Example E115.2 (100 mg, 0.35 mmol) in dichloromethane (5 ml) and DMF (1 ml). The mixture was stirred at room temperature for 18 h then solvents were removed in vacuo and azeotroped with toluene. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (34 mg, 22%).

Example E117 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-[(4-chloro-phenyl)-methyl-carbamoyl]-2-methyl-benzylamide

HBTU (296 mg, 0.78 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid from Example E15 (182 mg, 0.73 mmol) in DMF (5 ml) and DIEA (0.272 ml, 1.56 mmol). The mixture was stirred at room temperature for 2 h then 4-aminomethyl-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide from Example E115.2 (150 mg, 0.52 mmol) was added. The mixture was stirred for 2 h at room temperature then diluted with EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (209 mg, 83%).

Example E118 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-methyl-4-[methyl-(4-trifluoromethyl-phenyl)-carbamoyl]-benzylamide Example E118.1 4-Cyano-3-methyl-N-(4-trifluoromethyl-phenyl)-benzamide

A mixture of 4-cyano-3-methyl-benzoic acid from Example E6 (750 mg, 4.6 mmol) and thionyl chloride (1.02 ml, 14.0 mmol) in toluene (40 ml) was heated at reflux for 2 h. After cooling at room temperature, solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (25 ml) then 4-trifluoromethylaniline hydrochloride (1.11 g, 5.6 mmol) in dichloromethane (5 ml) and triethylamine (1.95 ml, 14.0 mmol) was added. The mixture was stirred at room temperature for 2 days, washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 20% EtOAc:80% cyclohexane) to yield the title compound (1.13 g, 80%).

Example E118.2 4-Cyano-3,N-dimethyl-N-(4-trifluoromethyl-phenyl)-benzamide

4-Cyano-3-methyl-N-(4-trifluoromethyl-phenyl)-benzamide from Example E118.1 (1.10 g, 3.6 mmol) was dissolved in DMF (10 ml) and cooled down to 0° C. Sodium hydride (60% dispersion in oil, 174 mg, 4.3 mmol) was added and the mixture was stirred for 30 min at room temperature. Methyl iodide (0.27 ml, 4.3 mmol) was added and the mixture was stirred for 20 h. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in EtOAc, washed with brine, dried and concentrated in vacuo to yield the title compound (1.08 g, 94%).

Example E118.3 4-Aminomethyl-3,N-dimethyl-N-(4-trifluoromethyl-phenyl)-benzamide

A solution of 4-cyano-3,N-dimethyl-N-(4-trifluoromethyl-phenyl)-benzamide from Example E118.2 (1.08 g, 3.4 mmol) in methanol (40 ml) at room temperature was treated with cobalt(II) chloride hexahydrate (1.61 g, 6.8 mmol). The mixture was stirred for 10 min then sodium borohydride (1.28 g, 34 mmol) was added portionwise. The mixture was stirred for 20 h then saturated NH4Cl solution (10 ml) was added. The mixture was stirred for 30 min, filtered through glass-fibre paper and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:9% methanol:90% dichloromethane) to yield the title compound (863 mg, 79%).

Example E118.4 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-methyl-4-[methyl-(4-trifluoromethyl-phenyl)-carbamoyl]-benzylamide

PyBroP (188 mg, 0.40 mmol) and 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid (82 mg, 0.38 mmol) were added to a solution of 4-aminomethyl-3,N-dimethyl-N-(4-trifluoromethyl-phenyl)-benzamide from Example E118.3 (100 mg, 0.31 mmol) in dichloromethane (5 ml) and DIEA (0.081 ml, 0.46 mmol). The mixture was stirred at room temperature for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a off-white powder identified as the title compound (22 mg, 14%).

Example E119 Cyclopropanecarboxylic acid 2-methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulene-6-carbonyl)-benzylamide Example E119.1 [2-Methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulene-6-carbonyl)-benzyl]-carbamic acid tert-butyl ester

A solution of 4-(tert-butoxycarbonylamino-methyl)-3-methyl-benzoic acid from Example E2h (400 mg, 1.5 mmol) in dichloromethane (20 ml) and triethylamine (to pH9) was treated with WSCD (573 mg, 3.0 mmol) and DMAP (183 mg, 1.5 mmol). The solution was stirred for 30 min at room temperature then 2-methyl-5,6-dihydro-4H-1-oxa-3,6-diaza-benzo[e]azulene from Example E6 (300 mg, 1.5 mmol) was added and the mixture was heated at reflux for 3 days. WSCD (287 mg, 1.5 mmol) was added and the mixture was heated at reflux for another 24 h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1N KHSO4, water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (62 mg, 9%).

Example E119.2 (4-Aminomethyl-3-methyl-phenyl)-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulen-6-yl)-methanone hydrochloride

[2-Methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulene-6-carbonyl)-benzyl]-carbamic acid tert-butyl ester from Example E119.1 (62 mg, 0.14 mmol) in methanol (0.5 ml) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (53 mg, 100%).

Example E119.3 Cyclopropanecarboxylic acid 2-methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulene-6-carbonyl)-benzylamide

Cyclopropanecarbonyl chloride (26 mg, 0.25 mmol) was added to a solution of (4-aminomethyl-3-methyl-phenyl)-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulen-6-yl)-methanone hydrochloride from Example E119.2 (85 mg, 0.22 mmol) in dichloromethane (5 ml) and triethylamine (to pH9) at room temperature. The mixture was stirred for 1 h then purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to give a white solid identified as the title compound (62 mg, 67%).

Example E120 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulene-6-carbonyl)-benzylamide

(4-Aminomethyl-3-methyl-phenyl)-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulen-6-yl)-methanone hydrochloride from Example E119.2 (89 mg, 0.225 mmol) was dissolved in dichloromethane (10 ml) and triethylamine (to pH9) at room temperature. 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid (53 mg, 0.25 mmol), DMAP (27 mg, 0.225 mmol) and PyBroP (165 mg, 0.36 mmol) were added and the mixture was heated at reflux for 18 h. The solution was diluted with EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:9% methanol:90% dichloromethane) to give a white solid identified as the title compound (84 mg, 69%).

Example E121 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzylamide Example E121.1 4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzonitrile

A mixture of 4-cyano-3-methyl-benzoic acid from Example E6 (557 mg, 3.4 mmol) and thionyl chloride (0.755 ml, 10.3 mmol) in toluene (100 ml) was heated at reflux for 2 h. After cooling to room temperature, solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (100 ml) and triethylamine (0.962 ml, 6.9 mmol) then 1-benzyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene from Example E5a (1.0 g, 3.4 mmol) was added. The mixture was stirred at room temperature for 2 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% pet. ether then EtOAc) to yield the title compound (844 mg, 56%).

Example E121.2 (4-Aminomethyl-3-methyl-phenyl)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone

A solution of 4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzonitrile from Example E121.1 (830 mg, 1.9 mmol) in methanol (10 ml) at room temperature was treated with cobalt(II) chloride hexahydrate (913 mg, 3.8 mmol). The mixture was stirred for 15 min then cooled down to 0° C. Sodium borohydride (726 mg, 19 mmol) was added portionwise and the reaction mixture was stirred for 2 h at room temperature. 35% Ammonia (5 ml) was added dropwise and the mixture was stirred for 30 min then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:9% methanol:90% dichloromethane) to yield the title compound (680 mg, 81%).

Example E121.3 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzylamide

HBTU (175 mg, 0.46 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid (86 mg, 0.34 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 2 h then (4-aminomethyl-3-methyl-phenyl)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E121.2 (100 mg, 0.23 mmol) and DIEA (0.12 ml, 0.69 mmol) were added. The mixture was stirred at room temperature for 18 h then solvents were removed in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 5% methanol:95% dichloromethane then 10% methanol:90% dichloromethane) to give a yellow foam identified as the title compound (114 mg, 79%).

Example E122 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-methyl-4-(2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-benzylamide

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzylamide from Example E121 (110 mg, 0.17 mmol) was dissolved in absolute ethanol (5 ml) and placed under an inert atmosphere. 10% Palladium on carbon (110 mg) and cyclohexene (0.176 ml, 1.7 mmol) were added and the mixture was heated at 60° C. for 3 h. The catalyst was filtered off through Celite® filter agent and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (45 mg, 48%).

Example E123 Cyclopropanecarboxylic acid 2-methyl-4-(2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-benzylamide Example E123.1 Cyclopropanecarboxylic acid 4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzylamide

DIEA (0.176 ml, 1.02 mmol) and cyclopropanecarbonyl chloride (0.033 ml, 0.36 mmol) were added to a solution of (4-aminomethyl-3-methyl-phenyl)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E121.2 (150 mg, 0.34 mmol) in dichloromethane (5 ml) at room temperature. The mixture was stirred for 20 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give the title compound (155 mg, 90%).

Example E123.2 Cyclopropanecarboxylic acid 2-methyl-4-(2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-benzylamide

Cyclopropanecarboxylic acid 4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzylamide from Example E123.1 (155 mg, 0.31 mmol) was dissolved in absolute ethanol (10 ml) and placed under an inert atmosphere. 10% Palladium on carbon (155 mg) and cyclohexene (0.311 ml, 3.1 mmol) were added and the mixture was heated at 60° C. for 18 h. The catalyst was filtered off through Celite® filter agent and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (67 mg, 53%).

Example E124 Cyclopropanecarboxylic acid 2-methyl-4-(2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulene-6-carbonyl)-benzylamide Example E124.1 2-Methyl-4-(2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulene-6-carbonyl)-benzonitrile

A mixture of 4-cyano-3-methyl-benzoic acid from Example E6 (147 mg, 0.91 mmol) was dissolved in dichloromethane (25 ml) and 2 drops of DMF and cooled down to 0° C. Oxalyl chloride (0.1 ml) was added slowly and the mixture was stirred for 2 h at room temperature. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (10 ml) and cooled down to 0° C. Triethylamine (0.5 ml) and 2-methyl-5,6-dihydro-4H-3-thia-1,6-diaza-benzo[e]azulene from Example E7 (165 mg, 0.76 mmol) in dichloromethane (10 ml) were added and the mixture was stirred for 2 days at room temperature. Another 0.91 mmol of acid chloride was formed as previously and added to the mixture. The solution was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% EtOAc:90% cyclohexane then 20% EtOAc:80% cyclohexane) to yield the title compound (220 mg, 80%).

Example E124.2 (4-Aminomethyl-3-methyl-phenyl)-(2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulen-6-yl)-methanone

A solution of 2-methyl-4-(2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulene-6-carbonyl)-benzonitrile from Example E124.1 (190 mg, 0.53 mmol) in methanol (15 ml) at room temperature was treated with cobalt(II) chloride hexahydrate (275 mg, 1.15 mmol). The mixture was stirred for 20 min then cooled down to 0° C. Sodium borohydride (200 mg, 5.3 mmol) was added portionwise and the mixture was stirred for 20 h at room temperature. Saturated NH4Cl (2 ml) was added dropwise and the mixture was stirred for 30 min then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:9% methanol:90% dichloromethane) to yield the title compound (100 mg, 52%).

Example E124.3 Cyclopropanecarboxylic acid 2-methyl-4-(2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulene-6-carbonyl)-benzylamide

DIEA (0.02 ml, 0.115 mmol) and cyclopropanecarbonyl chloride (0.008 ml, 0.088 mmol) were added to a solution of (4-aminomethyl-3-methyl-phenyl)-(2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulen-6-yl)-methanone from E124.2 (20 mg, 0.055 mmol) in dichloromethane (5 ml) at 0° C. The mixture was stirred for 20 h at room temperature then concentrated in vacuo and purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (11 mg, 46%).

Example E125 N-[4-(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzyl]-isobutyramide Example E125.1 4-[1-(4-Cyano-3-methyl-benzoyl)-9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl]-2-methyl-benzonitrile

A mixture of 4-cyano-3-methyl-benzoic acid from Example E6 (262 mg, 1.6 mmol) was dissolved in dichloromethane (20 ml) and 2 drops of DMF and cooled down to 0° C. Oxalyl chloride (0.6 ml) was added and the mixture was stirred for 0.5 h at room temperature. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (10 ml) and added to a solution of 9-chloro-2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene from Example E7 (190 mg, 0.8 mmol) and DIEA (0.5 ml) in dichloromethane (10 ml) and the mixture was stirred for 20 h. at room temperature. The solvents were removed in vacuo and the residue was taken up in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 40% EtOAc:60% cyclohexane) to yield the title compound (124 mg, 30%).

Example E125.2 4-(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzonitrile

4-[1-(4-Cyano-3-methyl-benzoyl)-9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl]-2-methyl-benzonitrile from E125.1 (124 mg, 0.24 mmol) was dissolved in MeOH 5 ml). 2M NaOH (2 ml) was added, and the mixture was stirred for 1 h. at room temperature. The solvents were removed in vacuo, and azeotroped with toluene. The residue was taken up in EtOAc, was with saturated NaHCO3 then brine, dried and concentrated in vacuo to yield the title compound (80 mg, 89%)

Example E125.3 (4-Aminomethyl-3-methyl-phenyl)-(9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone

A solution of 4-(9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzonitrile from E125.2 (80 mg, 0.2 mmol) in methanol (5 ml) at room temperature was treated with cobalt(II) chloride hexahydrate (101 mg, 0.4 mmol). The mixture was cooled to 0° C. then sodium borohydride (80 mg, 2.1 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 30 min. then for 2 h at room temperature then saturated NH4Cl was added. The mixture was stirred for 10 min then the solid was filtered off through Celite® filter agent and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:9% methanol:90% dichloromethane) to yield the title compound (24 mg, 30%).

Example E125.4 N-[4-(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzyl]-isobutyramide

Isobutyryl chloride (0.07 ml, 0.07 mmol) was added to a solution of (4-aminomethyl-3-methyl-phenyl)-(9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E125.3 (24 mg, 0.07 mmol) in dichloromethane (3 ml) and DIEA (0.10 ml, 0.57 mmol) at 0° C. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane to 10% methanol:90% dichloromethane) to give a colourless oil identified as the title compound 24 mg, 85%).

Example A In Vitro Testing

Compounds were assayed to determine their ability to inhibit the cellular consequences of AVP stimulation on intact cells. In the assay, the compounds of the invention cause significant inhibition of cellular activation at concentrations of 30 μM or less. Preferred compounds cause significant inhibition at concentrations of 300 nM.

Example B Tablet for Oral Administration

Tablets containing 100 mg of the compound of Example E8 as the active agent may be prepared from the following:

Compound of Example E8 200.0 g Corn starch 71.0 g Hydroxypropylcellulose 18.0 g Carboxymethylcellulose calcium 13.0 g Magnesium stearate 3.0 g Lactose 195.0 g Total 500.0 g

The materials are blended and then pressed to give 2000 tablets of 250 mg, each containing 100 mg of the compound of Example E8.

All the cited references are hereby incorporated in their entirety.

Schemes and Structures Example E1

Example E2

Examples E2a-g Example E2a 4-Aminomethyl-3-chloro-benzoic acid tert-butyl ester

Example E2b 4-(tert-Butoxycarbonylamino-methyl)-3-chloro-benzoic acid

Example E2c 4-(tert-Butoxycarbonylamino-methyl-3-nitro-benzoic acid

Example E2d 4-Cyano-3-methyl-benzoic acid

Example E2e 4-Cyano-2-methyl-benzoic acid

Example E2f 4-(tert-Butoxycarbonylamino-methyl)-2-fluoro-benzoic acid

Example E2g 4-Cyano-3,5-dimethyl-benzoic acid

Example E2h

Example E3

Example E4

Example E5

Example E5a

Example E6

Example E7

Example E8

Example E9

Example E10

Example E11

Example E12

Example E13

Example E14

Example E15

Example E15a

Example E16

Example E17

Example E18

Example E19

Example E20

Example E21

Example E22

Example E23

Example E24

Example E25

Example E26

Example E27

Example E28

Example E29

Example E30

Example E31

Example E32

Example E33

Example E34

Example E35

Example E36

Example E37

Example E38

Example E39

Example E40

Example E41

Example E41a

Example E41b

Example E41c

Example E42

Example E43

Example E44

Example E45

Example E46

Example E47

Example E48

Example E49

Example E50

Example E51

Example E52

Example E53

Example E54

Example E55

Example E56

Example E57

Example E58

Example E59

Example E60

Example E61

Example E62

Example E63

Example E64

Example E65

Example E66

Example E67

Example E68

Example E69

Example E70

Example E71

Example E72

Example E73

Example E74

Example E75

Example E76

Example E77

Example E78

Example E79

Example E80

Example E81

Example E82

Example E83

Example E84

Example E85

Example E86

Example E87

Example E88

Example E89

Example E90

Example E91

Example E92

Example E93

Example E94

Example E95

Example E96

Example E97

Example E98

Example E99

Example E100

Example E101

Example E102

Example E103

Example E104

Example E105

Example E106

Example E107

Example E108

Example E109

Example E110 and Example E111

Example E112

Example E113

Example E114

Example E115

Example E116

Example E117

Example E118

Example E119

Example E120

Example E121

Example E122

Example E123

Example E124

Example E125

Example Tables

The following compounds were prepared using methods analogous to those described above.

Example E5 and Compound number 2 have particular utility as intermediates.

Compound MS number R8 (ESI)+: [M + H]+ = 1H NMR: δ (ppm) 1 E5 H 2 Cl 234.0, 236.0 2.43 (3H, s), 2.98 (2H, d, J = 5.2 Hz), 3.34 (2H, t, J = 5.2 Hz), 6.59 (2H, d, J = 8.4 Hz), 6.90-6.95 (1H, m), 7.80-8.10 (1H, m)

Compound MS: number R1 R4 R7 [M + H]+ 3 E8 F Me 562.4  4 Me Me 558.4  5 Me Me 528.4  6 Me Me 514.3  7 Me Me 544.4  8 Me Me 556.6  9 Me Cl 587.4, 580.4 10 Me Cl 548.3 550.3 11 F Me 532.3 12 F Cl 582.4, 584.4 13 F Cl 552.3, 554.3 14 F F 566.2 15 Cl Cl 598.3, 600.4 16 Cl Cl 568.1 17 Cl Me 578.4, 580.4 18 Cl Me 548.3, 550.3 19 Me Me 532.5 20 Me Me 622.4 21 Me Cl 576.4, 578.3 22 Me Cl 564.4, 566.4 23 Me Cl 534.3, 536.3 24 Me Cl 564.4, 566.4 25 Me Cl 550.4, 552.4 26 Me Cl 536.4, 538.1 27 Me Me 544.4 28 Me Me 530.8 29 Me Me 516.5

Com- MS: pound [M + number R1 R4 R7 R8 R9 H]+ 30 Me H Me H 558.4 31 F Me H H 562.4

Compound MS: number R1 R4 R7 [M + H]+ 32 Me Cl 527.1, 529.1 33 Me Me 507.4

Compound MS: number R1 R4 R7 [M + H]+ 34 Me Me 493.4 35 Me Cl 513.1

Compound MS: number R1 R4 R9 [M + H]+ 36 Me Me 491.8

MS: Compound (ESI)+: number X2 R1 R4 R10 [M + H]+ 37 NH Me Cl 557.4 38 NH Me Me 557.0 39 O Me H 544.5 40 NH Me H 543.4

Compound MS: number X2 R1 R4 R10 [M + H]+ 41 S Me Me 544.2 42 S Me H 530.4 43 S Me H 560.4

Compound number R3 R4 R7 MS: [M + H]+ 44 Me Me 558.4 45 Me Me 528.4 46 Me Cl 578.3, 580.3 47 Me Cl 548.3, 550.3 48 F Me 562.4 49 F Me 532.4 50 F Cl 582.4, 584.3 51 F Cl 552.3, 554.3 52 Cl Cl 598.3, 600.3 53 Cl Cl 568.3 54 Cl Me 578.3, 580.3 55 Cl Me 548.3, 550.3

Compound number 1H NMR: δ(ppm)  3 E8 0.86 (9H, s), 1.33-1.39 (2H, m), 2.12 (3H, s), 2.27-2.38 (6H, m), 3.33-3.35 (4H, m), 3.68 (3H, s), 3.92, (1H, d, J = 14.3 Hz), 4.25 (2H, d, J = 5.4 Hz), 5.45 (1H, t, J = 5.4 Hz), 5.79 (1H, d, J = 14.3 Hz), 6.43 (1H, d, J = 8.0 Hz), 6.53 (1H, d, J = 8.0 Hz), 6.79-7.00 (4H, m), 7.17 (1H, s), 7.31 (1H, s)  4 0.88 (9H, s), 1.34-1.41 (2H, m), 2.09 (3H, s), 2.18 (3H, s), 2.29-2.36 (2H, m), 2.40 (4H, t, J = 4.7 Hz), 3.37 (4H, t, J = 4.7 Hz), 3.75 (3H, s), 3.94 (1H, d, J = 14.4 Hz), 4.24 (2H, d, J = 5.2 Hz), 4.95 (1H, t), 5.85 (1H, d, J = 14.4 Hz), 6.53 (1H, q, J = 7.9 Hz), 6.76 (1H, d, J = 5.7 Hz), 6.90 (1H, s), 7.02-7.11 (3H, m), 7.58 (1H, s)  5 0.05-0.09 (2H, m), 0.47-0.54 (2H, m), 0.81-0.86 (1H, m), 2.08 (3H, s), 2.16 (3H, s), 2.24 (2H, d, J = 6.4 Hz), 2.47-2.49 (4H, m), 3.38-3.44 (4H, m), 3.67 (3H, s), 3.92 (1H, d, J = 14.3 Hz), 4.22 (2H, m), 4.92 (1H, m), 5.85 (1H, d, J = 14.3 Hz), 6.43-6.56 (2H, m), 6.66-6.85 (3H, m), 7.07-7.24 (3H, m)  6 0.45-0.47 (4H, m), 1.64 (1H, m), 2.05 (3H, s), 2.13 (3H, s), 2.56 (4H, m), 3.32 (4H, m), 3.65 (3H, s), 3.90 (1H, d, J = 14.6 Hz), 4.18 (2H, m), 5.21 (1H, m), 5.82 (1H, d, J = 14.6 Hz), 6.43 (1H, d, J = 8.0 Hz), 6.53 (1H, d, J = 8.0 Hz), 6.80-6.85 (3H, m), 6.93 (1H, s), 7.04 (1H, s), 7.16 (1H, s)  7 0.84 (3H, s), 0.86 (3H, s), 1.28-1.37 (2H, m), 1.48-1.60 (1H, m), 2.01 (3H, s), 2.10 (3H, s), 2.22-2.35 (2H, m), 2.32 (4H, br t), 3.34 (4H, br t), 3.59 (3H, s), 3.90 (1H, d, J = 14.6 Hz), 4.16 (2H, d, J = 4.9 Hz), 5.15 (1H, t, J = 5.2 Hz), 5.81 (1H, d, J = 14.6 Hz), 6.40 (1H, d, J = 7.9 Hz), 6.51 (1H, d, J = 7.9 Hz), 6.69-6.83 (3H, m), 7.01 (1H, s), 7.11 (1H, s), 7.14 (1H, s)  8 1.06-1.23 (2H, m), 1.38-1.59 (4H, m), 1.63-1.78 (2H, m), 1.98-2.05 (1H, m), 2.07 (3H, s), 2.15 (3H, s), 2.22 (2H, d, J = 7.4 Hz), 2.35 (4H, t, J = 4.7 Hz), 3.33 (4H, t, J = 4.7 Hz), 3.67 (3H, s), 3.91 (1H, d, J = 14.6 Hz), 4.22 (2H, d, J = 5.2 Hz), 4.84 (1H, br t), 5.84 (1H, d, J = 14.6 Hz), 6.43 (1H, d, J = 8.2 Hz), 6.54 (1H, d, J = 8.2 Hz), 6.67 (1H, s), 6.76 (1H, s), 6.77-6.88 (2H, m), 7.07 (1Hs), 7.18 (1H, s)  9 0.88 (9H, s), 1.34-1.41 (2H, m), 2.09 (3H, s), 2.25-2.36 (2H, m), 2.36-2.41 (4H, m), 3.35-3.42 (4H, m), 3.72 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.24 (2H, d, J = 4.45 Hz), 5.02 (1H, br t), 5.83 (1H, d, J = 14.6 Hz), 6.59 (1H, s), 6.88 (1H, s), 7.01-7.09 (3H, m), 7.56-7.63 (2H, m) 10 0.11 (2H, q, J = 4.7 Hz), 0.52 (2H, q, J = 4.7 Hz), 0.76-0.93 (1H, m), 2.10 (3H, s), 2.31 (2H, d, J = 6.4 Hz), 2.45-2.62 (4H, m), 3.39-3.53 (4H, m), 3.79 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.23-4.25 (2H, m), 5.27 (1H, s), 5.81 (1H, d, J = 14.6 Hz), 6.58 (2H, s), 6.80-6.90 (2H, m), 7.07 (3H, s), 7.19 (1H, s) 11 0.05-0.11 (2H, m), 0.47-0.55 (2H, m), 0.75-0.89 (1H, m), 2.18 (3H, s), 2.24 (2H, d, J = 6.7 Hz), 2.47 (4H, m), 3.38 (4H, m), 3.75 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.31 (2H, d, J = 5.7 Hz), 5.13 (1H, t, J = 5.4 Hz), 5.82 (1H, d, J = 14.6 Hz), 6.47-6.58 (2H, m), 6.72-6.80 (2H, m), 6.87-6.95 (2H, m), 7.00-7.04 (1H, m), 7.08-7.17 (1H, m) 12 0.86 (9H, s), 1.33-1.39 (2H, m), 2.28-2.38 (6H, m), 3.37 (4H, m), 3.66 (3H, m), 3.94 (1H, d, J = 14.6 Hz), 4.28 (2H, d, J = 5.5 Hz), 5.41 (1H, t, J = 5.5 Hz), 5.78 (1H, d, J = 14.6 Hz), 6.56 (2H, s), 6.84-6.88 (2H, m), 7.00- 7.06 (2H, m), 7.18 (1H, s), 7.98 (1H, s) 13 0.27-0.29 (2H, m), 0.65-0.67 (2H, m), 0.94-1.10 (1H, m), 1.36-1.56 (2H, m), 2.59 (1H, d, J = 6.4 Hz), 2.76-2.89 (4H, m), 3.54-3.70 (4H, m), 3.83 (3H, s), 3.96 (1H, d, J = 14.6), 4.31-4.35 (2H, m), 5.81 (1H, d, J = 14.6 Hz), 6.63 (1H, s), 6.83-7.00 (1H, m), 7.11 (4H, s), 7.23-7.24 (1H, m), 7.70 (1H, s) 14 0.89 (9H, s), 1.37-1.43 (2H, m), 2.33-2.43 (6H, m), 3.35-3.39 (4H, m), 3.74 (3H, s), 3.96 (1H, d, J = 14.6 Hz), 4.34 (2H, d, J = 5.0 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.35-6.41 (1H, m), 6.62-6.73 (2H, m), 6.80 (1H, s), 6.89-6.93 (2H, m), 7.06-7.12 (1H, m) 15 0.87 (9H, s), 1.33-1.39 (2H, m), 2.28-2.38 (6H, m), 3.37 (4H, m), 3.66 (3H, m), 3.94 (1H, d, J = 14.6 Hz), 4.31 (2H, d, J = 5.5 Hz), 5.45 (1H, t, J = 5.5 Hz), 5.78 (1H, d, J = 14.6 Hz), 6.91 (1H, m), 7.03 (2H, m), 7.19 (2H, m), 7.84 (1H, s) 16 (CD3OD): 0.14-0.18 (2H, m), 0.52-0.59 (2H, m), 0.89 (1H, m), 2.28-2.30 (2H, m), 2.52-2.56 (4H, m), 3.43-3.47 (4H, m), 3.80 (3H, s), 3.97 (1H, d, J = 14.6 Hz), 4.34 (2H, d, J = 4.5 Hz), 5.73 (1H, d, J = 14.6 Hz), 6.64-6.77 (2H, m), 7.08-7.17 (2H, m), 7.23-7.28 (3H, m) 17 0.87 (9H, s), 1.36 (2H, m), 2.12 (3H, s), 2.32 (6H, m), 3.39 (4H, m), 3.66 (3H, s), 3.92 (1H, d, J = 14.3 Hz), 4.28 (2H, m), 5.43 (1H, m), 5.78 (1H, d, J = 14.3 Hz), 6.48 (1H, d, J = 7.9 Hz), 6.52 (1H, d, J = 7.9 Hz), 6.78 (1H, s), 6.88-6.98 (2H, m), 7.05 (1H, s), 7.17 (1H, m) 18 0.06-0.08 (2H, m), 0.48-0.51 (2H, m), 0.76-0.89 (1H, m), 2.15 (3H, s), 2.21-2.29 (2H, m), 2.44-2.48 (4H, m), 3.36-3.38 (4H, m), 3.68 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.30 (2H, d, J = 6.0 Hz), 5.33 (1H, m), 5.80 (1H, d, J = 14.6 Hz), 6.48-6.55 (2H, m), 6.77-7.00 (4H, m), 7.19-7.21 (2H, m) 19 CD3OD: 2.18 (3H, s), 2.22 (3H, s), 3.05-3.09 (4H, m), 3.47 (2H, s), 3.58- 3.62 (4H, m), 3.79 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.25 (2H, s), 5.75 (1H, d, J = 14.6 Hz), 6.47 (1H, d, J = 8.0 Hz), 6.59 (1H, d, J = 8.0 Hz), 6.97-7.06 (4H, m), 7.21 (1H, s) 20 2.02 (3H, s), 2.11 (3H, s), 2.39-2.50 (4H, m), 3.22 (2H, s), 3.32-3.43 (4H, m), 3.60 (3H, s), 3.90 (1H, d, J = 14.6 Hz), 4.16 (2H, d, J = 5.0 Hz), 5.12 (2H, s), 5.25 (1H, t, J = 5.0 Hz), 5.80 (1H, d, J = 14.6 Hz), 6.41 (1H, d, J = 7.9 Hz), 6.51 (1H, d, J = 7.9 Hz), 6.76-6.83 (3H, m), 7.02 (1H, s), 7.12-7.14 (2H, m), 7.28-7.31 (5H, m) 21 1.11-1.18 (2H, m), 1.45-1.56 (4H, m), 1.67-1.72 (2H, m), 1.98-2.01, (1H, m), 2.04 (3H, s), 2.22 (2H, d, J = 7.2 Hz), 2.29-2.50 (4H, m), 3.30-3.41 (4H, m), 3.62 (3H, s), 3.91 (1H, d, J = 14.6 Hz), 4.19-4.21 (2H, m), 5.04-5.06 (1H, m), 5.80 (1H, d, J = 14.6 Hz), 6.53-6.54 (2H, m), 6.80-6.84 (2H, m), 7.01-7.03 (2H, m), 7.16 (1H, s), 7.72 (1H, s) 22 0.84 (9H, s), 2.05 (2H, s), 2.12 (3H, s), 2.41-2.54 (4H, m), 3.27-3.39 (4H, m), 3.72 (3H, s), 3.92 (1H, d, J = 14.6 Hz), 4.26-4.27 (2H, m), 4.66-4.68 (1H, m), 5.85 (1H, d, J = 14.6 Hz), 6.58-6.59 (2H, m), 6.88-6.92 (2H, m), 6.98-7.00 (2H, m), 7.09 (1H, s), 7.21 (1H, s) 23 0.38-0.44 (4H, m), 1.57-1.58 (1H, m), 2.04 (3H, s), 2.53 (4H, m), 3.31 (4H, m), 3.62 (3H, s), 3.91 (1H, d, J = 14.6 Hz), 4.20 (2H, m), 5.08 (1H, m), 5.80 (1H, d, J = 14.6 Hz), 6.54-6.58 (2H, m), 6.80-6.86 (2H, m), 7.01-7.03 (2H, m), 7.16 (1H, s), 7.71 (1H, s) 24 0.85 (6H, d, J = 6.4 Hz), 1.23-1.36 (2H, m), 1.49-1.56 (1H, m), 2.01 (3H, s), 2.23-2.35 (6H, m), 3.36 (4H, m), 3.62 (3H, s), 3.91 (1H, d, J = 14.6 Hz), 4.18 (2H, m), 5.29 (1H, m), 5.78 (1H, d, J = 14.6 Hz), 6.48-6.56 (2H, m), 6.80-6.86 (2H, m), 6.98-7.02 (2H, m), 7.15 (1H, s), 8.12 (1H, s) 25 0.85 (6H, d, J = 6.4 Hz) 1.73 (1H, m), 2.05 (5H, m), 2.26-2.31 (4H, m), 3.34 (4H, m), 3.62 (3H, s), 3.91 (1H, d, J = 14.6 Hz), 4.21 (2H, m), 5.02 (1H, m), 5.80 (1H, d, J = 14.6 Hz), 6.54 (2H, m), 6.84-6.87 (2H, m), 7.02 (2H, m), 7.16 (1 H, s), 7.72 (1H, s) 26 0.85 (3H, t, J = 7.2 Hz), 1.40-1.49 (2H, m), 2.01 (3H, s), 2.22-2.28 (2H, m), 2.34 (4H, m) 3.35 (4H, m), 3.58 (3H, s), 3.90 (1H, d, J = 14.6 Hz), 4.18 (2H, m), 5.21 (1H, m), 5.77 (1H, d, J = 14.6 Hz), 6.51-6.55 (2H, m), 6.81-6.85 (2H, m), 7.00 (2H, m), 7.13 (1H, s), 7.88 (1H, s) 27 0.84 (9H, s), 2.04 (2H, s), 2.11 (3H, s), 2.18 (3H, s), 2.45 (4H, t, J = 4.7 Hz), 3.30 (4H, t, J = 4.7 Hz), 3.71 (3H, s), 3.92 (1H, d, J = 14.6 Hz), 4.24 (2H, d, J = 5.2 Hz), 4.66 (1H, br t), 5.86 (1H, d, J = 14.6 Hz), 6.41 (1H, s), 6.46 (1H, d, J = 7.9 Hz), 6.56 (1H, d, J = 7.9 Hz), 6.75 (1H, s), 6.88 (2H, s), 7.10 (1H, s), 7.20 (1H, s) 28 0.86 (6H, d, J = 6.7 Hz), 1.68-1.81 (1H, m), 2.05 (2H, d, J = 7.4 Hz), 2.09 (3H, s), 2.17 (3H, s), 2.32 (4H, t, J = 4.7 Hz), 3.33 (4H, t, J = 4.7 Hz), 3.69 (3H, s), 3.92 (1H, d, J = 14.6 Hz), 4.23 (2H, d, J = 4.9 Hz), 4.78 (1H, t, J = 4.9 Hz), 5.85 (1H, d, J = 14.6 Hz), 6.46 (1H, d, J = 7.9 Hz), 6.55 (1H, d, J = 7.9 Hz), 6.57 (1H, s), 6.76 (1H, s), 6.86 (2H, s), 7.08 (1 H, s), 7.19 (1H, s) 29 0.88 (3H, t, J = 7.4 Hz), 1.43-1.54 (2H, m), 2.12 (3H, s), 2.19 (3H, s), 2.28 (2H, t, J = 7.4 Hz), 2.38 (4H, t, J = 4.9 Hz), 3.35 (4H, t, J = 4.9 Hz), 3.73 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.25 (2H, d, J = 5.2 Hz), 4.66 (1H, br t), 5.87 (1H, d, J = 14.6 Hz), 6.29 (1H, s), 6.47 (1H, d, J = 7.7 Hz), 6.56 (1H, d, J = 7.7 Hz), 6.74 (1H, s), 6.89 (2H, s), 7.11 (1H, s), 7.21 (1H, s) 30 0.88 (9H, s), 1.32-1.42 (2H, m), 2.02 (3H, s), 2.14 (3H, s), 2.28-2.46 (6H, m), 3.30-3.42 (4H, m), 3.75 (3H, s), 3.94 (1H, d, J = 14.4 Hz), 4.26-4.32 (2H, m), 4.48-4.56 (1H, m), 5.87 (1H, d, J = 14.4 Hz), 6.07 (1H, s), 6.52 (1H, s), 6.78-6.97 (4H, m), 7.13 (1H, s) 31 0.88 (9H, s), 1.35-1.41 (2H, m), 2.28-2.42 (8H, m), 3.27-3.40 (4H, m), 3.82 (3H, s), 3.96 (1H, d, J = 14.4 Hz), 4.33 (2H, d, J = 5.4 Hz), 4.68-4.79 (1H, m), 5.80 (1H, s), 5.89 (1H, d, J = 14.4 Hz), 6.58-6.70 (2H, m), 6.88- 6.95 (2H, m), 6.96-7.12 (3H, m), 7.65 (1H, s) 32 0.88 (9H, s), 1.35-1.41 (2H, m), 2.00-2.18 (2H, m), 2.27-2.35 (2H, m), 2.36-2.43 (4H, m), 3.34-3.41 (4H, m), 3.44 (2H, s), 4.29 (2H, d, J = 5.2 Hz), 4.58-4.63 (1H, m), 6.48-6.61 (1H, m), 6.62-6.75 (1H, m), 6.88-7.03 (2H, m), 7.07-7.11 (2H, m) 33 0.87 (9H, s), 1.35-1.41 (2H, m), 2.16 (3H, s), 2.22 (3H, s), 2.23-2.36 (2H, m), 2.40 (4H, t, J = 4.7 Hz), 3.35 (4H, t, J = 4.7 Hz), 4.28-4.30 (2H, m), 4.50 (1H, br s), 6.52 (2H, br s), 6.88 (1H, s), 6.95 (2H, s), 7.11 (1H, s) 34 0.89 (9H, s), 1.36-1.43 (2H, m), 2.23 (3H, s), 2.31 (3H, s), 2.31-2.41 (2H, m), 2.43 (4H, t, J = 4.9 Hz), 3.40 (4H, t, J = 4.9 Hz), 3.95 (2H, t, J = 4.7 Hz), 4.31 (2H, t, J = 4.7 Hz), 4.41-4.44 (2H, m), 4.55-4.60 (1H, m), 6.47-6.51 (1H, m), 6.70 (1H, s), 6.81-7.00 (1H, m), 7.21-7.27 (2H, m), 7.34 (1H, s) 35 0.89 (9H, s), 1.36-1.43 (2H, m), 2.31 (3H, s), 2.32-2.39 (2H, m), 2.44 (4H, t, J = 4.9 Hz), 3.40 (4H, t, J = 4.9 Hz), 3.94 (2H, t, J = 4.4 Hz), 4.31 (2H, t, J = 4.4 Hz), 4.42 (2H, d, J = 5.4 Hz), 4.62 (1H, t, J = 5.2 Hz), 6.64- 6.73 (1H, m), 6.91 (1H, d, J = 2.2 Hz), 7.00-7.15 (1H, m), 7.24 (3H, d, J = 3.0 Hz) 36 0.88 (9H, s), 0.89 (3H, s), 1.32-1.42 (2H, m), 1.65-2.20 (4H, m), 2.30-2.45 (7H, m), 2.49 (2H, t, J = 5.2 Hz), 2.80-2.90 (1H, m), 3.36 (4H, br s), 3.60 (2H, t, J = 4.9 Hz), 4.25-4.40 (1H, m), 6.80-7.40 (6H, m), 7.84 (1H, s) 37 0.92 (9H, s), 1.42-1.49 (2H, m), 2.09 (3H, s), 2.48 (3H, s) 2.50-2.58 (4H, m), 2.80-3.03 (2H, m), 3.13-3.33 (1H, m), 3.40-3.53 (4H, m), 4.17-4.33 (2H, m), 4.90-5.08 (1H, m), 5.67-5.78 (1H, m), 6.54-6.58 (2H, m), 6.79-6.90 (2H, m), 7.10 (2H, s), 7.68 (2H, s), 8.13 (1H, d, J = 2.0 Hz) 38 0.89 (9H, s), 1.37-1.43 (2H, m), 2.13 (3H, s), 2.29 (3H, s), 2.30-2.47 (8H, m), 2.49 (3H, s), 2.76-2.88 (1H, m), 2.90-3.07 (1H, m), 3.31-3.42 (4H, m), 4.26 (2H, d, J = 4.2 Hz), 4.70-4.80 (1H, m), 4.96-5.08 (1H, m), 6.51 (1H, d, J = 7.9 Hz), 6.65 (2H, d, J = 7.4 Hz), 6.85 (1H, d, J = 7.7 Hz), 7.06 (1H, s), 7.86-7.97 (1H, m) 39 0.87 (9H, s), 1.33-1.39 (2H, m), 2.12 (3H, s), 2.27-2.36 (2H, m), 2.36- 2.43 (4H, m), 2.54 (3H, s), 2.82-2.91 (1H, m), 2.91-2.98 (1H, m), 3.20-3.27 (1H, m), 3.31-3.35 (4H, m), 4.27 (2H, t, J = 4.0 Hz), 4.54 (1H, t, J = 4.9 Hz), 5.11-5.16 (1H, m), 6.62-6.72 (2H, m), 6.88-6.98 (2H, m), 6.99 (1H, s), 7.15-7.23 (1H, m), 7.75-7.80 (1H, m) 40 0.82 (9H, s), 1.31-1.37 (2H, m), 2.20 (3H, s), 2.25-2.42 (6H, m), 3.32- 3.42 (4H, m), 3.55 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.06-4.11 (2H, m), 5.53 (1H, m), 5.77 (1H, d, J = 14.6 Hz), 6.49-6.57 (2H, m), 6.64-6.73 (2H, m), 6.80-6.94, (3H, m), 7.16 (1H, s), 7.67 (1H, s) 41 0.07-0.13 (2H, m), 0.49-0.55 (2H, m), 0.83-0.88 (1H, m), 2.17 (3H, s), 2.28 (2H, d, J = 6.4 Hz), 2.33 (3H, s), 2.49-2.53 (4H, m), 2.73 (3H, s), 3.02-3.17 (2H, m), 3.36-3.41 (4H, m), 4.27-4.31 (2H, m), 4.51 (1H, s), 5.11-5.18 (1H, m), 6.55 (1H, d, J = 7.9 Hz), 6.67 (1H, d, J = 7.0 Hz), 6.77 (1H, d, J = 7.0 Hz), 6.86 (1H, d, J = 7.9 Hz), 7.15 (1H, s), 8.15 (1H, s) 42 0.07-0.09 (2H, m), 0.46-0.54 (2H, m), 0.80-0.85, (1H, m), 2.15 (3H, s), 2.23-2.27 (2H, m), 2.45-2.49 (4H, m), 2.73 (3H, s), 3.10-3.18 (2H, m), 3.35-3.37 (4H, m), 3.48-3.68 (1H, m), 4.25-4.29 (2H, m), 4.48 (1H, m), 5.16 (1H, m), 6.67 (2H, m), 6.86 (1H, d, J = 7.9 Hz), 6.92-6.98 (1H, m), 7.12 (1H, s) 7.20 (1H, m) 8.36 (1H, d, J = 7.9 Hz) 43 0.88 (9H, s), 1.34-1.40 (2H, m), 2.14 (3H, s), 2.29-2.49 (6H, m), 2.72 (3H, s), 3.03-3.18 (2H, m), 3.31-3.35 (4H, m), 3.47-3.67 (1H, m), 4.21-4.31 (2H, m), 4.51-4.54 (1H, m), 5.12-5.19 (1H, m), 6.67 (2H, m), 6.85 (1H, d, J = 7.9 Hz), 6.92-6.97 (1H, m), 7.06-7.22 (2H, m), 8.36 (1H, dd, J = 1.2, 7.9 Hz) 44 0.85 (9H, s), 1.31-1.39 (2H, m), 1.99 (3H, s), 2.19 (3H, s), 2.24-2.40 (6H, m), 3.33-3.38 (4H, m), 3.53 (3H, s), 3.90 (1H, d, J = 14.6 Hz), 4.10-4.12 (2H, m), 5.56 (1H, m), 5.75 (1H, d, J = 14.6 Hz), 6.33-6.35 (1H, m), 6.52-6.56 (2H, m), 6.66-7.11 (3H, m), 7.14 (1H, s), 7.48 (1H, s) 45 0.01-0.06 (2H, m), 0.42-0.49 (2H, m), 0.75-0.81 (1H, m), 1.98 (3H, s), 2.17-2.25 (5H, m), 2.38-2.48 (4H, m), 3.32-3.41 (4H, m), 3.50 (3H, s), 3.89 (1H, d, J = 14.6 Hz), 4.11 (2H, m), 5.54 (1H, m), 5.75 (1H, d, J = 14.6 Hz), 6.34 (1H, dd, J = 1.0, 8.0 Hz), 6.50-6.54 (2H, m), 6.66-7.07 (3H, m), 7.13 (1H, s) 7.37 (1H, s) 46 0.88 (9H, s), 1.33-1.42 (2H, m), 2.24 (3H, s), 2.27-2.45 (6H, m), 3.35- 3.43 (4H, m), 3.68 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.20 (2H, d, J = 5.4 Hz), 5.01-5.07 (1H, m), 5.79 (1H, d, J = 14.6 Hz), 6.54 (1H, dd, J = 2.2, 8.4 Hz), 6.61-7.02 (5Hm), 7.05 (1H, d, J = 1.0 Hz), 7.53 (1H, d, J = 4.7 Hz) 47 0.01-0.06 (2H, m), 0.42-0.47 (2H, m), 0.76-0.80 (1H, m), 2.15-2.23 (5H, m), 2.41-2.46 (4H, m), 3.35-3.48 (4H, m), 3.54 (3H, s), 3.90 (1H, d, J = 14.6 Hz), 4.11 (2H, m), 5.46 (1H, m), 5.72 (1H, d, J = 14.6 Hz), 6.46 (1H, dd, J = 1.5, 8.5 Hz), 6.54-6.61 (2H, m), 6.67-6.73 (1H, m), 6.81-7.09 (2H, m), 7.13 (1H, s), 7.99 (1H, s) 48 0.84 (9H, s), 1.31-1.37 (2H, m), 1.99 (3H, s), 2.24-2.33 (6H, m), 3.34 (4H, m), 3.57 (3H, s), 3.90 (1H, d, J = 14.6 Hz), 4.08 (2H, m), 5.70 (1H, d, J = 14.6 Hz), 6.01 (1Hm), 6.34 (1H, m), 6.53-6.60 (2H, m), 6.70 (1H, s), 6.82-6.91 (2H, m), 7.10 (1H, s), 7.49 (1H, s) 49 0.02-0.08 (2H, m), 0.44-0.51 (2H, m), 0.77-0.82 (1H, m), 2.02 (3H, s), 2.16-2.24 (2H, m), 2.42-2.44 (4H, m), 3.36-3.42 (4H, m), 3.57 (3H, s), 3.92 (1H, d, J = 14.6 Hz), 4.11 (2H, m), 5.72 (1H, d, J = 14.6 Hz), 5.86 (1H, m), 6.36 (1H, dd, J = 1.0, 8.0 Hz), 6.54-6.89 (5H, m), 7.12 (1H, s), 7.27 (1H, s) 50 0.87 (9H, s), 1.33-1.40 (2H, m), 2.27-2.40 (6H, m), 3.34-3.42 (4H, m), 3.60 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.16 (2H, d, J = 5.2 Hz), 5.72 (1H, d, J = 14.6 Hz), 5.81 (1H, t, J = 5.4, 11.1 Hz), 6.50 (1H, dd, J = 2.2, 8.4 Hz), 6.60-6.73 (3H, m), 6.91-7.02 (3H, m), 8.00 (1H, s) 51 0.02-0.08 (2H, m), 0.44-0.48 (2H, m), 0.77-0.81 (1H, m), 2.20-2.24, (2H, m), 2.43 (4H, m), 3.37-3.47 (4H, m), 3.57 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.14 (2H, m), 5.70 (1H, d, J = 14.6 Hz), 5.82 (1H, m), 6.48 (1H, dd, J = 2.0, 8.5 Hz), 6.58-6.72 (3H, m), 6.89-7.00 (2H, m), 7.14 (1H, s), 7.92 (1H, s) 52 0.89 (9H, s), 1.34-1.42 (2H, m), 2.29-2.46 (6H, m), 3.35-3.44 (4H, m), 3.66 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 4.21 (2H, d, J = 5.4 Hz), 5.14-5.24 (1H, m), 5.76 (1H, d, J = 14.6 Hz), 6.58 (1H, dd, J = 2.2, 8.4 Hz), 6.74-7.00 (4H, m), 7.07 (1H, s), 7.22 (1H, s) 53 0.02-0.07 (2H, m), 0.43-0.48 (2H, m), 0.77-0.81 (1H, m), 2.19-2.24 (2H, m), 2.42-2.47 (4H, m), 3.37-3.41 (4H, m), 3.56 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.10 (2H, m), 5.68 (1H, d, J = 14.6 Hz), 5.89 (1H, m), 6.49 (1H, dd, J = 2.0, 8.5 Hz), 6.68-6.96 (5H, m), 7.14 (1H, s), 7.93 (1H, s) 54 0.82 (9H, s), 1.33-1.41 (2H, m), 1.99 (3H, s), 2.28-2.38 (6H, m), 3.36- 3.37 (4H, m), 3.60 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.07 (2H, m), 5.69 (1H, d, J = 14.6 Hz), 6.06 (1H, m), 6.37 (1H, m), 6.61-6.82 (3H, m), 6.94 (2H, m), 7.14 (1H, s), 7.46 (1H, s) 55 0.02-0.07 (2H, m), 0.43-0.50 (2H, m), 0.76-0.81 (1H, m), 1.97 (3H, s), 2.16-2.23 (2H, m), 2.41-2.45 (4H, m), 3.36-3.44, (4H, m), 3.54 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.05 (2H, m), 5.68 (1H, d, J = 14.6 Hz), 6.00 (1H, m), 6.34 (1H, m), 6.58-6.79 (4H, m), 6.90 (1H, s), 7.11 (1H, s), 7.35 (1H, s)

Compound number R3 R1 1H NMR: δ (ppm) MS 109 E10 Cl 0.42-0.90 (6H, m), 1.28 (6H, m), 1.78-1.80 (2H, m), 2.08 (1H, m), 2.95- 3.01 (2H, m), 3.66 (3H, s), 3.76 (1H, d, J = 14.6 Hz), 5.55 (1H, d, J = 14.6 Hz), 5.95 (1H, m), 6.97 (1H, dd, J = 8.4, 2.1 Hz), 7.03 (1H, s), 7.07 (1H, d, J = 8.4 Hz), 7.09 (1H, d, J = 2.1 Hz), 7.14 (1H, s) (ESI)+: [M + H]+ = 442.3, 444.3 110 Me 0.58-0.90 (6H, m), 1.23- 2.13 (9H, m), 2.33 (3H, s), 2.95-3.03 (2H, m), 3.68 (3H, s), 3.76 (1H, d, J = 14.6 Hz), 5.59 (1H, d, J = 14.6 Hz), 5.80 (1H, m), 6.15 (1H, s), 6.81-6.83 (2H, m), 6.97-7.00 (1H, m), 7.14 (1H, s) (ESI)+: [M + H]+ = 422.4 111 H 0.58-0.81 (6H, m), 1.31- 1.74 (6H, m), 1.69-1.80 (2H, m), 2.09-2.16 (1H, m), 2.89-2.98 (2H, m), 3.64 (3H, s), 3.80 (1H, d, J = 14.6 Hz), 5.58 (1H, d, J = 14.6 Hz), 6.49 (1H, m), 6.95-7.23 (5H, m), 7.39 (1H, s) (APCI)+: [M + H]+ = 408.3 112 Me CH3 113 Me (ESI)+: [M + H]+ = 458.7 114 Me (ESI)+: [M + H]+ = 492.2, 494.2 115 Me (ESI)+: [M + H]+ = 492.6, 494.2 116 Me (ESI)+: [M + H]+ = 492.2, 494.2 117 Me (ESI)+: [M + H]+ = 488.7 118 Me (ESI)+: [M + H]+ = 472.7 119 Me (ESI)+: [M + H]+ = 472.7 120 Me (ESI)+: [M + H]+ = 493.2 121 Me (ESI)+: [M + H]+ = 459.2 122 Me (ESI)+: [M + H]+ = 459.2 123 Me (ESI)+: [M + H]+ = 464.6 124 Me (ESI)+: [M + H]+ = 498.1 125 Me (ESI)+: [M + H]+ = 464.2 126 Me (ESI)+: [M + H]+ = 476.6 127 Me (ESI)+: [M + H]+ = 448.6 128 Me (ESI)+: [M + H]+ = 449.6 129 Me (ESI)+: [M + H]+ = 539.3 130 Me CH2CH3 (ESI)+: [M + H]+ = 410.7 131 Me CH2CH2CH3 (ESI)+: [M + H]+ = 424.7 132 Me C(CH3)3 (ESI)+: [M + H]+ = 438.3 133 Me (ESI)+: [M + H]+ = 464.7 134 Me CH2(CH2)3CH3 (ESI)+: [M + H]+ = 452.8 135 Me CH(CH2CH3)CH2CH2CH2CH3 (ESI)+: [M + H]+ = (ESI)+: [M + H]+ = 480.4 136 Me (ESI)+: [M + H]+ = 532.3 137 Me (ESI)+: [M + H]+ = 472.7 138 Me (ESI)+: [M + H]+ = 486.7 139 Me (ESI)+: [M + H]+ = 498.7 140 Me (ESI)+: [M + H]+ = 478.6 141 Me (ESI)+: [M + H]+ = 488.7 142 Me (ESI)+: [M + H]+ = 502.7 143 Me CH2CO2CH2CH3 (ESI)+: [M + H]+ = 468.2 144 Me CH2CH2CO2CH3 (ESI)+: [M + H]+ = 468.2 145 Me CH2(CH2)2CO2CH2CH3 (ESI)+: [M + H]+ = 496.7

MS Compound (ESI): number R1 R3 X [M + H]+ = 1H NMR: δ (ppm) 146 Cl S 458.4, 460.4 0.51-0.98 (6H, m), 1.11- 1.99 (7H, m), 2.30-2.41 (1H, m), 2.67 (3H, s), 2.83-3.08 (4H, m), 3.42- 3.62 (1H, m), 5.55 (1H, s), 7.10 (1H, d, J = 8.4 Hz), 7.25 (1H, d d, J = 2.5, 8.4 Hz), 8.38 (1H, d, J = 2.5 Hz) 147 Me S 438.2 0.55-0.62 (1H, m), 0.62- 0.72 (2H, m), 0.72-0.85 (1H, m), 0.85-1.00 (2H, m), 1.10-1.45 (4H, m), 1.45-1.95 (4H, m), 2.35- 2.50 (1H, m), 2.43 (3H, s), 2.68 (3H, s), 2.85- 3.10 (4H, m), 3.45-3.65 (1H, m), 4.75-4.85 (1H, m), 5.45-5.65 (1H, m), 7.00-7.15 (2H, m), 8.14 (1H, s)

Compound MS number R3 (ESI)+: [M + H]+ = 148 E10.2 Cl 149 Me 354.2 150 H 340.2

Compound MS number R8 (ESI)+: [M + H]+ = 151 E12 CH(CH3)2 396.4 152 CH2CH3 396.4 153 430.4 154 444.4 155 436.1 156 464.2, 466.2 157 464.3, 466.3 158 CH2CH2CH2CH3 410.4 159 394.4 160 458.4 161 CH2CH(CH3)2 410.4 162 410.3 163 431.1 164 472.4 165 446.4 166 431.4 167 436.3 168 CH2CF3 436.3 169 434.4 170 444.4 171 444.3 172 444.2 173 454.2 174 454.4 175 498.3 176 520.4 177 488.4

Com- MS pound (ESI)+: number R1 [M + H]+ = 178 E13 533.3 179 522.2, 524.2 180 536.4 181 519.7 182 438.2 183 504.7 184 436.7 185 474.7 186 508.6 187 488.7 188 454.7 189 426.2 190 556.2, 558.2 191 CH3 412.2 192 424.2 193 532.3

Com- MS pound R1 (ESI)+: number [M + H]+ = 194 CH2CH2CH2CH2CH3 458.4 E14 195 CH2CH3 416.4, 418.4 196 (CH2)2CN 441.5, 443.5 197 484.4, 486.4 198 482.4, 484.4 199 520.6, 522.6 200 548.5, 550.5 201 522.6, 524.6 202 464.5, 466.5 203 470.5, 472.5 204 CH2OH 418.3, 420.3 205 CO2CH(CH3)2 474.4, 476.4 206 600.6, 602.6 207 CH2CH(CH3)2 444.5, 446.5 208 CH2CH2OH 432.5 209 CN 413.4, 415.5 210 446.5, 448.5 211 434.3, 436.3 212 509.5, 511.5 213 428.4, 430.4 214 514.6, 516.6 215 414.4, 416.5 216 490.6, 492.6 217 540.6, 542.6 218 472.3, 474.4 219 489.4, 491.4 220 530.5, 532.5 221 COC(CH3)3 472.5, 474.5 222 CONH2 431.5, 533.5 223 499.5, 501.5 224 506.6, 508.6

Compound number R3 e R8 MS 1H NMR: δ (ppm) 225 H 0 CH2CH2C(CH3)3 (ESI)+: [M + H]+ = 535.5 0.45-0.80 (2H, m), 0.88 (9H, s), 1.20-1.62 (7H, m), 1.62-2.19 E16 (10H, m), 2.33-2.46 (2H, m), 3.72 (3H, s), 3.79 (1H, d, J = 14.6 Hz), 5.61 (1H, d, J = 14.6 Hz), 5.63-5.70 (1H, m), 6.10 (1H, s), 7.02 (2H, t, J = 8.4 Hz), 7.10-7.19 (3H, m), 7.26-7.28 (2H, m) 226 Cl 2 CO2C(CH3)3 (ESI)+: [M + H]+ = 613.4, 615.4 0.43-0.62 (1H, m), 0.64-0.83 (1H, m), 0.91-1.14 (2H, m), 1.22-1.81 (11H, m), 1.44 (9H, s), 1.98-2.07 (2H, m), 2.16 (2H, t, J = 7.7 Hz), 2.61 (2H, brs), 2.98 (2H, d, J = 5.4 Hz), 3.70 (3H, s), 3.75 (1H, d, J = 14.6 Hz), 4.02 (2H, d, J = 12.4 Hz), 5.55 (1H, d, J = 14.6 Hz), 5.95 (1H, t, J = 5.2 Hz), 6.96 (1H, dd, J = 2.0, 8.4 Hz), 7.04 (1H, d, J = 8.4 Hz), 7.09-7.13 (2H, m), 7.35 (1H, s) 227 H 0 CO2C(CH3)3 — d4-MeOH δ 0.46-0.80 (2H, m), 1.13-1.84 (11H, m), 1.44 (9H, s), 2.13-2.37 (2H, m), 2.74 (2H, brs), 2.89 (2H, t, J = 6.2 Hz), 3.72 (3H, s), 3.80 (1H, d, J = 14.6 Hz), 4.07 (2H, d, J = 13.4 Hz), 5.47 (1H, d, J = 14.6 Hz), 7.01-7.09 (1H, m), 7.14 (1H, s), 7.16-7.22 (1H, m), 7.26-7.37 (2H, m), 7.82-7.92 (2H, m) 228 Me 1 CO2C(CH3)3 0.48-0.61 (1H, m), 0.63-1.81 (1H, m), 0.92-1.14 (2H, m), 1.16-1.30 (2H, m), 1.42 (9H, s), 1.50-2.21 (10H, m), 2.31 (3H, s), 2.53-2.72 (2H, m), 2.95 (2H, t, J = 5.9 Hz), 3.31-3.53 (1H, m), 3.67 (3H, s), 3.75 (1H, d, J = 14.6 Hz), 3.98-4.03 (2H, m), 5.53 (1H, d, J = 14.6 Hz), 6.10 (1H, brt), 6.71 (1H, s), 6.80 (1H, d, J = 7.9 Hz), 6.86 (1H, s), 6.97 (1H, d, J = 7.9 Hz), 7.10 (1H, s) 229 H 0 (ESI)+: [M + H]+ = 505.5 0.19 (2H, d, J = 4.7 Hz), 0.41-0.80 (4H, m), 0.80-0.99 (2H, m), 1.06-1.60 (6H, m), 1.61-1.93 (4H, m), 2.18-2.30 (2H, m), 2.30-2.45 (2H, m), 2.48 (2H, d, J = 6.7 Hz), 2.91 (2H, t, J = 6.4 Hz), 3.16-3.30 (2H, m), 3.68 (3H, s), 3.78 (1H, d, J = 14.6 Hz), 5.54 (1H, d, J = 14.6 Hz), 6.42-6.74 (1H, m), 6.95-7.18 (4H, m), 7.20-7.30 (2H, m) 230 Cl 0 CH2CH2C(CH3)3 (APCI)+: [M + H]+ = 569.5, 571.5 0.42-0.82 (2H, m), 0.86 (9H, s), 1.19-2.14 (17H, m), 2.28-2.34 (2H, m), 2.86-3.00 (4H, m), 3.65 (3H, s), 3.76 (1H, d, J = 14.6 Hz), 5.52 (1H, d, J = 14.6 Hz), 6.01-6.03 (1H, m), 6.94 (1H, dd, J = 2.2, 8.4 Hz), 7.03 (1H, d, J = 8.4 Hz), 7.10-7.11 (2H, m), 7.72 (1H, s) 231 Cl 0 (APCI)+: [M + H]+ = 539.4, 541.4 d4-MeOH: 0.37-0.43 (2H, m), 0.57-0.80 (4H, m), 1.05-2.01 (12H, m), 2.15-2.24 (1H, m), 2.44-2.52 (1H, m), 2.91-3.04 (6H, m), 3.61-3.69 (2H, m), 3.71 (3H, s), 3.80 (1H, d, J = 14.6 Hz), 5.43 (1H, d, J = 14.6 Hz), 7.03 (1H, dd, J = 2.2, 8.4 Hz), 7.15 (1H, s), 7.20 (1H, d, J = 8.4 Hz), 7.33 (1H, d, J = 2.2 Hz) 232 Me 0 CH2CH2C(CH3)3 (APCI)+: [M + H]+ = 549.5 0.51-0.82 (2H, m), 0.86 (9H, s), 1.12-1.84 (13H, m), 1.91-2.11 (4H, m), 2.20-2.36 (5H, m), 2.94-3.02 (4H, m), 3.66 (3H, s), 3.75 (1H, d, J = 14.6 Hz), 5.55 (1H, d, J = 14.6 Hz), 6.53 (1H, s), 6.80 (1H, d, J = 7.9 Hz), 6.85 (1H, s), 6.97 (1H, d, J = 7.9 Hz), 7.12 (1H, s) 233 Me 0 (APCI)+: [M + H]+ = 519.4 d4-MeOH: 0.39-0.76 (6H, m), 1.05-2.02 (16H, m), 2.20-2.26 (1H, m), 2.34 (3H, s), 2.44-2.50 (1H, m), 2.88-3.00 (4H, m), 3.69 (3H, s), 3.75 (1H, d, J = 14.6 Hz), 5.43 (1H, d, J = 14.6 Hz), 6.86-6.89 (1H, m), 7.03-7.13 (3H, m), 7.79 (1H, t, J = 5.9 Hz), 7.85 (1H, s)

Com- pound num- ber R3 R8 X MS 1H NMR: δ (ppm) 234 Cl CH2CH2C(CH3)3 S  585.5, 0.50-0.56 (1H, m), 587.6 0.88 (9H, s), 1.11-1.19 (2H, m), 1.35-1.49 (4H, m), 1.56-2.10 (9H, m), 2.28-2.34 (3H, m), 2.67 (3H, s), 2.83-3.12 (6H, m), 3.42-3.60 (2H, m), 4.76-4.83 (1H, m), 5.39-5.44 (1H, m), 7.10 (1H, d, J = 8.4 Hz), 7.26 (1H, dd, J = 2.5, 8.4 Hz), 8.38 (1H, d, J = 2.5 Hz) 235 Me CH2CH2C(CH3)3 S 565.4 0.42-0.62 (1H, m), 0.72-0.84 (1H, m), 0.87 (9H, s), 1.08-1.20 (2H, m), 1.30-1.50 (4H, m), 1.56-1.75 (6H, m), 1.75-1.95 (5H, m), 1.96-2.10 (1H, m), 2.25-2.35 (1H, m), 2.43 (3H, s), 2.69 (3H, s), 2.85-3.05 (6H, m), 3.40-3.65 (1H, m), 4.75-4.85 (1H, m), 5.35-5.45 (1H, m), 7.00-7.15 (2H, m), 8.15 (1H, s)

Com- pound num- ber R3 e MS 1H NMR: δ (ppm) 236 Me 1 (APCI)+: 0.44-0.68 (1H, m), 0.69-0.87 E17 [M + H]+ = 579.5 (1H, m), 1.19-2.32 (15H, m), 2.40 (3H, s), 2.88-3.03 (4H, m), 3.28-3.43 (4H, m), 3.52-3.75 (1H, m), 3.84 (1H, d, J = 14.6 Hz), 3.96 (3H, s), 5.50 (1H, d, J = 14.6 Hz), 7.07 (1H, d, J = 7.9 Hz), 7.22 (1H, d, J = 7.9 Hz), 7.28 (1H, s), 7.96 (1H, s) 237 Cl 2 (ESI)+: CD3OD δ 0.54-0.70 (1H, m), [M + H]+ = 0.72-0.89 (1H, m), 1.12-1.98 513.4, 515.4 (14H, m), 2.20-2.29 (3H, m), 2.89-2.98 (4H, m), 3.30-3.39 (2H, m), 3.87 (1H, d, J = 14.6 Hz), 3.98 (3H, s), 5.51 (1H, d, J = 14.6 Hz), 7.24 (1H, dd, J = 2.2, 8.4 Hz), 7.37 (1H, d, J = 8.4 Hz), 7.56 (1H, d, J = 2.2 Hz), 7.91 (1H, s), 8.00 (1H, s) 238 H 0 (ESI)+: CD3OD δ 0.44-0.63 (1H, m), [M + H]+ = 451.3 0.66-0.83 (1H, m), 1.10-2.03 (11H, m), 2.21-2.31 (1H, m), 2.47-2.61 (1H, m), 2.89-2.92 (2H, m), 2.98-3.14 (2H, m), 3.34-3.42 (2H, m), 3.87 (1H, d, J = 14.6 Hz), 3.99 (3H, s), 5.53 (1H, d, J = 14.6 Hz), 7.24 (1H, dd, J = 2.0, 8.4 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.38-7.53 (2H, m), 7.98 (1H, s)

MS Compound (ESI)+: number R1 R3 [M + H]+ = 1H NMR: δ (ppm) 239 Me Me 432.1 E18 240 CH(CH3)2 Me 460.2 241 Me 508.2 242 Me (494.2 243 Me 562.2 244 Me 528.2, 530.2 245 Me 528.2, 530.2 246 Me 528.2, 530.2 247 Me 524.2 248 Me 508.7 0.50-0.80 (2H, m), 1.20-1.80 (7H, m), 2.05-2.20 (1H, m), 2.35 (3H, s), 2.40 (3H, s), 2.67 (2H, t, J = 6.4 Hz), 3.71 (3H, s), 3.75 (1H, d, J = 14.5 Hz), 4.29 (1H, t, J = 6.5 Hz), 6.59 (1H, d, J = 14.5 Hz), 5.71 (1H, s), 6.79 (1H, s), 6.79-6.89 (1H, m), 6.99 (1H, d, J = 7.9 Hz), 7.23-7.31 (2H, m), 7.66 (2H, d, J = 8.2 Hz) 249 Me 519.7 250 Me 562.2 251 Me 551.3 252 Me 534.1, 536.1 253 Me 498.2 254 CH2CF3 Me 500.2 255 Me 607.1, 609.1 256 Me 542.2 257 CH2CH3 Me 446.1 0.55-0.90 (2H, m), 1.20-1.90 (10H, m), 2.08-2.20 (1H, m), 2.36 (3H, s), 2.86 (2H, tJ = 6.0 Hz) 2.95-3.15 (2H, m), 3.71 (3H, s), 3.75 (1H, d, J = 14.6 Hz), 4.12-4.16 (1H, m), 5.60 (1H, d, J = 14.6 Hz), 5.77 (1H, s), 6.80 (1H, s), 6.83 (1H, d, J = 7.9 Hz), 7.01 (1H, d, J = 7.9 Hz), 7.17 (1H, s) 258 CH2CH2CH3 Me 460.6 259 CH2CH2CH2CH3 Me 474.2 260 CH2CH2CH2CH3 Cl 494.2, 496.2 0.55-0.85 (2H, m), 0.92 (3H, t, J = 7.3 Hz), 1.25-1.85 (11H, m), 2.05-2.20 (1H, m), 2.80-3.00 (4H, m), 3.72 (3H, s), 3.76 (1H, d, J = 14.6 Hz), 4.10-4.20 (1H, m), 5.59 (1H, d, J = 14.6 Hz), 5.91 (1H, s), 7.00-7.10 (3H, m), 7.19 (1H, s) 261 Cl 528.1, 530.1 0.50-0.80 (2H, m), 1.20-1.80 (7H, m), 2.00-2.15 (1H, m), 2.40 (3H, s), 2.60-2.75 (2H, m), 3.71 (3H, s), 2.60-2.75 (2H, m), 3.71 (3H, s), 3.75 (1H, d, J = 14.6 Hz), 4.64 (1H, t, J = 6.5 Hz), 5.57 (1H, d, J = 14.6 Hz), 6.29 (1H, s), 6.95-7.10 (3H, m), 7.16 (1H, s), 7.25-7.35 (2H, m), 7.71 (2H, d, J = 8.2 Hz) 262 H 446.2 0.50-0.80 (1H, m), 1.30 (6H, d, J = 6.7 Hz), 1.32-1.48 (4H, m), 1.50-1.90 (5H, m), 2.10-2.20 (1H, m) 2.75-3.00 (2H, m), 3.72 (3H, s), 3.81 (1H, d, J = 14.6 Hz), 4.25-4.45 (1H, m), 5.62 (1H, d, J = 14.6 Hz), 6.21 (1H, s), 6.95-7.10 (2H, m), 7.10-7.20 (2H, m), 7.25-7.30 (1H, m) 263 H 510.1 0.45-0.75 (1H, m), 1.20-1.85 (8H, m), 2.00-2.15 (1H, m), 2.60-2.70 (2H, m), 3.73 (3H, s), 3.79 (1H, d, J = 14.6 Hz), 3.84 (3H, s), 4.30-4.40 (1H, m), 5.60 (1H, d, J = 14.6 Hz), 5.90 (1H, s), 6.90-7.10 (4H, m), 7.10-7.20 (2H, m), 7.25-7.30 (1H, m), 7.70-7.80 (2H, m)

Com- pound num- ber R12 MS 264 Me (ESI)+: E19 [M + H]+ = 557.4 265 CH(CH3)2 (ESI)+: [M + H]+ = 585.4 266 (ESI)+: [M + H]+ = 633.6 267 (ESI)+: [M + H]+ = 619.5 268 (ESI)+: [M + H]+ = 687.4, 689.4 269 (ESI)+: [M + H]+ = 653.4, 655.4 270 (ESI)+: [M + H]+ = 653.5, 655.5 271 (ESI)+: [M + H]+ = 653.5, 655.5 272 (ESI)+: [M + H]+ = 649.6 273 (ESI)+: [M + H]+ = 633.5 274 (ESI)+: [M + H]+ = 644.5 275 (ESI)+: [M + H]+ = 687.5 276 (ESI)+: [M + H]+ = 676.5 277 (ESI)+: [M + H]+ = 659.4, 661.4 278 (ESI)+: [M + H]+ = 623.5 279 CH2CF3 (ESI)+: [M + H]+ = 625.5 280 (ESI)+: [M + H]+ = 732.4, 734.4 281 (ESI)+: [M + H]+ = 667.5 282 CH2CH3 (ESI)+: [M + H]+ = 571.4 283 CH2CH2CH3 (ESI)+: [M + H]+ = 585.5 284 CH2CH2CH2CH3 (ESI)+: [M + H]+ = 599.5

Com- pound number R12 MS 285 Me (ESI)+: E20 [M + H]+ = 521.5 286 (ESI)+: [M + H]+ = 583.4 287 (ESI)+: [M + H]+ = 617.5, 619.5 288 (ESI)+: [M + H]+ = 617.5, 619.5 289 (ESI)+: [M + H]+ = 617.3, 619.3 290 (ESI)+: [M + H]+ = 613.5 291 (ESI)+: [M + H]+ = 597.5 292 (ESI)+: [M + H]+ = 618.5, 620.5 293 (ESI)+: [M + H]+ = 584.4 294 (ESI)+: [M + H]+ = 589.3 295 (ESI)+: [M + H]+ = 623.5, 625.5 296 (ESI)+: [M + H]+ = 589.2 297 (ESI)+: [M + H]+ = 601.5 298 (ESI)+: [M + H]+ = 573.4 299 (ESI)+: [M + H]+ = 574.4 300 (ESI)+: [M + H]+ = 664.6 301 CH2CH3 (ESI)+: [M + H]+ = 535.3 302 CH2CH2CH3 (ESI)+: [M + H]+ = 549.4 303 (ESI)+: [M + H]+ = 547.4 304 C(CH3)3 (ESI)+: [M + H]+ = 563.5 305 (ESI)+: [M + H]+ = 589.5 306 CH2(CH2)3CH3 (ESI)+: [M + H]+ = 577.5 307 CH(CH2CH3)CH2CH2CH2CH3 (ESI)+: [M + H]+ = 605.6 308 (ESI)+: [M + H]+ = 657.6 309 (ESI)+: [M + H]+ = 597.4 310 (ESI)+: [M + H]+ = 611.5 311 (ESI)+: [M + H]+ = 623.6 312 (ESI)+: [M + H]+ = 603.5 313 (ESI)+: [M + H]+ = 613.5 314 (ESI)+: [M + H]+ = 627.6 315 CH2CH2CO2CH3 (ESI)+: [M + H]+ = 593.4 316 CH2(CH2)2CO2CH2CH3 (ESI)+: [M + H]+ = 621.6

Compound number R8 MS 317 (ESI)+: [M + H]+ = 507.4 E21 318 CH2CH2CH3 (ESI)+: [M + H]+ = 493.5 319 (ESI)+: [M + H]+ = 541.5 320 (ESI)+: [M + H]+ = 555.5 321 (ESI)+: [M + H]+ = 547.4 322 CH2CH2CH2CH2CH3 (ESI)+: [M + H]+ = 521.5 323 (ESI)+: [M + H]+ = 569.4 324 CH2CH2CH(CH3)2 (ESI)+: [M + H]+ = 521.5 325 (ESI)+: [M + H]+ = 542.4 326 (ESI)+: [M + H]+ = 547.4 327 CH2CH2CF3 (ESI)+: [M + H]+ = 547.3 328 (ESI)+: [M + H]+ = 545.5 329 CH2CH2OH (ESI)+: [M + H]+ = 495.6 330 (ESI)+: [M + H]+ = 555.5 331 (ESI)+: [M + H]+ = 555.3 332 (ESI)+: [M + H]+ = 566.4 333 (ESI)+: [M + H]+ = 566.4 334 (ESI)+: [M + H]+ = 566.5 335 (ESI)+: [M + H]+ = 631.5 336 (ESI)+: [M + H]+ = 609.5 337 (ESI)+: [M + H]+ = 631.6

Com- pound num- ber R8 MS 338 (ESI)+: E22 [M + H]+ = 597.6, 599.6 339 CH2CH2CH3 (ESI)+: [M + H]+ = 555.6, 557.6 340 CH2(CH2)2CN (ESI)+: [M + H]+ = 580.7, 582.7 341 (ESI)+: [M + H]+ = 631.8, 633.8 342 (ESI)+: [M + H]+ = 623.6, 625.6 343 (ESI)+: [M + H]+ = 621.6, 623.6 344 (ESI)+: [M + H]+ = 659.8, 661.8 345 (ESI)+: [M + H]+ = 687.7, 689.7 346 (ESI)+: [M + H]+ = 661.8, 663.8 347 (ESI)+: [M + H]+ = 603.7, 605.7 348 CH2CH2OH (ESI)+: [M + H]+ = 557.5, 559.5 349 CH2CO2CH(CH3)2 (ESI)+: [M + H]+ = 613.6, 615.6 350 CH2CH2CH(CH3)2 (ESI)+: [M + H]+ = 583.6, 585.6 351 CH2CH2CH2OH (ESI)+: [M + H]+ = 571.6, 573.6 352 CH2CN (ESI)+: [M + H]+ = 552.6, 554.6 353 (ESI)+: [M + H]+ = 648.7, 650.7 354 (ESI)+: [M + H]+ = 567.7, 569.6 355 (ESI)+: [M + H]+ = 653.8, 655.8 356 (ESI)+: [M + H]+ = 553.6, 555.6 357 (ESI)+: [M + H]+ = 629.8, 631.8 358 (ESI)+: [M + H]+ = 679.8, 681.8 359 (ESI)+: [M + H]+ = 611.6, 613.6 360 (ESI)+: [M + H]+ = 628.7, 630.7 361 CH2COC(CH3)3 (ESI)+: [M + H]+ = 611.7, 613.7 362 CH2CONH2 (ESI)+: [M + H]+ = 570.6, 572.6 363 (ESI)+: [M + H]+ = 638.8, 640.8 364 (ESI)+: [M + H]+ = 645.8, 647.8

Compound number R12 MS 365 E23 (ESI)+: [M + H]+ = 658.5 366 (ESI)+: [M + H]+ = 647.5 367 (ESI)+: [M + H]+ = 661.7 368 (ESI)+: [M + H]+ = 644.5 369 (ESI)+: [M + H]+ = 563.5 370 (ESI)+: [M + H]+ = 629.6 371 (ESI)+: [M + H]+ = 561.4 372 (ESI)+: [M + H]+ = 599.4 373 (ESI)+: [M + H]+ = 633.5 374 (ESI)+: [M + H]+ = 613.5 375 (ESI)+: [M + H]+ = 579.5 376 (ESI)+: [M + H]+ = 551.5 377 (ESI)+: [M + H]+ = 683.5 378 CH3 (ESI)+: [M + H]+ = 537.4 379 (ESI)+: [M + H]+ = 549.4 380 (ESI)+: [M + H]+ = 657.6

Compound number R3 R9 MS 1H NMR: δ (ppm)   381 E24 Me CH2CH2C(CH3)3 (APCI)+: 0.41-0.82 (2H, m), 0.86 (9H, s), [M + H]+ = 1.33-1.50 (7H, m), 1.73 (2H, m), 550.4 2.12 (1H, m), 2.27-2.39 (6H, m), 2.29 (3H, s), 2.90-2.93 (2H, m), 3.31-3.35 (4H, m), 3.64 (3H, s), 3.74 (1H, d, J = 14.6 Hz), 4.78 (1H, m), 5.54 (1H, d, J = 14.6 Hz), 6.77 (1H, dd, J = 1.0, 8.0 Hz), 6.88 (1H, s), 6.95 (1H, d, J = 8.0 Hz), 7.03 (1H, d, J = 1.0 Hz), 7.11 (1H, s) 382 Me CH2CH2CH2SCH3 (ESI)+: — [M + H]+ = 554.6 383 Me CH2CH2OCH3 (ESI)+: — [M + H]+ = 524.7 384 Me CH2CH2CH2CF3 (ESI)+: — [M + H]+ = 576.6 385 Me CH2CH2N(CH2CH3)2 (ESI)+: — [M + H]+ = 565.6 386 Me CH2CH2CH2F (ESI)+: — [M + H]+ = 526.6 387 Me CH2CH2CH2OH (ESI)+: — [M + H]+ = 524.6 388 Me CH2C(CH3)3 (ESI)+: 0.55-0.84 (2H, m), 0.84 (9H, s), 1.18- [M + H]+ = 1.75 (7H, m), 2.04-2.16 (3H, m), 536.5 2.34 (3H, s), 2.44-2.48 (4H, m), 2.93-2.97 (2H, m), 3.26-3.29 (4H, m), 3.70 (3H, s), 3.75 (1H, d, J = 14.6 Hz), 4.35-4.39 (1H, bs), 5.58 (1H, d, J = 14.6 Hz), 5.84 (1H, s), 6.79-6.83 (2H, m), 6.98 (1H, m), 7.16 (1H, s) 389 Me (APCI)+: [M + H]+ = 548.5 0.46-0.71 (2H, m), 1.11-1.27 (4H, m), 1.37-1.59 (7H, m), 1.69-1.78 (4H, m), 1.95-2.17 (2H, m), 2.21 (2H, d, J = 7.4 Hz), 2.30 (3H, s), 2.32-2.36 (4H, m), 2.85-2.98 (2H, m), 3.29-3.32 (4H, m), 3.64 (3H, s), 3.74 (1H, d, J = 14.6 Hz), 4.67- 4.71 (1H, m), 5.55 (1H, d, J = 14.6 Hz), 6.78 (1H, d, J = 8.0 Hz), 6.87- 6.88 (2H, m), 6.95 (1H, d, J = 8.0 Hz), 7.11 (1H, s) 390 Me CH2CH2CH(CH3)2 (APCI)+: 0.48-0.72 (2H, m), 0.86 (6H, t, J = [M + H]+ = 6.4 Hz), 1.18-1.38 (5H, m), 1.46- 536.5 1.60 (3H, m), 1.68-1.79 (2H, m), 2.07-2.18 (1H, m), 2.28-2.38 (9H, m), 2.88-2.96 (2H, m), 3.31-3.34 (4H, m), 3.65 (3H, s), 3.75 (1H, d, J = 14.6 Hz), 4.71-4.75 (1H, m), 5.55 (1H, d, J = 14.6 Hz), 6.78 (1H, d, J = 7.9 Hz), 6.88 (1H, s), 6.96 (1H, d, J = 7.9 Hz), 7.04 (1H, dd, J = 1.2, 7.9 Hz), 7.12 (1H, s) 391 Me CH2CH(CH3)2 (APCI)+: 0.46-0.71 (2H, m), 0.85 [M + H]+ = (6H, t, J = 6.4 Hz), 1.19-1.27 522.4 (2H, m), 1.37-1.54 (3H, m), 1.68-1.78 (3H, m), 2.04 (2H, d, J = 7.4 Hz), 2.05-2.17 (1H, m) 2.29 (3H, s), 2.29- 2.33 (4H, m), 2.87-2.98 (2H, m), 3.28-3.32 (4H, m), 3.64 (3H, s), 3.74 (1H, d, J = 14.6 Hz), 4.68-4.72 (1H, m), 5.55 (1H, d, J = 14.6 Hz), 6.78 (1H, d, J = 8.0 Hz), 6.88 (1H, s), 6.93 (1H, s), 6.95 (1H, d, J = 8.0 Hz), 7.11 (1H, s) 392 Me CH2CH2CH3 (APCI)+: 0.47-0.89 (2H, m), 0.87 [M + H]+ = (3H, t, J = 7.2 Hz), 1.18-1.27 508.4 (2H, m), 1.37-1.54 (5H, m), 1.68-1.78 (2H, m), 2.07- 2.17 (1H, m), 2.23-2.26 (2H, m), 2.29 (3H, s), 2.34- 2.38 (4H, m), 2.87-2.97 (2H, m), 3.30-3.34 (4H, m), 3.64 (3H, s), 3.74 (1H, d, J = 14.6 Hz), 4.72-4.76 (1H, m), 5.54 (1H, d, J = 14.6 Hz), 6.78 (1H, d, J = 8.0 Hz) 6.87- 6.88 (2H, m), 6.95 (1H, d, J = 8.0 Hz), 7.11 (1H, s) 393 Cl (APCI)+: [M + H]+ = 568.4, 570.4 0.41-0.56 (1H, m), 0.60- 0.75 (1H, m), 0.78 (1H, d, J = 6.4 Hz), 0.94-1.14 (2H, m), 1.14-1.55 (9H, m), 1.57-1.72 (4H, m), 1.83- 2.00 (2H, m), 2.18 (2H, d, J = 6.9 Hz), 2.29 (4H, t, J = 4.9 Hz), 2.70-2.90 (2H, m), 3.22 (4H, t, J = 4.9 Hz), 3.58 (3H, s), 3.66 (1H, d, J = 14.6 Hz), 5.17 (1H, t, J = 5.4 Hz), 5.38 (1H, d, J = 14.6 Hz), 6.86 (1H, d, J = 2.2 Hz), 6.91 (1H, s), 7.03 (1H, s), 7.12 (1H, d, J = 2.2 Hz) 394 Cl CH2CH2CH(CH3)2 (APCI)+: 0.40-0.59 (1H, m), 0.60- [M + H]+ = 0.80 (1H, m), 0.86 (6H, d, 556.4, 558.4 J = 6.7 Hz), 1.09-1.65 (9H, m), 1.65-1.81 (2H, m), 2.01-2.17 (1H, m), 2.30- 2.41 (2H, m), 2.41 (4H, t, J = 4.9 Hz) 2.92 (2H, t, J = 5.9 Hz), 3.38 (4H, t, J = 4.9 Hz), 3.70 (3H, s), 3.77 (1H, d, J = 14.6 Hz), 5.07 (1H, t, J = 5.4 Hz) 5.52 (1H, d, J = 14.6 Hz), 6.94 (1H, d, J = 2.2 Hz), 7.02 (1H, s), 7.12 (1H, s), 7.32 (1H, d, J = 2.2 Hz) 395 Cl CH2CH(CH3)2 (APCI)+: 0.38-0.60 (1H, m), 0.60- [M + H]+ = 0.78 (1H, m), 0.82 (6H, d, 542.4, 544.4 J = 6.7 Hz), 1.10-1.40 (2H, m), 1.40-1.56 (2H, m), 1.63-1.80 (4H, m), 2.03 (2H, d, J = 7.4 Hz), 2.12 (2H, s), 2.31 (4H, t, J = 4.9 Hz), 2.85-2.94 (2H, m), 3.30 (4H, t, J = 4.9 Hz), 3.64 (3H, s), 3.72 (1H, d, J = 14.6 Hz), 4.75 (1H, t, J = 5.7 Hz), 5.49 (1H, d, J = 14.6 Hz), 6.93 (1H, d, J = 2.2 Hz), 6.98 (1H, s), 7.11 (1H, s), 7.15 (1H, d, J = 2.2 Hz) 396 Cl CH2CH2CH3 (APCI)+: 0.39-0.60 (1H, m), 0.60- [M + H]+ = 0.83 (1H, m), 0.88 (3H, t, 528.3, 530.3 J = 7.4 Hz), 1.17-1.63 (9H, m), 1.64-1.83 (2H, m), 2.00-2.15 (1H, m), 2.25- 2.35 (2H, m), 2.40 (4H, t, J = 4.9 Hz), 2.90-3.00 (2H, m), 3.35 (4H, t, J = 4.9 Hz), 3.72 (3H, s), 4.59 (1H, t, J = 5.7 Hz), 5.54 (1H, d, J = 14.6 Hz), 6.90-7.04 (2H, m), 7.10-7.19 (2H, m) 397 Cl (APCI)+: [M + H]+ = 540.3, 542.3 d6-DMSO: 0.02-0.04 (2H, m), 0.41-0.47 (2H, m), 0.80-1.75 (10H, m), 2.03 (1H, m), 2.14 (2H, d, J = 6.5 Hz), 2.30-2.34 (4H, m), 2.74 (2H, m), 3.20-3.28 (4H, m), 3.67 (3H, s), 3.70 (1H, d, J = 14.6 Hz), 5.34 (1H, d, J = 14.6 Hz), 6.29 (1H, m), 7.02 (1H, dd, J = 2.5, 8.0 Hz), 7.08 (1H, s), 7.25 (1H, d, J = 8.0 Hz), 7.42 (1H, d, J = 2.5 Hz) 398 Me (APCI)+: [M + H]+ = 520.4 0.06-0.08 (2H, m), 0.46- 0.53 (2H, m), 0.81 (1H, m), 1.13-1.79 (9H, m), 2.09 (1H, m), 2.23 (2H, m), 2.30 (3H, s), 2.45-2.49 (4H, m), 2.92 (2H, m), 3.33-3.37 (4H, m), 3.65 (3H, s), 3.74 (1H, d, J = 14.6 Hz), 4.69 (1H, m), 5.54 (1H, d, J = 14.6 Hz), 6.67 (1H, s), 6.78 (1H, dd, J = 1.0, 8.0 Hz), 6.86 (1H, d, J = 1.0 Hz), 6.96 (1H, d, J = 8.0 Hz), 7.11 (1H, s) 399 Cl CH2CH2C(CH3)3 (APCI)+: 0.42-0.81 (2H, m), 0.87 [M + H]+ = (9H, s), 1.22-1.40 (7H, m), 570.3, 572.3 1.74-1.78 (2H, m), 2.08 (1H, m), 2.28-2.40 (6H, m), 2.87-2.92 (2H, m), 3.33- 3.37 (4H, m), 3.63 (3H, s), 3.74 (1H, d, J = 14.6 Hz), 4.89 (1H, m), 5.51 (1H, d, J = 14.6 Hz), 6.93 (1H, dd, J = 2.2, 8.4 Hz), 7.03 (1H, d, J = 8.4 Hz), 7.10 (1H, s), 7.20 (1H, d, J = 2.2 Hz), 8.10 (1H, s) 400 H CH2CH2C(CH3)3 (APCI)+: 0.40-0.46 (1H, m), 0.63- [M + H]+ = 0.68 (1H, m), 0.82 (9H, s), 536.4 1.26-1.67 (7H, m), 1.73- 1.79 (2H, m), 2.03-2.08 (1H, m), 2.34-2.37 (6H, m), 2.82-2.94 (2H, m), 3.32 (4H, m), 3.64 (3H, s), 3.77 (1H, d, J = 14.6 Hz), 4.80 (1H, t, J = 5.4 Hz), 5.56 (1H, d, J = 14.6 Hz), 6.95 (1H, m), 7.05-7.12 (3H, m), 7.19 (1H, m), 7.32 (1H, s) 401 H (ESI)+: [M + H]+ = 506.3 0.04-0.11 (2H, m), 0.46- 0.53 (2H, m), 0.61-0.72 (1H, m), 0.72-0.89 (1H, m), 1.20-1.59 (6H, m), 1.69- 1.81 (2H, m), 2.04-2.17 (1H, m), 2.23 (2H, d, J = 6.4 Hz), 2.46 (4H, t, J = 4.9 Hz), 2.81-3.05 (2H, m), 3.35 (4H, t, J = 4.9 Hz), 3.69 (3H, s), 3.79 (1H, d, J = 14.6 Hz), 4.56 (1H, t, J = 5.6 Hz), 5.60 (1H, d, J = 14.6 Hz), 6.67 (1H, s), 6.96-7.26 (4H, m), 7.15 (1H, s) 402 H (ESI)+: [M + H]+ = 520.3 —

Compound 1H NMR: number R3 R9 X MS δ (ppm) 403 Cl CH2CH2C(CH3)3 S (ESI)+: 0.49-0.60 (1H, m), 0.88 [M + H]+ = (9H, s), 1.11-1.24 (2H, m), 586.6, 588.6 1.34-1.41 (4H, m), 1.47-1.87 (5H, m), 2.28-2.41 (5H, m), 2.67 (3H, s), 2.82-3.18 (4H, m), 3.29-3.33 (4H, m), 3.37-3.59 (1H, m), 4.34-4.38 (1H, m), 4.76-4.83 (1H, m), 7.10 (1H, d, J, = 8.4 Hz), 7.25 (1H, dd, J = 2.5, 8.4 Hz), 8.38 (1H, d, J = 2.5 Hz) 404 Me S (ESI)+: [M + H]+ = 536.3 0.05-0.15 (2H, m), 0.40-0.60 (3H, m), 0.70-0.90 (2H, m), 1.10-1.20 (2H, m), 1.45- 1.95 (5H, m), 2.24 (2H, d, J = 6.7 Hz), 2.35-2.55 (8H, m), 2.69 (3H, s), 2.85-3.05 (4H, m), 3.30-3.40 (4H, m), 3.46- 3.65 (1H, m), 4.32-4.38 (1H, m), 4.74-4.86 (1H, m), 7.00-7.15 (2H, m), 8.14(1H, s)

Compound 1H NMR: number R3 R9 X MS δ (ppm) 405 Me CH2CH2C(CH3)3 NH 0.45-0.55 (1H, m), 0.75-0.90 (10H, m), 1.10-1.20 (1H, m), 1.20-1.90 (8H, m), 2.30-2.45 (13H, m), 2.65-3.00 (4H, m), 3.30-3.40 (5H, m), 4.35-4.45 (1H, m), 4.70- 4.80 (1H, m), 6.95-7.15 (2H, m), 7.95- 8 05 (1H, m)

Compound number R1 R3 R8 MS 1H NMR: δ (ppm) 406 E49 F H H (APCI)+: d4 MeOH 2.29-2.36 (2H, m), [M + H]+ = 3.47 (2H, t, J = 7.7 Hz), 3.50- 465.3 3.78 (8H, m), 4.02 (3H, s), 4.03 (1H, d), 4.16 (2H, t, J = 5.4 Hz), 5.87 (1H, d, J = 15.0 Hz), 6.88-7.05 (4H, m), 7.24-7.31 (1H, m), 7.39-7.43 (1H, m), 8.02 (1H, s) 407 H F Cl (APCI)+: — [M + H]+ = 499.4, 501.4 408 Me H H (APCI)+: d4-MeOH 2.07 (3H, s), 2.25- [M + H]+ = 2.35 (2H, m), 3.43-3.49 (2H, 461.4 m), 3.52-3.73 (8H, m), 4.03 (3H, s), 3.98-4.07 (3H, m), 5.90 (1H, d, J = 14.6 Hz), 6.71 (1H, d, J = 8.9 Hz), 6.81-6.88 (2H, m), 7.04-7.07 (2H, m), 7.22-7.29 (1H, m), 7.40 (1H, d, J = 7.7 Hz), 8.02 (1H, s)

Compound number R1 R3 R8 R12 MS 1H NMR: δ (ppm) 409 E50 F H H CH2CH2C(CH3)3 (APCI)+: (9H, s), 1.35-1.46 (2H, m), 1.90-1.95 [M + H]+ = (2H, m), 2.42-2.70 (11H, m), 2.95- 549.4 3.08 (1H, m), 3.47-3.59 (1H, m), 3.79 (3H, s), 3.90-4.03 (2H, m), 5.87 (1H, d, J = 14.8 Hz), 6.31 (1H, s), 6.70 (3H, s), 6.89-7.04 (3H, m), 7.04-7.13 (1H, m), 7.21 (1H, s) 410 H Cl H CH2CH(CH3)2 (APCI)+: 0.84-0.88 (6H, m), 1.69-2.08 (5H, m), [M + H]+ = 2.37-2.53 (10H, m), 3.68 (3H, s), 537.4, 539.3 3.83-4.03 (3H, m), 4.33-4.42 (1H, brs), 5.81 (1H, d, J = 14.6 Hz), 6.40- 6.44 (2H, m), 6.54-7.34 (5H, m), 7.21 (1H, s) 411 H Cl H CH2CH2CH3 (APCI)+: 0.84-0.90 (3H, m), 1.41-1.54 (2H, m), [M + H]+ = 1.80-2.00 (2H, m), 2.24-2.54 (12H, 523.3, 525.4 m), 3.68 (3H, s), 3.81-4.01 (3H, m), 4.33-4.42 (1H, brs), 5.80 (1H, d, J = 14.6 Hz), 6.40-7.34 (7H, m), 7.21 (1H, s) 412 Me H Me (APCI)+: [M + H]+ = 557.5 1.06-1.26 (3H, m), 1.40-1.63 (6H, m), 1.63-1.78 (2H, m), 1.78-1.96 (1H, m), 1.96-2.10 (4H, m),2.10-2.29 (6H, m), 2.30-2.60 (8H, m), 3.76 (3H, s), 3.81- 4.00 (3H, m), 5.89 (1H, d, J = 14.6 Hz), 6.00 (1H, s), 6.40-6.62 (2H, m), 6.73 (1H, s), 6.98 (1H, d, J = 7.9 Hz), 7.12 (1H, brs), 7.20 (1H, brs) 413 Me H Me CH2C(CH3)3 (ESI)+: 0.85 (9H, s), 1.95-2.01 (3H, m), 2.01- [M + H]+ = 2.11 (1H, m), 2.16 (2H, s), 2.19 (3H, 545.4 s), 2.70-2.82 (6H, m), 2.85-3.07 (6H, m), 3.73-3.85 (5H, m), 3.90 (1H, d, J = 14.6 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.39 (1H, d, J = 8.7 Hz), 6.43- 6.56 (2H, m), 6.88 (1H, s), 6.92 (1H, s), 6.95-7.10 (1H, m), 7.12 (1H, s), 7.18 (1H, s) 414 Me H Me CH2CH(CH2CH3)2 (ESI)+: 0.83 (6H, t, J = 7.4 Hz), 1.20- [M + H]+ = 1.40 (7H, m), 1.40-1.52 (1H, m), 1.90- 559.5 2.10 (8H, m), 2.19 (3H, s), 2.41 (2H, d, J = 6.7 Hz), 2.70-2.85 (3H, m), 2.85- 2.92 (3H, m), 3.79 (3H, s), 3.80-3.90 (2H, m), 5.83 (1H, d, J = 14.6 Hz), 6.37-6.60 (2H, m), 6.80 (1H, s), 6.87- 6.97 (2H, m), 7.13 (2H, d, J = 16.1 Hz) 415 Me H Me CH2CH2CH(CH3)2 (APCI)+: 0.86 (6H, d, J = 6.7 Hz), 1.33- [M + H]+ = 1.45 (2H, m), 1.46-1.62 (1H, m), 1.82- 545.5 1.93 (2H, m), 2.01 (3H, s), 2.10-2.25 (2H, m), 2.29-2.40 (2H, m), 2.40-2.59 (8H, m), 2.79-2.91 (1H, m), 3.48-3.60 (1H, m), 3.60-3.80 (3H, m), 3.80-3.96 (3H, m), 3.98-4.10 (1H, m), 5.88 (1H, d, J = 14.6 Hz), 6.19 (1H, s), 6.41-6.52 (2H, m), 6.52-6.60 (1H, m), 6.75 (1H, s), 6.97 (1H, d, J = 7.7 Hz) 7.12 (1H, s), 7.19 (1H, s) 416 Me H Me CH2CH(CH3)2 (APCI)+: 0.90 (6H, d, J = 6.7 Hz), 1.28 [M + H]+ = (2H, t, J = 7.4 Hz), 1.72-1.88 (1H, m), 531.2 1.90-2.07 (7H, m), 2.19 (3H, s), 2.26 (2H, d, J = 7.2 Hz), 2.61-2.88 (8H, m), 3.45 (1H, s), 3.78 (2H, s), 3.81-3.91 (2H, m), 5.86 (1H, d, J = 14.6 Hz), 6.40-6.60 (3H, m), 6.83 (1H, s), 6.95 (1H, d, J = 8.2 Hz), 7.13-7.19 (2H, m) 417 Me H Me CH2CH2CH3 (APCI)+: 0.88 (3H, t, J = 7.4 Hz), 1.39- [M + H]+ = 1.60 (2H, m), 1.80-1.95 (2H, m), 1.96- 517.4 2.06 (2H, m), 2.19(3H, s), 2.29-2.38 (2H, m), 2.39-2.64 (12H, m), 3.75 (3H, s), 3.80-3.96 (3H, m), 5.88 (1H, d, J = 14.6 Hz), 6.23 (1H, s), 6.40-6.60 (2H, m), 6.76 (1H, s), 6.98 (1H, d, J = 7.7 Hz), 7.04-7.20 (2H, m) 418 F H H CH2CH(CH3)2 (APCI)+: 0.85 (6H, d, J = 6.4 Hz), 1.71- [M + H]+ = 1.76 (1H, m), 1.89-1.95 (2H, m), 2.04 521.4 (2H, d, J = 7.2 Hz), 2.43 (10H, m), 3.74 (3H, s), 3.93-3.98 (3H, m), 5.86 (1H, d, J = 14.6 Hz), 6.67-6.72 (4H, m), 6.91-7.08 (4H, m), 7.20 (1H, s) 419 F H H (APCI)+: [M + H]+ = 547.5 1.10-1.17 (2H, m), 1.44-1.58 (4H, m), 1.64-1.73 (2H, m), 1.87-2.03 (3H, m), 2.22 (2H, d, J = 7.2 Hz), 2.42 (10H, m), 3.72 (3H, s), 3.92-3.97 (3H, m), 5.86 (1H, d, J = 14.6 Hz), 6.66-6.72 (3H, m), 6.76 (1H, s), 6.87- 7.07 (4H, m), 7.19 (1H, s) 420 F H H CH2CH(CH2CH3)2 (APCI)+: 0.81 (6H, t, J = 7.3 Hz), 1.21- [M + H]+ = 1.37 (5H, m), 1.88-1.93 (2H, m), 2.10 549.5 (2H, d, J = 6.7 Hz), 2.41 (10H, m), 3.73 (3H, s), 3.93-3.98 (3H, m), 5.87 (1H, d, J = 14.6 Hz), 6.67-6.72 (4H, m), 6.87-7.07 (4H, m), 7.20 (1H, s) 421 F H H CH2CH2CH(CH3)2 (APCI)+: 0.83 (6H, d, J = 6.4 Hz), 1.27- [M + H]+ = 1.35 (2H, m), 1.50 (1H, m), 1.85-1.94 535.4 (2H, m), 2.24-2.40 (12H, m), 3.69 (3H, s), 3.90-3.95 (3H, m), 5.84 (1H, d, J = 14.6 Hz), 6.63-6.69 (3H, m), 6.86 (1H, d, J = 11.9 Hz), 6.97- 7.02 (4H, m), 7.16 (1H, s) 422 F H H CH2C(CH3)3 (ESI)+: 0.83 (9H, s), 1.92-2.00 (2H, m), 2.03 [M + H]+ = (2H, s), 2.47-2.54 (10H, m), 3.79 535.4 (3H, s), 3.93-3.98 (3H, m), 5.88 (1H, d, J = 14.6 Hz), 6.20 (1H, s), 6.67-6.70 (3H, m), 6.91-6.96 (2H, m), 7.03-7.13 (2H, m), 7.21-7.22 (1H, m) 423 F H H CH2CH2CH3 (APCI)+: 0.85 (3H, t, J = 7.4 Hz), 1.47 [M + H]+ = (2H, m), 1.90 (2H, m), 2.25 (2H, m), 507.4 2.43 (10H, m), 3.73 (3H, s), 3.95 (3H, m), 5.86 (1H, d, J = 14.6 Hz), 6.67-6.72 (4H, m), 6.87-7.08 (4H, m), 7.20 (1H, s) 424 Me H H (ESI)+: [M + H]+ = 515.3 0.07-0.13 (2H, m), 0.47-0.54 (2H, m), 0.81-0.92 (1H, m), 1.87-1.96 (3H, brt), 2.01 (3H, s), 2.27 (2H, d, J = 6.7 Hz), 2.42-2.64 (10H, m), 3.78 (3H, s), 3.86-4.01 (3H, m), 5.92 (1H, d, J = 14.8 Hz), 6.06 (1H, s), 6.48 (1H, brd, J = 9.6 Hz), 6.70 (2H, s), 6.92 (1H, d, J = 7.4 Hz), 6.94- 7.11 (3H, m), 7.22 (1H, s) 425 F H H (ESI)+: [M + H]+ = 519.3 0.05-0.12 (2H, m), 0.46-0.53 (2H, m), 0.81-0.87 (1H, m), 1.87-1.98 (2H, m), 2.25 (2H, d, J = 6.7 Hz), 2.38- 2.62 (10H, m), 3.78 (3H, s), 3.98 (2H, t, J = 5.7 Hz), 3.96 (1H, d, J = 14.6 Hz), 5.88 (1H, d, J = 14.6 Hz), 6.21 (1H, s), 6.68-6.74 (3H, m), 6.89- 6.96 (2H, m), 7.03-7.13 (2H, m), 7.22 (1H, s) 426 H Cl Me CH2CH2C(CH3)3 (APCI)+: 0.89 (9H, s), 1.38-1.50 (2H, m), 1.79- [M + H]+ = 1.91 (2H, m), 2.16 (3H, s), 2.43-2.60 579.4, 581.4 (8H, m), 2.60-2.79 (4H, m), 3.46 (3H, s), 3.74 (2H, s), 3.86 (2H, t, J = 5.9 Hz), 5.78 (1H, d, J = 14.6 Hz), 6.26 (1H, s), 6.47 (1H, d, J = 6.7 Hz), 6.67-6.84 (4H, m), 7.21 (1H, s) 427 H Cl Cl CH2CH2C(CH3)3 (APCI)+: 0.88 (9H, s), 1.35 (1H, d, J = 6.7 Hz), [M + H]+ = 1.37-1.47 (2H, m), 1.83-1.90 (1H, m), 599.3 2.42-2.78 (10H, m), 3.46 (3H, s), 3.74 (2H, s), 3.88 (2H, t, J = 6.2 Hz), 3.94-4.00 (1H, m), 5.77 (1H, d, J = 14.6 Hz), 6.50 (1H, dd, J = 2.2, 8.7 Hz), 6.61 (1H, dd, J = 2.2, 8.7 Hz), 6.73 (1H, d, J = 2.2 Hz), 6.81 (1H, s), 6.83 (1H, s), 6.84-7.00 (2H, m), 7.22 (1H, s) 428 H F Cl CH2CH2C(CH3)3 (APCI)+: 0.87 (9H, s), 1.26 (1H, d, J = 5.2 Hz), [M + H]+ = 1.32-1.41 (2H, m), 1.88-1.91 (1H, m), 583.4, 585.4 2.30-2.41 (2H, m), 2.42-2.63 (8H, m), 3.44 (3H, s), 3.69 (2H, s), 3.82-3.93 (2H, m), 5.78 (1H, d, J = 14.8 Hz), 6.33 (1H, dd, J = 2.2, 14.1 Hz), 6.43-6.51 (1H, m), 6.54-6.70 (2H, m), 6.86 (1H, s), 6.97 (1H, d, J = 2.2 Hz), 7.02- 7.10 (2H, m), 7.19 (1H, s) 429 Cl H Cl CH2CH2C(CH3)3 (ESI)+: 0.88 (9H, s), 1.35-1.41 (2H, m), 1.88- [M + H]+ = 2.12 (4H, m), 2.29-2.35 (2H, m), 2.38- 599.4 2.57 (8H, m), 3.46 (3H, s), 3.72-3.76 (2H, m), 3.92-4.08 (2H, m), 5.85 (1H, d, J = 14.6 Hz), 6.43 (1H, s), 6.56-6.74 (2H, m), 6.98 (1H, s), 7.08 (1H, d, J = 8.7 Hz), 7.21 (1H, s), 7.27 (1H, s) 430 F H Cl CH2CH2C(CH3)3 (APCI)+: 0.88 (9H, s), 1.36-1.42 (2H, m), 1.84- [M + H]+ = 2.03 (4H, m), 2.31-2.39 (2H, m), 2.40- 583.4, 585.4 2.62 (8H, m), 3.46 (3H, s), 3.76 (2H, s), 3.92-4.04 (2H, m), 5.85 (1H, d, J = 14.1 Hz), 6.52 (1H, s), 6.57-6.80 (3H, m), 6.95-7.06 (2H, m), 7.21 (1H, s) 431 H F Me CH2CH2C(CH3)3 (APCI)+: 0.89 (9H, s), 1.35-1.41 (2H, m), 1.88- [M + H]+ = 1.97 (2H, m), 2.05-2.13 (1H, m), 2.21 563.5 (3H, s), 2.28-2.34 (2H, m), 2.34-2.54 (9H, m), 3.37 (3H, s), 3.68 (3H, s), 3.91 (2H, t, J = 6.4 Hz), 5.96- 6.01 (1H, m), 6.24-6.28 (1H, m), 6.33- 6.42 (1H, m), 6.42-6.48 (1H, m), 6.54- 6.60 (1H, m), 6.72 (1H, d, J = 7.9 Hz), 7.48-7.51 (1H, m) 432 Me H Me CH2CH2C(CH3)3 (ESI)+: 0.88 (9H, t, J = 12.9 Hz), 1.35- [M + H]+ = 1.42 (2H, m), 1.72-2.00 (2H, m), 2.02 559.5 (3H, s), 2.22 (3H, s), 2.28-2.35 (2H, m), 2.37-2.62 (10H, m), 3.77 (3H, s), 3.88-3.96 (3H, m), 5.89 (1H, d, J = 11.6 Hz), 6.45-6.62 (3H, m), 6.73 (1H, s), 6.94-7.01 (1H, m), 7.13 (1H, s), 7.19-7.22 (1H, m) 433 Me H Cl CH2CH2C(CH3)3 (ESI)+: 0.88 (9H, t, J = 12.9 Hz), 1.36- [M + H]+ = 1.43 (2H, m), 1.91-2.02 (2H, m), 2.05 579.4, 581.5 (3H, s), 2.30-2.37 (2H, m), 2.39-2.63 (10H, m), 3.75 (3H, s), 3.82-3.98 (3H, m), 5.87 (1H, d, J = 14.6 Hz), 6.25 (1H, s), 6.53-6.70 (2H, m), 6.96 (2H, s), 7.13-7.23 (2H, m) 434 Cl H Me CH2CH2C(CH3)3 (APCI)+: 0.88 (9H, s), 1.32-1.43 (2H, m), 1.61- [M + H]+ = 1.82 (1H, m), 1.89-2.02 (2H, m), 2.23 579.4, 581.4 (3H, s), 2.28-2.37 (2H, m), 2.37-2.68 (9H, m), 3.78 (3H, s), 3.96-4.01 (3H, m), 5.86 (1H, d, J = 14.6 Hz), 6.00 (1H, s), 6.48-6.61 (2H, m), 6.61-6.70 (2H, m), 6.75 (1H, s), 7.14 (1H, d, J = 8.2 Hz), 6.22 (1H, s) 435 F H Me CH2CH2C(CH3)3 (APCI)+: 0.87 (9H, s), 1.35-1.41 (2H, m), 1.88- [M + H]+ = 1.97 (2H, m), 2.05-2.13 (1H, m), 2.21 563.4 (3H, s), 2.28-2.34 (2H, m), 2.34-2.54 (9H, m), 3.76 (3H, s), 3.90-4.04 (3H, m), 5.85 (1H, d, J = 12.1 Hz), 6.18 (1H, s), 6.47-6.60 (2H, m), 6.67-6.79 (2H, m), 6.91 (1H, d, J = 9.3 Hz), 7.05 (1H, d, J = 9.3 Hz), 7.20 (1H, s) 436 Cl H H CH2CH2C(CH3)3 (APCI)+: 0.88 (9H, s), 1.29 (2H, d, J = 6.7 Hz), [M + H]+ = 1.31-1.42 (2H, m), 1.59-1.82 (2H, m), 565.4, 567.4 1.92-1.97 (2H, m), 2.29-2.35 (2H, m), 2.35.2.67 (9H, m), 3.80 (3H, s), 3.91- 4.04 (2H, m), 5.89 (1H, d, J = 15 Hz), 6.03 (1H, s), 6.60-6.80 (2H, m), 6.94 (1H, d, J = 7.9 Hz), 7.07-7.19 (2H, m), 7.23 (1H, s) 437 H Cl H CH2CH2C(CH3)3 (APCI)+: 0.88 (9H, s), 1.32-1.43 (2H, m), 1.80- [M + H]+ = 1.93 (2H, m), 2.27-2.38 (2H, m), 2.38- 565.5, 567.4 2.58 (9H, m), 3.61 (1H, s), 3.77 (3H, s), 3.86 (1H, t, J = 6.2 Hz), 4.02 (1H, s), 5.85 (1H, d, J = 14.8 Hz), 6.02 (1H, s), 6.45 (1H, dd, J = 2.2, 8.4 Hz), 6.67-6.69 (1H, m), 6.69-6.91 (2H, m), 6.91-7.12 (2H, m) 438 H F H CH2CH2C(CH3)3 (APCI)+: 0.88 (9H, s), 1.35-1.46 (2H, m), 1.80- [M + H]+ = 1.94 (2H, m), 2.30-2.41 (2H, m), 2.41- 549.4 2.62 (9H, m), 3.57 (1H, s), 3.76 (3H, s), 3.87 (2H, t, J = 6.4 Hz), 3.99 (1H, d, J = 14.6 Hz), 5.85 (1H, d, J = 14.6 Hz), 6.16 (1H, s), 6.39 (1H, dd, J = 2.2, 21.8 Hz), 6.62-6.75 (1H, m), 6.77 (1H, d, J = 6.7 Hz), 6.87 (1H, d, J = 6.7 Hz), 6.97-7.12 (2H, m), 7.23 (1H, s) 439 Me H H CH2CH2C(CH3)3 (ESI)+: 0.88 (9H, s), 1.38-1.53 (2H, m), 1.82- [M + H]+ = 1.96 (2H, m), 1.96-2.06 (3H, s), 2.53- 545.4 2.69 (4H, m), 2.69-2.80 (2H, m), 2.80- 2.96 (2H, m), 3.73 (3H, s), 3.82-3.93 (2H, m), 5.90 (1H, d, J = 14.3 Hz), 6.37 (1H, s), 6.46 (1H, d, J = 7.7 Hz), 6.69 (2H, s), 6.90-7.01 (2H, m), 7.02-7.13 (2H, m), 7.14-7.27 (2H, m), 7.83-8.13 (3H, m)

Com- pound R1 R8 R9 R10 MS 1H NMR: δ (ppm) 440 Me H H Me (APCI)+: 0.88 (9H, s), 1.35-1.50 [M + H]+ = (2H, m), 1.60-1.85 (2H, 559.6 m), 1.90-2.05 (8H, m), 2.35-2.40 (2H, m), 2.40- 2.70 (8H, m), 3.79 (3H, s), 3.85-3.95 (2H, m), 4.00-4.10 (2H, m), 5.85- 5.96 (1H, m), 6.41-7.28 (7H, m) 441 Me H Me H (APCI)+: 0.88 (9H, s), 1.36-1.42 [M + H]+ = (2H, m), 1.60-1.70 (2H, 559.6 m), 1.85-2.15 (10H, m), 2.25-2.60 (8H, m), 3.77 (3H, s), 3.90-3.92 (3H, m), 5.80-6.00 (2H, m), 6.45-6.55 (2H, m), 6.75- 7.22 (5H, m) 442 F Me H H (ESI)+: 0.92 (9H, s), 1.49-1.56 [M + H]+ = (2H, m), 1.85-2.03 (2H, 563.4 m), 2.41 (3H, s), 2.50- 2.97 (13H, m), 3.83 (3H, s), 3.88-4.03 (3H, m), 5.78-5.99 (2H, m), 6.57- 6.75 (3H, m), 6.92-7.08 (3H, m)

Compound number R1 R3 R8 R12 X a MS 443 E51 Me H Me CH2CH(CH3)2 CH 3 (ESI)+: [M + H]+ = 530.5 444 Me H Me CH2CH2CH3 CH 3 (ESI)+: [M + H]+ = 516.5 445 Me H Me CH 3 (ESI)+: [M + H]+ = 564.5 446 Me H Me CH 3 (ESI)+: [M + H]+ = 570.5 447 Me H Me CH 3 (ESI)+: [M + H]+ = 578.5 448 Me H Me CH 3 (ESI)+: [M + H]+ = 570.5 449 Me H Me CH 3 (ESI)+: [M + H]+ = 598.4 450 Me H Me CH 3 (ESI)+: [M + H]+ = 598.5 451 Me H Me CH 3 (ESI)+: [M + H]+ = 598.5 452 Me H Me CH2CH2CH2CH2CH3 CH 3 (ESI)+: [M + H]+ = 544.5 453 Me H Me CH 3 (ESI)+: [M + H]+ = 528.5 454 Me H Me CH 3 (ESI)+: [M + H]+ = 592.5 455 Me H Me CH2CH2CH(CH3)2 CH 3 (ESI)+: [M + H]+ = 544.5 456 Me H Me CH 3 (ESI)+: [M + H]+ = 554.4 457 Me H Me CH 3 (ESI)+: [M + H]+ = 584.5 458 Me H Me CH 3 (ESI)+: [M + H]+ = 565.5 459 Me H Me CH 3 (ESI)+: [M + H]+ = 553.4 460 Me H Me CH 3 (ESI)+: [M + H]+ = 606.6 461 Me H Me CH 3 (ESI)+: [M + H]+ = 580.5 462 Me H Me CH 3 (ESI)+: [M + H]+ = 565.4 463 Me H Me CH 3 (ESI)+: [M + H]+ = 565.4 464 Me H Me CH 3 (ESI)+: [M + H]+ = 570.4 465 Me H Me CH2CH2CF3 CH 3 (ESI)+: [M + H]+ = 570.4 466 Me H Me CH 3 (ESI)+: [M + H]+ = 568.5 467 Me H Me CH 3 (ESI)+: [M + H]+ = 567.5 468 Me H Me CH 3 (ESI)+: [M + H]+ = 578.5 469 Me H Me CH 3 (ESI)+: [M + H]+ = 578.5 470 Me H Me CH 3 (ESI)+: [M + H]+ = 578.5 471 Me H Me CH 3 (ESI)+: [M + H]+ = 589.5 472 Me H Me CH 3 (ESI)+: [M + H]+ = 589.5 473 Me H Me CH 3 (ESI)+: [M + H]+ = 589.5 474 Me H Me CH 3 (ESI)+: [M + H]+ = 632.5 475 Me H Me CH 3 (ESI)+: [M + H]+ = 654.6 476 Me H Me CH 3 (ESI)+: [M + H]+ = 622.6 477 Me H Me CH2CH(CH3)2 N 2 (ESI)+: [M + H]+ = 517.5 478 Me H Me CH2CH2CH3 N 2 (ESI)+: [M + H]+ = 503.5 479 Me H Me N 2 (ESI)+: [M + H]+ = 551.4 480 Me H Me N 2 (ESI)+: [M + H]+ = 565.5 481 Me H Me N 2 (ESI)+: [M + H]+ = 557.3 482 Me H Me N 2 (ESI)+: [M + H]+ = 585.4 483 Me H Me N 2 (ESI)+: [M + H]+ = 585.4 484 Me H Me N 2 (ESI)+: [M + H]+ = 585.4 485 Me H Me CH2CH2CH2CH2CH3 N 2 (ESI)+: [M + H]+ = 531.4 486 Me H Me N 2 (ESI)+: [M + H]+ = 515.5 487 Me H Me N 2 (ESI)+: [M + H]+ = 579.5 488 Me H Me CH2CH2CH(CH3)2 N 2 (ESI)+: [M + H]+ = 531.5 489 Me H Me CH2C(CH3)3 N 2 (ESI)+: [M + H]+ = 531.4 490 Me H Me N 2 (ESI)+: [M + H]+ = 541.4 491 Me H Me N 2 (ESI)+: [M + H]+ = 571.5 492 Me H Me N 2 (ESI)+: [M + H]+ = 552.4 493 Me H Me N 2 (ESI)+: [M + H]+ = 540.4 494 Me H Me N 2 (ESI)+: [M + H]+ = 593.5 495 Me H Me N 2 (ESI)+: [M + H]+ = 567.4 496 Me H Me N 2 (ESI)+: [M + H]+ = 552.4 497 Me H Me N 2 (ESI)+: [M + H]+ = 552.5 498 Me H Me N 2 (ESI)+: [M + H]+ = 557.4 499 Me H Me CH2CH2CF3 N 2 (ESI)+: [M + H]+ = 557.4 500 Me H Me N 2 (ESI)+: [M + H]+ = 555.5 501 Me H Me N 2 (ESI)+: [M + H]+ = 565.4 502 Me H Me N 2 (ESI)+: [M + H]+ = 565.4 503 Me H Me N 2 (ESI)+: [M + H]+ = 565.4 504 Me H Me N 2 (ESI)+: [M + H]+ = 576.5 505 Me H Me N 2 (ESI)+: [M + H]+ = 576.4 506 Me H Me N 2 (ESI)+: [M + H]+ = 576.4 507 Me H Me N 2 (ESI)+: [M + H]+ = 619.4 508 Me H Me N 2 (ESI)+: [M + H]+ = 641.5 509 Me H Me N 2 (ESI)+: [M + H]+ = 609.5 510 H F H CH2CH(CH3)2 N 2 (ESI)+: [M + H]+ = 507.4 511 H F H CH2CH2CH3 N 2 (ESI)+: [M + H]+ = 493.4 512 H F H N 2 (ESI)+: [M + H]+ = 541.4 513 H F H N 2 (ESI)+: [M + H]+ = 555.4 514 H F H N 2 (ESI)+: [M + H]+ = 547.3 515 H F H N 2 (ESI)+: [M + H]+ = 575.3 516 H F H N 2 (ESI)+: [M + H]+ = 575.3 517 H F H N 2 (ESI)+: [M + H]+ = 575.3 518 H F H CH2CH2CH2CH2CH3 N 2 (ESI)+: [M + H]+ = 521.4 519 H F H N 2 (ESI)+: [M + H]+ = 505.4 520 H F H N 2 (ESI)+: [M + H]+ = 569.4 521 H F H N 2 (ESI)+: [M + H]+ = 531.3 522 H F H N 2 (ESI)+: [M + H]+ = 561.4 523 H F H N 2 (ESI)+: [M + H]+ = 583.4 524 H F H N 2 (ESI)+: [M + H]+ = 557.3 525 H F H N 2 (ESI)+: [M + H]+ = 547.3 526 H F H CH2CH2OH N 2 (ESI)+: [M + H]+ = 495.3 527 H F H N 2 (ESI)+: [M + H]+ = 555.3 528 H F H N 2 (ESI)+: [M + H]+ = 566.3 529 H F H N 2 (ESI)+: [M + H]+ = 566.4 530 H F H N 2 (ESI)+: [M + H]+ = 566.3 531 H F H N 2 (ESI)+: [M + H]+ = 629.4 532 H F H N 2 (ESI)+: [M + H]+ = 609.3 533 H F H N 2 (ESI)+: [M + H]+ = 599.4

Com- pound number R8 R12 X MS 534 E52 Cl CH2CH2CH2CH2CH2CH3 N (ESI)+: [M + H]+ = 583.6 535 Cl CH2(CH2)2CH3 N (ESI)+: [M + H]+ = 555.6 536 Cl CH2(CH2)2CN N (ESI)+: [M + H]+ = 566.5 537 Cl N (ESI)+: [M + H]+ = 617.7 538 Cl N (ESI)+: [M + H]+ = 609.8 539 Cl N (ESI)+: [M + H]+ = 607.7 540 Cl N (ESI)+: [M + H]+ = 645.8 541 Cl N (ESI)+: [M + H]+ = 673.7 542 Cl N (ESI)+: [M + H]+ = 647.7 543 Cl N (ESI)+: [M + H]+ = 589.6 544 Cl N (ESI)+: [M + H]+ = 595.6 545 Cl CH2CO2CH(CH3)2 N (ESI)+: [M + H]+ = 599.7 546 Cl CH2CH2CH(CH3)2 N (ESI)+: [M + H]+ = 569.6 547 Cl CH2CH2CN N (ESI)+: [M + H]+ = 552.5 548 Cl CH2CH2CH2OH N (ESI)+: [M + H]+ = 557.6 549 Cl CH2CN N (ESI)+: [M + H]+ = 538.5 550 Cl CH2CH2OCH2CH3 N (ESI)+: [M + H]+ = 571.5 551 Cl CH2CH2CH2F N (ESI)+: [M + H]+ = 559.6 552 Cl N (ESI)+: [M + H]+ = 634.8 553 Cl N (ESI)+: [M + H]+ = 553.5 554 Cl N (ESI)+: [M + H]+ = 639.8 555 Cl N (ESI)+: [M + H]+ = 539.6 556 Cl N (ESI)+: [M + H]+ = 615.7 557 Cl N (ESI)+: [M + H]+ = 665.6 558 Cl N (ESI)+: [M + H]+ = 597.6 559 Cl N (ESI)+: [M + H]+ = 614.7 560 Cl CH2COC(CH3)3 N (ESI)+: [M + H]+ = 597.6 561 Cl CH2CONH2 N (ESI)+: [M + H]+ = 556.5 562 Cl N (ESI)+: [M + H]+ = 624.6 563 Cl N (ESI)+: [M + H]+ = 631.6 564 H CH2(CH2)4CH3 CH (ESI)+: [M + H]+ = 548.6 565 H CH2(CH2)2CH3 CH (ESI)+: [M + H]+ = 520.6 566 H CH2(CH2)3OH CH (ESI)+: [M + H]+ = 536.6 567 H CH (ESI)+: [M + H]+ = 582.5 568 H CH (ESI)+: [M + H]+ = 574.6 569 H CH (ESI)+: [M + H]+ = 572.5 570 H CH (ESI)+: [M + H]+ = 610.7 571 H CH (ESI)+: [M + H]+ = 638.7 572 H CH (ESI)+: [M + H]+ = 612.6 573 H CH (ESI)+: [M + H]+ = 554.5 574 H CH (ESI)+: [M + H]+ = 560.1 575 H CH2CO2CH(CH3)2 CH (ESI)+: [M + H]+ = 564.6 576 H CH2CH2CH(CH3)2 CH (ESI)+: [M + H]+ = 534.6 577 H CH2CH2CN CH (ESI)+: [M + H]+ = 517.5 578 H CH2CN CH (ESI)+: [M + H]+ = 503.5 579 H CH2CH2OCH2CH3 CH (ESI)+: [M + H]+ = 536.6 580 H CH2CH2CH2F CH (ESI)+: [M + H]+ = 524.6 581 H CH (ESI)+: [M + H]+ = 599.6 582 H CH (ESI)+: [M + H]+ = 518.6 583 H CH (ESI)+: [M + H]+ = 604.6 584 H CH (ESI)+: [M + H]+ = 504.5 585 H CH (ESI)+: [M + H]+ = 580.5 586 H CH (ESI)+: [M + H]+ = 630.7 587 H CH (ESI)+: [M + H]+ = 562.5 588 H CH (ESI)+: [M + H]+ = 579.5 589 H CH2COC(CH3)3 CH (ESI)+: [M + H]+ = 562.6 590 H CH2CONH2 CH (ESI)+: [M + H]+ = 521.5 591 H CH (ESI)+: [M + H]+ = 589.5 592 H CH (ESI)+: [M + H]+ = 596.6

Com- pound number X R8 R19 MS 593 E53 N H Me (ESI)+: [M + H]+ = 503.2 594 N H (ESI)+: [M + H]+ = 565.3 595 N H (ESI)+: [M + H]+ = 599.3 596 N H (ESI)+: [M + H]+ = 599.3 597 N H (ESI)+: [M + H]+ = 599.3 598 N H (ESI)+: [M + H]+ = 595.3 599 N H (ESI)+: [M + H]+ = 579.3 600 N H (ESI)+: [M + H]+ = 579.3 601 N H (ESI)+: [M + H]+ = 600.3 602 N H (ESI)+: [M + H]+ = 566.3 603 N H (ESI)+: [M + H]+ = 571.3 604 N H (ESI)+: [M + H]+ = 571.3 605 N H (ESI)+: [M + H]+ = 583.3 606 N H (ESI)+: [M + H]+ = 555.3 607 N H (ESI)+: [M + H]+ = 556.3 608 N H (ESI)+: [M + H]+ = 646.4 609 N H CH2CH3 (ESI)+: [M + H]+ = 517.3 610 N H CH2CH2CH3 (ESI)+: [M + H]+ = 531.3 611 N H (ESI)+: [M + H]+ = 529.3 612 N H C(CH3)3 (ESI)+: [M + H]+ = 545.3 613 N H (ESI)+: [M + H]+ = 571.3 614 N H CH2(CH2)3CH3 (ESI)+: [M + H]+ = 559.3 615 N H CH(CH2CH3)CH2CH2CH2CH3 (ESI)+: [M + H]+ = 587.4 616 N H (ESI)+: [M + H]+ = 639.4 617 N H (ESI)+: [M + H]+ = 579.3 618 N H (ESI)+: [M + H]+ = 593.3 619 N H (ESI)+: [M + H]+ = 605.4 620 N H (ESI)+: [M + H]+ = 585.3 621 N H (ESI)+: [M + H]+ = 595.3 622 N H (ESI)+: [M + H]+ = 609.4 623 N H CH2CH2CO2CH3 (ESI)+: [M + H]+ = 575.3 624 N H CH2CH2CH2CO2CH2CH3 (ESI)+: [M + H]+ = 603.4 625 CH Me CH3 (ESI)+: [M + H]+ = 516.4 626 CH Me (ESI)+: [M + H]+ = 578.4 627 CH Me (ESI)+: [M + H]+ = 612.4 628 CH Me (ESI)+: [M + H]+ = 612.4 629 CH Me (ESI)+: [M + H]+ = 612.4 630 CH Me (ESI)+: [M + H]+ = 608.5 631 CH Me (ESI)+: [M + H]+ = 592.4 632 CH Me (ESI)+: [M + H]+ = 592.4 633 CH Me (ESI)+: [M + H]+ = 613.4 634 CH Me (ESI)+: [M + H]+ = 579.4 635 CH Me (ESI)+: [M + H]+ = 579.4 636 CH Me (ESI)+: [M + H]+ = 584.4 637 CH Me (ESI)+: [M + H]+ = 584.4 638 CH Me (ESI)+: [M + H]+ = 596.4 639 CH Me (ESI)+: [M + H]+ = 568.4 640 CH Me (ESI)+: [M + H]+ = 569.4 641 CH Me (ESI)+: [M + H]+ = 659.5 642 CH Me CH2CH2CH3 (ESI)+: [M + H]+ = 544.4 643 CH Me (ESI)+: [M + H]+ = 542.4 644 CH Me C(CH3)3 (ESI)+: [M + H]+ = 558.4 645 CH Me (ESI)+: [M + H]+ = 584.4 646 CH Me CH2(CH2)3CH3 (ESI)+: [M + H]+ = 572.4 647 CH Me CH(CH2CH3)CH2CH2CH2CH3 (ESI)+: [M + H]+ = 600.5 648 CH Me (ESI)+: [M + H]+ = 652.5 649 CH Me (ESI)+: [M + H]+ = 592.5 650 CH Me (ESI)+: [M + H]+ = 606.5 651 CH Me (ESI)+: [M + H]+ = 618.5 652 CH Me (ESI)+: [M + H]+ = 598.4 653 CH Me (ESI)+: [M + H]+ = 608.5 654 CH Me (ESI)+: [M + H]+ = 622.5 655 CH Me CH2CH2CH2CO2CH2CH3 (ESI)+: [M + H]+ = 616.5

Compound number X R8 R19 MS 656 E54 N H Me (ESI)+: [M + H]+ = 539.2 657 N H CH(CH3)2 (ESI)+: [M + H]+ = 567.3 658 N H (ESI)+: [M + H]+ = 615.3 659 N H (ESI)+: [M + H]+ = 601.3 660 N H (ESI)+: [M + H]+ = 669.3 661 N H (ESI)+: [M + H]+ = 635.3 662 N H (ESI)+: [M + H]+ = 635.3 663 N H (ESI)+: [M + H]+ = 635.3 664 N H (ESI)+: [M + H]+ = 631.3 665 N H (ESI)+: [M + H]+ = 615.3 666 N H (ESI)+: [M + H]+ = 626.3 667 N H (ESI)+: [M + H]+ = 669.3 668 N H (ESI)+: [M + H]+ = 658.4 669 N H (ESI)+: [M + H]+ = 641.3 670 N H (ESI)+: [M + H]+ = 605.3 671 N H CH2CF3 (ESI)+: [M + H]+ = 607.3 672 N H (ESI)+: [M + H]+ = 716.2 673 N H (ESI)+: [M + H]+ = 649.3 674 N H CH2CH3 (ESI)+: [M + H]+ = 553.3 675 N H CH2CH2CH3 (ESI)+: [M + H]+ = 567.3 676 N H CH2CH2CH2CH3 (ESI)+: [M + H]+ = 581.3 677 CH Me CH3 (ESI)+: [M + H]+ = 552.3 678 CH Me CH(CH3)2 (ESI)+: [M + H]+ = 580.4 679 CH Me (ESI)+: [M + H]+ = 628.5 680 CH Me (ESI)+: [M + H]+ = 614.4 681 CH Me (ESI)+: [M + H]+ = 682.4 682 CH Me (ESI)+: [M + H]+ = 648.4 683 CH Me (ESI)+: [M + H]+ = 648.4 684 CH Me (ESI)+: [M + H]+ = 648.4 685 CH Me (ESI)+: [M + H]+ = 644.5 686 CH Me (ESI)+: [M + H]+ = 628.5 687 CH Me (ESI)+: [M + H]+ = 639.5 688 CH Me (ESI)+: [M + H]+ = 682.4 689 CH Me (ESI)+: [M + H]+ = 671.5 690 CH Me (ESI)+: [M + H]+ = 654.4 691 CH Me (ESI)+: [M + H]+ = 618.5 692 CH Me (ESI)+: [M + H]+ = 729.2 693 CH Me (ESI)+: [M + H]+ = 662.4 694 CH Me CH2CH3 (ESI)+: [M + H]+ = 566.3 695 CH Me CH2CH2CH3 (ESI)+: [M + H]+ = 580.4 696 CH Me CH2CH2CH2CH3 (ESI)+: [M + H]+ = 594.4

Compound number R1 R10 R12 X2 MS 1H NMR 697 F Cl S (ESI)+: [M + H]+ = 569.5, 571.3 0.05-0.15 (2H, m), 0.45-0.55 (2H, m), 0.80-0.90 (1H, m), 1.90-2.00 (2H, m), 2.24 (2H, d, J = 6.4 Hz), 2.35-2.70 (10H, m), 2.73 (3H, s) 2.95-3.25 (2H, m), 3.45-3.55 (1H, m), 3.99 (2H, t, J = 6.4 Hz), 5.15-5.25 (1H, m), 6.60-6.75 (3H, m), 6.90-7.05 (2H, m), 8.41 (1H, d, J = 2.5 Hz) 698 Cl Me S (ESI)+: [M + H]+ = 643.3, 645.4 1.22 (6H, d, J = 6.9 Hz), 1.87-1.99 (2H, m), 2.34 (3H, s), 2.45-2.52 (10H, m), 2.74 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.03-3.18 (2H, m), 3.45 (2H, s), 3.45-3.54 (1H, m), 3.95 (2H, t, J = 6.2 Hz), 5.13-5.19 (1H, m), 6.52 (1H, d, J = 8.6 Hz), 6.57 (1H, d, J = 8.2 Hz), 6.75 (1H, dd, J = 2.2, 8.6 Hz), 6.81 (1H, d, J = 8.2 Hz), 7.15 (2H, d, J = 8.2 Hz), 7.21 (2H, d, J = 8.2 Hz), 7.38 (1H, d, J = 2.2 Hz), 8.18 (1H, s) 699 Cl Me S (ESI)+: [M + H]+ = 595.4, 597.4 0.89 (9H, s), 1.38- 1.44 (2H, m), 1.89- 1.99 (2H, m), 2.34, (3H, s), 2.35-2.41 (2H, m), 2.47-2.56 (10H, m), 2.73 (3H, s), 3.01-3.18 (2H, m), 3.45-3.57 (1H, m), 3.95 (2H, t, J = 6.4 Hz), 5.12-5.19, (1H, m), 6.52 (1H, d, J = 8.6 Hz), 6.57 (1H, d, J = 8.4 Hz), 6.75 (1H, dd, J = 2.2, 8.4 Hz), 6.80 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 2.2 Hz), 8.17 (1H, s)

Compound number R4 1H NMR: δ (ppm) 700 (ESI)+: [M + H]+ = 543.6 0.85 (9H, s), 1.30- 1.41 (4H, m), 2.10 (3H, s), 2.28-2.45 (6H, m), 2.71-2.82 (2H, m), 3.25-3.34 (2H, m), 3.52-3.65 (2H, m), 3.71 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 5.85 (1H, d, J = 14.6 Hz), 6.65 (1H, s), 6.75- 7.01 (5H, m), 7.07- 7.17 (3H, m) 701 (ESI)+: [M + H]+ = 472.7 2.17 (3H, s), 2.29 (2H, t, J = 5.7 Hz), 2.40 (2H, t, J = 5.7 Hz), 2.53 (2H, t, J = 7.2 Hz), 2.87 (2H, t, J = 7.2 Hz), 3.52 (2H, brs), 3.79 (3H, s), 3.77-3.83 (2H, m), 3.95 (1H, d, J = 14.6 Hz), 5.89 (1H, d, J = 14.6 Hz), 6.19 (1H, s), 6.62- 6.74 (2H, m), 6.81- 6.94 (3H, m), 7.02- 7.08 (1H, m), 7.16 (1H, s) 702 (ESI)+: [M + H]+ = 527.7 1.61-1.68 (2H, m), 1.68-1.91 (3H, m), 1.92-2.08 (2H, m), 2.14 (3H, s), 2.28- 2.51 (4H, m), 2.72- 2.89 (2H, m), 2.93- 3.08 (2H, m), 3.21- 3.34 (2H, m), 3.46- 3.69 (4H, m), 3.80 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 5.87 (1H, d, J = 14.6 Hz), 6.51 (1H, s), 6.68 (2H, s), 6.74-6.89 (2H, m), 6.94-7.08 (2H, m), 7.13 (1H, s) 703 (ESI)+: [M + H]+ = 499.7 — 704 (ESI)+: [M + H]+ = 556.7 — 705 (ESI)+: [M + H]+ = 632.0 (MeCN adduct) — 706 (ESI)+: [M + H]+ = 444.3 — 707 (ESI)+: [M + H]+ = 516.4 — 708 (ESI)+: [M + H]+ = 506.3 — 709 (ESI)+: [M + H]+ = 486.4 — 710 E56 (ESI)+: [M + H]+ = 553.4 711 (ESI)+: [M + H]+ = 458.3 — 712 (ESI)+: [M + H]+ = 472.4 — 713 (ESI)+: [M + H]+ = 460.4 — 714 (ESI)+: [M + H]+ = 558.4 — 715 (ESI)+: [M + H]+ = 473.3 — 716 (ESI)+: [M + H]+ = 512.4 — 717 (ESI)+: [M + H]+ = 512.4 — 718 (ESI)+: [M + H]+ = 476.3 — 719 (ESI)+: [M + H]+ = 462.3 — 720 (ESI)+: [M + H]+ = 530.4 — 721 (ESI)+: [M + H]+ = 502.4 — 722 (ESI)+: [M + H]+ = 502.4 — 723 (ESI)+: [M + H]+ = 487.3 — 724 (ESI)+: [M + H]+ = 593.4 — 725 (ESI)+: [M + H]+ = 553.4 — 726 (ESI)+: [M + H]+ = 530.4 — 727 (ESI)+: [M + H]+ = 603.4 — 728 (ESI)+: [M + H]+ = 603.4 — 729 (ESI)+: [M + H]+ = 565.4 — 730 (ESI)+: [M + H]+ = 548.4 — 731 (ESI)+: [M + H]+ = 527.5 — 732 (ESI)+: [M + H]+ = 550.3 — 733 (ESI)+: [M + H]+ = 492.4 — 734 (ESI)+: [M + H]+ = 506.4 — 735 (ESI)+: [M + H]+ = 508.4 — 736 (ESI)+: [M + H]+ = 509.3 — 737 (ESI)+: [M + H]+ = 536.4 — 738 (ESI)+: [M + H]+ = 515.4 — 739 (ESI)+: [M + H]+ = 501.4 — 740 (ESI)+: [M + H]+ = 501.4 — 741 (ESI)+: [M + H]+ = 557.5 — 742 (ESI)+: [M + H]+ = 488.4 —

Com- pound num- ber R15 R16 743 H (ESI)+: [M + H]+ = 466.1 744 H (ESI)+: [M + H]+ = 494.2 745 H (ESI)+: [M + H]+ = 550.3 746 H (ESI)+: [M + H]+ = 510.3 747 H (ESI)+: [M + H]+ = 566.3 748 H (ESI)+: [M + H]+ = 509.3 749 H (ESI)+: [M + H]+ = 467.2 750 H (ESI)+: [M + H]+ = 467.2 751 H (ESI)+: [M + H]+ = 593.3 752 H (ESI)+: [M + H]+ = 549.3 753 H (ESI)+: [M + H]+ = 498.3 754 H CH3 (ESI)+: [M + H]+ = 404.2 755 H CH2CH3 (ESI)+: [M + H]+ = 418.2 756 H CH2CH(CH3)3 (ESI)+: [M + H]+ = 446.2 757 H CH2CH2CH3 (ESI)+: [M + H]+ = 432.2 758 H (ESI)+: [M + H]+ = 430.2 759 H CH2(CH2)4CH3 (ESI)+: [M + H]+ = 474.3 760 H (ESI)+: [M + H]+ = 458.2 761 H (ESI)+: [M + H]+ = 486.3 762 H C(CH3)2CH2CH3 (ESI)+: [M + H]+ = 460.2 763 H CH(CH2CH3)2 (ESI)+: [M + H]+ = 460.3 764 H CH2CH2CH(CH3)2 (ESI)+: [M + H]+ = 460.2 765 H (ESI)+: [M + H]+ = 506.3 766 H (ESI)+: [M + H]+ = 506.3 767 H (ESI)+: [M + H]+ = 486.3 768 H (ESI)+: [M + H]+ = 480.2 769 H (ESI)+: [M + H]+ = 564.2 770 H (ESI)+: [M + H]+ = 548.2 771 H (ESI)+: [M + H]+ = 510.3 772 H (ESI)+: [M + H]+ = 548.2 773 H (ESI)+: [M + H]+ = 494.3 774 H (ESI)+: [M + H]+ = 528.2 775 H (ESI)+: [M + H]+ = 508.2 776 H (ESI)+: [M + H]+ = 524.3 777 H (ESI)+: [M + H]+ = 481.2 778 H (ESI)+: [M + H]+ = 481.2 779 H (ESI)+: [M + H]+ = 495.3 780 H (ESI)+: [M + H]+ = 486.2 781 H (ESI)+: [M + H]+ = 470.2 782 H CH2CH2F (ESI)+: [M + H]+ = 436.2 783 H CH2CH2OH (ESI)+: [M + H]+ = 434.2 784 H CH2CH2CH2OH (ESI)+: [M + H]+ = 448.2 785 H CH2(CH2)3OH (ESI)+: [M + H]+ = 462.2 786 H CH2(CH2)4OH (ESI)+: [M + H]+ = 476.2 787 H (ESI)+: [M + H]+ = 462.2 788 H (ESI)+: [M + H]+ = 502.2 789 H CH2(CH2)2SCH3 (ESI)+: [M + H]+ = 478.2 790 H (ESI)+: [M + H]+ = 503.2 791 H CH2CH2N(CH3)2 (ESI)+: [M + H]+ = 461.2 792 H (ESI)+: [M + H]+ = 531.4 793 H CH2(CH2)2N(CH3)2 (ESI)+: [M + H]+ = 475.2 794 H (ESI)+: [M + H]+ = 563.3 795 H CH2CH2NHCOCH3 (ESI)+: [M + H]+ = 475.2 796 H (ESI)+: [M + H]+ = 545.3 797 H CH2CO2CH3 (ESI)+: [M + H]+ = 462.2 798 H (ESI)+: [M + H]+ = 558.4 799 H CH2CO2CH(CH3)2 (ESI)+: [M + H]+ = 490.3 800 H (ESI)+: [M + H]+ = 590.3 801 H CH2CONH2 (ESI)+: [M + H]+ = 447.1 802 H CH2CN (ESI)+: [M + H]+ = 429.2 803 H CH2CH2CN (ESI)+: [M + H]+ = 443.2 804 H CH2(CH2)4CN (ESI)+: [M + H]+ = 485.3 805 H CH2CF3 (ESI)+: [M + H]+ = 472.2 806 CH3 (ESI)+: [M + H]+ = 494.4 807 CH2CH2CH3 (ESI)+: [M + H]+ = 567.4 808 CH3 CH2CH3 (ESI)+: [M + H]+ = 432.3 809 CH2CH3 (ESI)+: [M + H]+ = 509.4 810 CH2CH2CN (ESI)+: [M + H]+ = 534.3 811 CH2CO2CH2CH3 (ESI)+: [M + H]+ = 566.4 812 CH3 (ESI)+: [M + H]+ = 544.4 813 CH3 CH2CH2CH2CH3 (ESI)+: [M + H]+ = 460.3 814 CH3 CH2(CH2)4CH3 (ESI)+: [M + H]+ = 488.4 815 CH(CH3)2 (ESI)+: [M + H]+ = 514.5 816 CH2CH3 CH2CH3 (ESI)+: [M + H]+ = 446.2 817 CH(CH3)2 CH(CH3)2 (ESI)+: [M + H]+ = 474.4 818 CH3 (ESI)+: [M + H]+ = 509.4 819 CH2CH3 (ESI)+: [M + H]+ = 550.4 820 CH(CH3)2 CH2CH2OCH3 (ESI)+: [M + H]+ = 490.4 821 CH3 (ESI)+: [M + H]+ = 508.4 822 CH2CH2OCH3 CH2CH2OCH3 (ESI)+: [M + H]+ = 506.3 823 CH3 C6H5 (ESI)+: [M + H]+ = 480.3 824 CH2CH2OH C6H5 (ESI)+: [M + H]+ = 510.4 825 CH3 (ESI)+: [M + H]+ = 514.4 826 CH3 (ESI)+: [M + H]+ = 481.4 827 CH3 (ESI)+: [M + H]+ = 481.3 828 CH2CH3 (ESI)+: [M + H]+ = 502.4 829 CH3 CH3 (ESI)+: [M + H]+ = 418.3 830 CH3 (ESI)+: [M + H]+ = 538.3 831 CH3 (ESI)+: [M + H]+ = 484.3 832 CH3 CH2CO2H (ESI)+: [M + H]+ = 460.4 833 CH3 CH2CH2CH2CO2H (ESI)+: [M + H]+ = 490.4 834 CH3 CH2CN (ESI)+: [M + H]+ = 443.3 835 CH3 CH2CH2CN (ESI)+: [M + H]+ = 457.3 836 CH2CH2N(CH3)2 (ESI)+: [M + H]+ = 551.5 837 CH2CH2OH (ESI)+: [M + H]+ = 524.4 838 CH2CN (ESI)+: [M + H]+ = 519.4

Compound number R4 MS 839 E57 840 841

Com- pound 1H number R13 R14 MS NMR 842 E58 Me CH2CH2CH2CH3 (ESI)+: [M + H]+ = 557.6 843 H (ESI)+: [M + H]+ = 660.7 — 844 H CH2C6H5 (ESI)+: — [M + H]+ = 577.6 845 H CH2CH2C6H5 (ESI)+: — [M + H]+ = 591.7 846 H (ESI)+: [M + H]+ = 595.7 — 847 H (ESI)+: [M + H]+ = 555.6 — 848 H CH2CH(CH3)2 (ESI)+: — [M + H]+ = 543.6

Com- pound 1H number R4 MS NMR 849 (ESI)+: [M + H]+ = 603.7 — 850 (ESI)+: [M + H]+ = 573.6 —

Compound number R13 R14 MS 1H NMR 851 E59 H (ESI)+: [M + H]+ = 586.6 852 H CH2C6H5 (ESI)+: — [M + H]+ = 563.6 853 H (ESI)+: [M + H]+ = 569.6 —

Compound number R12 MS 868 E60 CH2CH2CH2CH2CH2CH3 (ESI)+: [M + H]+ = 543.4 869 CH2CH2CH3 (ESI)+: [M + H]+ = 501.4 870 CH2(CH2)3OH (ESI)+: [M + H]+ = 531.3 871 CH2(CH2)2CN (ESI)+: [M + H]+ = 526.4 872 (ESI)+: [M + H]+ = 569.4 873 (ESI)+: [M + H]+ = 567.3 874 (ESI)+: [M + H]+ = 605.5 875 (ESI)+: [M + H]+ = 633.5 876 (ESI)+: [M + H]+ = 607.4 877 (ESI)+: [M + H]+ = 549.4 878 CH2CH2OH (ESI)+: [M + H]+ = 503.3 879 CH2CO2CH(CH3)2 (ESI)+: [M + H]+ = 559.3 880 CH2CH2CH(CH3)2 (ESI)+: [M + H]+ = 529.4 881 CH2CH2CH2OH (ESI)+: [M + H]+ = 517.4 882 CH2CN (ESI)+: [M + H]+ = 498.4 883 CH2CH2OCH2CH3 (ESI)+: [M + H]+ = 531.4 884 (ESI)+: [M + H]+ = 594.4 885 (ESI)+: [M + H]+ = 599.4 886 (ESI)+: [M + H]+ = 499.4 887 (ESI)+: [M + H]+ = 575.4 888 (ESI)+: [M + H]+ = 625.5 889 CH2COC(CH3)3 (ESI)+: [M + H]+ = 557.4 890 CH2CONH2 (ESI)+: [M + H]+ = 516.4 891 (ESI)+: [M + H]+ = 584.4 892 (ESI)+: [M + H]+ = 591.4

Compound number R12 MS 893 CH2CH2CH3 (ESI)+: [M + H]+ = 515.5 894 CH2CH(CH3)2 (ESI)+: [M + H]+ = 529.5 895 (ESI)+: [M + H]+ = 563.4 896 (ESI)+: [M + H]+ = 569.4 897 (ESI)+: [M + H]+ = 577.5 898 (ESI)+: [M + H]+ = 597.4 899 (ESI)+: [M + H]+ = 597.4 900 (ESI)+: [M + H]+ = 597.5 901 CH2CH2CH2CH2CH3 (ESI)+: [M + H]+ = 543.4 902 (ESI)+: [M + H]+ = 527.4 903 (ESI)+: [M + H]+ = 591.5 904 CH2CH2CH(CH3)2 (ESI)+: [M + H]+ = 543.5 905 (ESI)+: [M + H]+ = 553.4 906 (ESI)+: [M + H]+ = 583.5 907 (ESI)+: [M + H]+ = 564.4 908 (ESI)+: [M + H]+ = 552.4 909 (ESI)+: [M + H]+ = 605.5 910 (ESI)+: [M + H]+ = 564.4 911 (ESI)+: [M + H]+ = 564.4 912 (ESI)+: [M + H]+ = 569.3 913 (ESI)+: [M + H]+ = 567.5 914 CH2CH2OH (ESI)+: [M + H]+ = 517.4 915 (ESI)+: [M + H]+ = 577.5 916 (ESI)+: [M + H]+ = 577.5 917 (ESI)+: [M + H]+ = 577.4 918 (ESI)+: [M + H]+ = 588.5 919 (ESI)+: [M + H]+ = 588.5 920 (ESI)+: [M + H]+ = 588.5 921 (ESI)+: [M + H]+ = 653.5 922 (ESI)+: [M + H]+ = 631.5 923 (ESI)+: [M + H]+ = 653.6 924 (ESI)+: [M + H]+ = 621.6

Compound number R8 R19 MS 925 E62 Cl Me (ESI)+: [M + H]+ = 535.5 926 Cl (ESI)+: [M + H]+ = 597.5 927 Cl (ESI)+: [M + H]+ = 631.5 928 Cl (ESI)+: [M + H]+ = 631.5 929 Cl (ESI)+: [M + H]+ = 631.5 930 Cl (ESI)+: [M + H]+ = 627.6 931 Cl (ESI)+: [M + H]+ = 611.5 932 Cl (ESI)+: [M + H]+ = 611.6 933 Cl (ESI)+: [M + H]+ = 632.5 934 Cl (ESI)+: [M + H]+ = 598.5 935 Cl (ESI)+: [M + H]+ = 598.5 936 Cl (ESI)+: [M + H]+ = 603.5 937 Cl (ESI)+: [M + H]+ = 603.4 938 Cl (ESI)+: [M + H]+ = 615.6 939 Cl (ESI)+: [M + H]+ = 587.5 940 Cl (ESI)+: [M + H]+ = 588.5 941 Cl (ESI)+: [M + H]+ = 678.6 942 Cl CH2CH3 (ESI)+: [M + H]+ = 549.4 943 Cl CH2CH2CH3 (ESI)+: [M + H]+ = 563.5 944 Cl (ESI)+: [M + H]+ = 561.5 945 Cl C(CH3)3 (ESI)+: [M + H]+ = 577.5 946 Cl (ESI)+: [M + H]+ = 603.6 947 Cl CH2(CH2)3CH3 (ESI)+: [M + H]+ = 591.5 948 Cl CH(CH2CH3)CH2CH2CH2CH3 (ESI)+: [M + H]+ = 619.6 949 Cl (ESI)+: [M + H]+ = 671.6 950 Cl (ESI)+: [M + H]+ = 611.6 951 Cl (ESI)+: [M + H]+ = 625.6 952 Cl (ESI)+: [M + H]+ = 637.6 953 Cl (ESI)+: [M + H]+ = 617.5 954 Cl (ESI)+: [M + H]+ = 627.6 955 Cl (ESI)+: [M + H]+ = 641.6 956 Cl CH2CH2CH2CO2CH2CH3 (ESI)+: [M + H]+ = 635.6 957 Me (ESI)+: [M + H]+ = 577.4 958 Me (ESI)+: [M + H]+ = 611.3 959 Me (ESI)+: [M + H]+ = 611.3 960 Me (ESI)+: [M + H]+ = 611.3 961 Me (ESI)+: [M + H]+ = 607.4 962 Me (ESI)+: [M + H]+ = 591.4 963 Me (ESI)+: [M + H]+ = 591.3 964 Me (ESI)+: [M + H]+ = 612.3 965 Me (ESI)+: [M + H]+ = 578.3 966 Me (ESI)+: [M + H]+ = 583.3 967 Me (ESI)+: [M + H]+ = 617.3 968 Me (ESI)+: [M + H]+ = 583.3 969 Me (ESI)+: [M + H]+ = 595.3 970 Me (ESI)+: [M + H]+ = 567.3 971 Me (ESI)+: [M + H]+ = 568.3 972 Me (ESI)+: [M + H]+ = 658.4 973 Me CH2CH3 (ESI)+: [M + H]+ = 529.3 974 Me CH2CH2CH3 (ESI)+: [M + H]+ = 543.4 975 Me (ESI)+: [M + H]+ = 541.3 976 Me C(CH3)3 (ESI)+: [M + H]+ = 557.3 977 Me (ESI)+: [M + H]+ = 583.4 978 Me CH2(CH2)3CH3 (ESI)+: [M + H]+ = 571.4 979 Me CH(CH2CH3)CH2CH2CH2CH3 (ESI)+: [M + H]+ = 599.5 980 Me (ESI)+: [M + H]+ = 651.4 981 Me (ESI)+: [M + H]+ = 591.3 982 Me (ESI)+: [M + H]+ = 605.4 983 Me (ESI)+: [M + H]+ = 617.4 984 Me (ESI)+: [M + H]+ = 597.3 985 Me (ESI)+: [M + H]+ = 607.4 986 Me (ESI)+: [M + H]+ = 621.4 987 Me CH2N(CH3)2 (ESI)+: [M + H]+ = 558.3 988 Me CH2CH2CH2CO2CH2CH3 (ESI)+: [M + H]+ = 615.4

Compound number R8 R19 MS 989 E63 Me Me (ESI)+: [M + H]+ = 551.3 990 Me CH(CH3)2 (ESI)+: [M + H]+ = 579.4  991 Me (ESI)+: [M + H]+ = 627.4  992 Me (ESI)+: [M + H]+ = 613.3  993 Me (ESI)+: [M + H]+ = 681.3  994 Me (ESI)+: [M + H]+ = 647.3  995 Me (ESI)+: [M + H]+ = 647.3  996 Me (ESI)+: [M + H]+ = 643.3  997 Me (ESI)+: [M + H]+ = 627.4  998 Me (ESI)+: [M + H]+ = 638.4  999 Me (ESI)+: [M + H]+ = 681.3 1000 Me (ESI)+: [M + H]+ = 670.4 1001 Me (ESI)+: [M + H]+ = 653.3 1002 Me CH2CF3 (ESI)+: [M + H]+ = 619.3 1003 Me (ESI)+: [M + H]+ = 728.3 1004 Me (ESI)+: [M + H]+ = 661.3 1005 Me CH2CH3 (ESI)+: [M + H]+ = 565.3 1006 Me CH2CH2CH3 (ESI)+: [M + H]+ = 579.3 1007 Me CH2CH2CH2CH3 (ESI)+: [M + H]+ = 593.3 1008 Cl CH3 (ESI)+: [M + H]+ = 571.4 1009 Cl CH(CH3)2 (ESI)+: [M + H]+ = 599.5 1010 Cl (ESI)+: [M + H]+ = 647.6 1011 Cl (ESI)+: [M + H]+ = 633.6 1012 Cl (ESI)+: [M + H]+ = 701.4 1013 Cl (ESI)+: [M + H]+ = 667.5 1014 Cl (ESI)+: [M + H]+ = 667.5 1015 Cl (ESI)+: [M + H]+ = 667.5 1016 Cl (ESI)+: [M + H]+ = 663.6 1017 Cl (ESI)+: [M + H]+ = 647.6 1018 Cl (ESI)+: [M + H]+ = 658.5 1019 Cl (ESI)+: [M + H]+ = 701.5 1020 Cl (ESI)+: [M + H]+ = 690.5 1021 Cl (ESI)+: [M + H]+ = 673.4 1022 Cl (ESI)+: [M + H]+ = 637.5 1023 Cl CH2CF3 (ESI)+: [M + H]+ = 639.5 1024 Cl (ESI)+: [M + H]+ = 748.5 1025 Cl (ESI)+: [M + H]+ = 687.5 1026 Cl CH2CH3 (ESI)+: [M + H]+ = 585.4 1027 Cl CH2CH2CH3 (ESI)+: [M + H]+ = 599.5 1028 Cl CH2CH2CH2CH3 (ESI)+: [M + H]+ = 613.6

Com- pound num- ber R12 1H NMR: δ (ppm) 1029 CH2CH2C(CH3)3 (ESI)+: 0.88 (9H, s), 1.33-1.41 E64 [M + (2H, m), 1.74-1.82 (2H, H]+ = m), 2.14 (3H, s) 2.15- 557.6 2.28 (2H, m), 2.29-2.38 (6H, m), 2.42-2.54 (2H, m), 3.31-3.39 (2H, m), 3.54-3.63 (2H, m), 3.79 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 5.91 (1H, d, J = 14.6 Hz), 6.16 (1H, s), 6.62-6.71 (2H, m), 6.79- 6.91 (3H, m), 7.01-7.13 (2H, m) 1030 (ESI)+: [M + H]+ = 541.5 1.61-2.11 (8H, m), 2.12 (3H, s), 2.14-2.26 (1H, m), 2.27-2.41 (8H, m), 2.50 (2H, t, J = 7.0 Hz), 3.32 (2H, brs), 3.56 (2H, brs), 3.76 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 5.90 (1H, d, J = 14.6 Hz), 6.42 (1H, s), 6.63-6.67 (2H, m), 6.74-7.23 (5H, m)

Com- pound num- ber R4 MS 1H NMR 1031 E65 (APCI)+: [M + H]+ = 413.4 1.38-1.60 (1H, m), 1.84-2.00 (2H, m), 2.00-2.14 (1H, m), 2.38 (2H, t, J = 7.7 Hz), 2.64-2.77 (1H, m), 2.77-2.91 (1H, m), 2.87 (2H, t, J = 7.7 Hz), 2.95- 3.08 (1H, m), 4.32- 4.36 (2H, m), 4.99 (1H, d, J = 13.6 Hz), 5.61 (1H, s), 6.58 (1H, d, J = 7.7 Hz), 6.80- 6.87 (1H, m), 6.91-6.95 (2H, m), 7.01-7.12 (3H, m), 7.14-7.21 (3H, m), 7.25-7.35 (3H, m) 1032 NHCH2(CH2)3OH — — 1033 — — 1034 — —

Compound number G 1H NMR: δ (ppm) 1035 E66 (ESI)+: [M + H]+ = 542.5 0.88 (9H, s), 1.34-1.40 (2H, m), 2.13 (3H, s), 2.28-2.40 (8H, m), 2.44 (3H, s), 2.77-2.87 (3H, m), 2.87-3.05 (2H, m), 3.28-3.41 (3H, m), 3.52-3.67 (2H, m), 5.08 (1H, dd, J = 4.2, 12.9 Hz), 6.64 (2H, d, J = 7.9 Hz), 6.75 (1H, d, J = 7.9 Hz), 6.85 (1H, t, J = 7.4 Hz), 7.06 (1H, s), 7.17 (1H, t, J = 7.6 Hz), 8.00- 8.17 (1H, m) 1036 (APCI)+: [M + H]+ = 559.4 0.88 (9H, s), 1.23-1.40 (4H, m), 2.16 (3H, s), 2.34-2.37 (6H, m), 2.73 (3H, s), 2.78-2.84 (2H, m), 3.09-3.57 (7H, m), 5.15-5.20 (1H, m), 6.67 (2H, m), 6.77 (1H, d, J = 7.9 Hz), 6.96 (1H, m), 7.12 (1H, s), 7.23 (1H, m), 8.37 (1H, dd, J = 1.5, 8.2 Hz) 1037 (ESI)+: [M + H]+ = 559.4 0.88 (9H, s), 1.36-1.43 (2H, m), 2.15 (3H, s), 2.23 (3H, s), 2.35-2.46 (8H, m), 2.83 (2H, t, J = 7.4 Hz), 3.31-3.39 (2H, m), 3.37 (3H, s), 3.48 (3H, s), 3.63 (2H, t, J = 4.4 Hz), 5.70 (1H, s), 5.74 (1H, s), 6.49-6.56 (1H, m), 6.65- 6.72 (1H, m), 6.83-6.94 (2H, m), 7.01-7.08 (2H, m), 7.19 (1H, s) 1038 (ESI)+: [M + H]+ = 547.5 0.88 (9H, s), 1.03-1.40 (8H, m), 1.58- 1.83 (3H, m), 1.94-2.08 (2H, m), 2.15 (3H, s), 2.26-2.45 (8H, m), 2.81 (2H, t, J = 7.4 Hz), 3.24 (3H, s), 3.29 (2H, t, J = 4.4 Hz), 3.58 (2H, t, J = 4.4 Hz), 3.91 (1H, d, J = 8.2 Hz), 6.37-6.43 (1H, m), 6.61-6.70 (2H, m), 6.85 (1H, d, J = 7.9 Hz), 7.01-7.06 (2H, m), 7.20 (1H, s) 1039 (APCI)+: [M + H]+ = 505.2 0.28-0.38 (2H, m), 0.49-0.59 (2H, m), 0.73-0.81 (1H, m), 0.88 (9H, s), 1.34- 1.40 (2H, m), 2.15 (3H, s), 2.25-2.45 (8H, m), 2.82 (2H, t, J = 7.7 Hz), 3.24 (3H, s), 3.31 (2H, t, J = 5.2 Hz), 3.59 (2H, t, J = 5.2 Hz), 4.44 (1H, s), 6.49- 6.55 (1H, m), 6.73 (1H, d, J = 6.7 Hz), 6.84 (1H, d, J = 7.9 Hz), 6.94-7.02 (2H, m), 7.07-7.15 (2H, m) 1040 (ESI)+: [M + H]+ = 510.3, 512.4 0.51-0.54 (2H, m), 0.80-0.89 (2H, m), 0.88 (9H, s), 1.35-1.41 (2H, m), 1.53- 1.62 (1H, m), 2.23 (3H, s), 2.29-2.43 (5H, m), 2.44-2.50 (2H, m), 2.85-2.91 (2H, m), 3.14-3.24 (1H, m), 3.31-3.38 (2H, m), 3.56-3.63 (2H, m), 6.93-7.02 (4H, m), 7.18-7.25 (3H, m) 1041 (ESI)+: [M + H]+ = 491.5 0.88 (9H, s), 1.99 (1H, d, J = 6.4 Hz), 1.34-1.40 (2H, m), 1.80 (1H, s), 2.26 (3H, s), 2.28-2.40 (4H, m), 2.49-2.55 (2H, m), 2.90-2.97 (2H, m), 3.39 (2H, t, J = 4.7 Hz), 3.62 (2H, t, J = 4.7 Hz), 4.55 (2H, s), 6.72-6.83 (2H, m), 6.90- 6.96 (1H, m), 7.01-7.12 (3H, m), 7.25 (1H, s), 9.20 (1H, s) 1042 (ESI)+: [M + H]+ = 506.8 0.89 (9H, s), 1.34-1.40 (2H, m), 1.93- 2.08 (2H, m), 2.26 (3H, s), 2.26-2.43 (6H, m), 2.46-2.53 (2H, m), 2.79 (2H, t, J = 6.7 Hz), 2.88-2.94 (2H, m), 3.37 (2H, t, J = 4.9 Hz), 3.62 (2H, t, J = 4.9 Hz), 3.73 (3H, s), 3.83 (2H, t, J = 6.4 Hz), 6.40-6.48 (1H, m), 6.66 (1H, d, J = 3.0 Hz), 6.67-6.81 (1H, m), 6.99 (2H, s), 7.23 (1H, s) 1043 (ESI)+: [M + H]+ = 510.8 0.89 (9H, m), 1.36-1.42 (2H, m), 1.97-2.07 (2H, m), 2.28 (3H, s), 2.28- 2.44 (6H, m), 2.46-2.54 (2H, m), 2.80 (2H, t, J = 6.7 Hz), 3.33-3.42 (2H, m), 3.58-3.70 (2H, m), 3.84 (2H, t, J = 6.7 Hz), 6.76 (1H, d, J = 8.9 Hz), 6.87 (1H, dd, J = 2.2, 8.7 Hz), 7.02 (2H, s), 7.12 (1H, d, J = 2.2 Hz), 7.25 (1H, s) 1044 (ESI)+: [M + H]+ = 490.8 0.89 (9H, s), 1.34-1.41 (2H, m), 1.92- 1.99 (2H, m), 2.06 (3H, s), 2.25 (3H, s), 2.28-2.43 (6H, m), 2.43-2.52 (2H, m), 2.70-2.81 (2H, m), 2.88-2.96 (2H, m), 3.35-3.43 (2H, m), 3.56-3.68 (2H, m), 3.80-3.90 (2H, m), 6.64 (1H, s), 6.77-6.89 (2H, m), 6.92-7.06 (3H, m) 1045 (ESI)+: [M + H]+ = 518.4 0.88 (9H, s), 1.34-1.41 (2H, m), 2.23 (3H, s), 2.28-2.42 (6H, m), 2.43-2.51 (2H, m), 2.85-2.91 (2H, m), 3.36 (2H, t, J = 4.9 Hz), 3.43 (3H, s), 3.61 (2H, t, J = 4.9 Hz), 6.83 (1H, dd, J = 2.5, 8.7 Hz), 6.94 (2H, s), 7.20-7.27 (3H, m) 1046 (ESI)+: [M + H]+ = 518.4 0.88 (9H, s), 1.34-1.40 (2H, m), 2.20 (3H, s), 2.26-2.39 (6H, m), 2.45 (2H, t, J = 7.9 Hz), 2.85 (2H, t, J = 7.9 Hz), 3.31 (3H, s), 3.24-3.33 (2H, m), 3.59 (2H, d, J = 3.2 Hz), 6.82-7.03 (3H, m), 7.06-7.14 (1H, m), 7.19 (1H, s), 7.38 (1H, s) 1047 (ESI)+: [M + H]+ = 491.6 0.88 (9H, s), 1.34-1.40 (2H, m), 2.15 (3H, s), 2.28-2.46 (8H, m), 2.82 (2H, t, J = 7.9 Hz), 3.31 (2H, t, J = 4.7 Hz), 3.59 (2H, t, J = 4.7 Hz), 6.48-6.62 (2H, m), 6.75 (1H, d, J = 7.2 Hz), 6.83 (1H, d, J = 7.2 Hz), 6.90-6.98 (2H, m), 7.11 (1H, s) 1048 (APCI)+: [M + H]+ = 528.1, 530.3 0.87 (9H, s), 1.32-1.39 (2H, m), 2.16 (3H, s), 2.24-2.46 (8H, m), 2.81 (2H, t, J = 7.2 Hz), 3.28 (2H, t, J = 4.4 Hz), 3.33 (3H, s), 3.57 (2H, t, J = 4.4 Hz), 6.85 (1H, d), 6.94-7.07 (3H, m), 7.11- 7.19 (2H, m), 7.52 (1H, d, J = 7.7 Hz) 1049 (ESI)+: [M + H]+ = 538.7 0.87 (9H, s), 1.33-1.39 (2H, m), 2.11 (3H, s), 2.25-2.43 (8H, m), 2.75-2.88 (4H, m), 3.28 (2H, t, J = 4.9 Hz), 3.58 (2H, t, J = 4.9 Hz), 3.83-3.91 (1H, m), 4.60-4.71 (1H, m), 6.69-6.82 (3H, m), 6.90 (1H, s), 7.06 (1H, t, J = 7.2 Hz), 7.25-7.52 (6H, m) 1050 (ESI)+: [M + H]+ = 540.7 0.87 (9H, s), 1.33-1.40 (2H, m), 2.19 (3H, s), 2.26-2.49 (8H, m), 2.85 (2H, t, J = 7.7 Hz), 3.32 (2H, t, J = 4.7 Hz), 3.59 (2H, t, J = 4.7 Hz), 5.07-5.23 (2H, m), 6.71-6.81 (2H, m), 6.83-6.93 (2H, m), 6.98-7.09 (2H, m), 7.11-7.28 (5H, m) 1051 (ESI)+: [M + H]+ = 539.7 0.87 (9H, s), 1.33-1.40 (2H, m), 2.15 (3H, s), 2.24-2.46 (8H, m), 2.81 (2H, t, J = 8.2 Hz), 3.30 (2H, t, J = 4.4 Hz), 3.59 (2H, t, J = 4.4 Hz), 4.08-4.24 (2H, m), 5.68-5.89 (1H, m), 6.48-6.59 (3H, m), 6.72-6.93 (4H, m), 6.95-7.23 (4H, m) 1052 (ESI)+: [M + H]+ = 538.7 0.87 (9H, s), 1.33-1.40 (2H, m), 2.20 (3H, s), 2.27-2.39 (6H, m), 2.42-2.47 (2H, m), 2.85 (2H, t, J = 7.4 Hz), 3.32 (2H, t, J = 4.7 Hz), 3.59 (2H, t, J = 4.7 Hz), 4.02-4.48 (4H, m), 6.78- 7.34 (11H, m) 1053 E67 (ESI)+: [M + H]+ = 490.7 0.89 (9H, s), 1.34-1.41 (2H, m), 1.94- 2.03 (2H, m), 2.23 (3H, s), 2.26 (3H, s), 2.28-2.40 (6H, m), 2.47-2.53 (2H, m), 2.78 (2H, t, J = 6.7 Hz), 2.88-2.94 (2H, m), 3.36 (2H, t, J = 4.7 Hz), 3.61 (2H, t, J = 4.7 Hz), 3.84 (2H, t, J = 6.4 Hz), 6.68 (2H, s), 6.93 (1H, s), 6.99 (3H, s) 1054 (APCI)+: [M + H]+ = 526.1, 528.2 0.92 (9H, s), 1.34-1.45 (5H, m), 1.47- 1.54 (5H, m), 1.55-1.78 (2H, m), 2.00-2.13 (1H, m), 2.20 (3H, s), 2.42- 2.53 (2H, m), 2.70-2.81 (1H, m), 2.82-2.93 (2H, m), 3.03-3.13 (2H, m), 3.58-3.72 (2H, m), 6.51-6.61 (1H, m), 6.68-6.77 (1H, m), 6.90 (2H, s), 7.09 (2H, d, J = 2.2 Hz) ppm. 1055 (ESI)+: [M + H]+ = 617.5 0.88 (9H, s), 1.29-1.42 (2H, m), 2.24- 2.43 (12H, m), 2.47-2.60 (2H, m), 2.88-3.02 (2H, m), 3.37-3.58 (2H, m), 3.59-3.71 (2H, m), 3.93 (1H, dd, J = 7.2, 13.4 Hz), 4.31 (1H, dd, J = 3.2, 13.4 Hz), 4.51-4.78 (2H, m), 4.79-4.82 (1H, m), 6.80-6.90 (1H, m), 7.01-7.06 (2H, m), 7.12-7.16 (1H, m), 7.17-7.23 (1H, m), 7.28-7.39 (2H, m) ppm. 1056 (ESI)+: [M + H]+ = 496.5 0.89 (9H, s), 1.35-1.41 (2H, m), 2.32 (3H, s), 2.36-2.42 (6H, m), 2.51-2.57 (2H, m), 2.93-3.00 (2H, m), 3.40 (2H, t, J = 4.7 Hz), 3.63 (2H, t, J = 4.4 Hz), 3.95 (2H, t, J = 4.4 Hz), 4.31 (2H, t, J = 4.4 Hz), 6.42-6.48 (1H, m), 6.62 (1H, dd, J = 3.0, 9.6 Hz), 7.11-7.19 (1H, m), 7.22-7.24 (1H, m), 7.31 (1H, s) ppm.

Compound number G 1H NMR 1057 (ESI)+: [M + H]+ = 513.6 CDCl3 δ 0.05-0.09 (2H, m), 0.42- 0.52 (2H, m), 0.71-0.89 (1H, m), 2.13 (3H, s), 2.17-2.22 (2H, m), 2.28-2.52 (6H, m), 2.79-2.86 (2H, m), 3.22-3.35 (2H, m), 3.56-3.72 (2H, m), 3.74 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 5.89 (1H, d, J = 14.6 Hz), 6.58-6.71 (2H, m), 6.75-6.90 (2H, m), 6.91-7.06 (2H, m), 7.08-7.22 (2H, m) ppm. 1058 (ESI)+: [M + H]+ = 510.7 CDCl3 δ 0.03-0.08 (2H, m), 0.43- 0.50 (2H, m), 0.77-0.86 (1H, m), 2.19 (3H, s), 2.18-2.21 (2H, m), 2.36-2.47 (6H, m), 2.84 (2H, t, J = 7.4 Hz), 3.32 (2H, t, J = 4.9 Hz), 3.60 (2H, t, J = 4.9 Hz), 5.03-5.26 (2H, m), 6.74-6.78 (1H, m), 6.82- 6.91 (2H, m), 6.98-7.07 (2H, m), 7.11-7.18 (2H, m), 7.19-7.24 (4H, m) ppm. 1059 (ESI)+: [M + H]+ = 509.7 CDCl3 δ 0.03-0.08 (2H, m), 0.45- 0.50 (2H, m), 0.71-0.89 (1H, m), 2.15 (3H, s), 2.19-2.22 (2H, m), 2.34-2.45 (6H, m), 2.83 (2H, t, J = 7.2 Hz), 3.31 (2H, brs), 3.60 (2H, brs), 4.03-4.34 (2H, m), 5.62-5.97 (1H, m), 6.48-6.59 (3H, m), 6.72-6.93 (5H, m), 6.97-7.03 (1H, m), 7.07-7.16 (2H, m) ppm. 1060 (ESI)+: [M + H]+ = 508.7 CDCl3 δ 0.06-0.10 (2H, m), 0.47- 0.54 (2H, m), 0.72-0.89 (1H, m), 2.21 (3H, s), 2.19-2.24 (2H, m), 2.38-2.49 (6H, m), 2.85 (2H, t, J = 7.4 Hz), 3.34 (2H, t, J = 4.9 Hz), 3.62 (2H, t, J = 4.9 Hz), 4.00-4.50 (4H, m), 6.73-7.31 (11H, m) ppm.

Compound number R1 R3 R8 R13 n MS 1H NMR: δ (ppm) 1061 E90 H F H 0 (APCI)+: [M + H]+ = 517.4 0.03-0.12 (3H, m), 0.45-0.54 (3H, m), 0.77-0.91 (2H, m), 1.70-1.82 (3H, m), 1.88-2.03 (2H, m), 2.03-2.17 (1H, m), 2.22 (2H, d, J = 4.9 Hz), 2.98- 3.17 (2H, m), 3.65 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 4.10-4.30 (2H, m), 5.80 (1H, d, J = 14.6 Hz), 6.53- 6.79 (4H, m), 6.88-7.00 (3H, m), 7.21 (1H, s) 1062 F H F CH2CH2CH3 0 (ESI)+: d4-MeOH 0.95 [M + H]+ = (9H, s), 1.50-1.56 565.3 (2H, m), 1.80-1.91 (4H, m), 2.35-2.41 (1H, m), 2.52-2.58 (1H, m), 2.74-2.81 (2H, m), 3.30-3.33 (3H, m), 3.81 (3H, s), 4.00 (1H, d, J = 14.6 Hz), 4.32 (2H, s), 5.73 (1H, d, J = 14.6 Hz), 6.39-6.46 (1H, m), 6.77-6.83 (1H, m), 6.93-7.01 (3H, m), 7.12-7.18 (1H, m), 7.24 (1H, s) 1063 H Me Cl CO2C(CH3)3 2 (APCI)+: 1.44 (9H, s), 1.34- [M + H]+ = 1.71 (5H, m), 621.5, 2.12-2.30 (2H, m), 623.5 2.32 (3H, s), 2.53- 2.72 (4H, m), 3.80 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 3.93-4.04 (2H, m), 4.19-4.42 (2H, m), 5.81 (1H, d, J = 14.6 Hz), 6.17 (1H, s), 6.57-7.20 (7H, m), 7.38 (1H, s) 1064 Cl H H CO2C(CH3)3 0 (APCI)+: 1.43 (9H, s), 1.47- [M − 1.62 (2H, m), Boc + H]+ = 1.65-1.78 (2H, m), 479.4, 2.16-2.31 (1H, m), 481.4 2.57-2.72 (2H, m), 3.77 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 4.00-4.13 (2H, m), 4.33-4.36 (2H, m), 5.86 (1H, d, J = 14.6 Hz), 6.18- 6.24 (1H, m), 6.51 (1H, s), 6.67-6.70 (2H, m), 6.89-6.98 (3H, m), 7.04-7.11 (1H, m), 7.21-7.27 (2H, m) 1065 F H Me CO2C(CH3)3 1 (APCI)+: 1.43 (9H, s), 1.50- [M − 1.63 (2H, m), Boc + H]+ = 1.82-2.00 (2H, m), 492.2 2.01-2.11 (2H, m), 2.13-2.23 (1H, m), 2.20 (3H, s), 2.53- 2.71 (3H, m), 3.79 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 3.96-4.04 (3H, m), 4.19-4.42 (1H, m), 5.83 (1H, d, J = 14.6 Hz), 6.31- 6.42 (1H, m), 6.43-6.58 (2H, m), 6.78-6.83 (2H, m), 6.85-6.96 (2H, m), 7.21 (1H, s) 1066 Me H H CO2C(CH3)3 2 (APCI)+: 0.91-1.12 (2H, m), [M − 1.30-1.64 (6H, m), Boc + H]+ = 1.43 (9H, s), 2.11 487.5 (3H, s), 2.22 (2H, t, J = 7.2 Hz), 2.48- 2.64 (2H, m), 3.79 (3H, s), 3.93-4.09 (3H, m), 4.929-4.44 (1H, m), 5.87 (1H, d, J = 14.6 Hz), 6.11 (1H, brs), 6.65- 6.68 (2H, m), 6.70-6.84 (3H, m), 6.85-6.92 (1H, m), 6.99-7.05 (1H, m) 7.15 (1H, s), 7.21 (1H, s) 1067 Me H H CO2C(CH3)3 1 (APCI)+: 0.91-1.11 (2H, m), [M − 1.44 (9H, s), 1.49- Boc + H]+ = 1.72 (4H, m), 473.5 1.84-2.06 (2H, m), 2.09 (3H, s), 2.58- 2.74 (2H, m), 3.76 (3H, s), 3.93-4.06 (3H, m), 4.17-4.31 (1H, m), 5.87 (1H, d, J = 14.6 Hz), 6.25 (1H, brs), 6.64- 6.67 (2H, m), 6.74-6.76 (3H, m), 6.94-6.98 (1H, m), 7.01-7.08 (1H, m), 7.12 (1H, s), 7.21 (1H, s) 1068 Cl H H CH2CH2C(CH3)3 0 (APCI)+: 0.87 (9H, s), 1.34- [M + H]+ = 1.40 (2H, m), 563.4, 1.65-1.95 (5H, m), 565.4 2.08-2.14 (2H, m), 2.27-2.33 (2H, m), 2.93-2.97 (2H, m), 3.73 (3H, s), 3.97 (1H, d, J = 14.6 Hz), 4.33 (1H, d, J = 5.9 Hz), 5.85 (1H, d, J = 14.6 Hz), 6.20-6.22 (1H, m), 6.66-6.71 (3H, m), 6.91-6.98 (4H, m), 7.03-7.07 (1H, m), 7.22 (1H, s) 1069 Cl H H 0 (APCI)+: [M + H]+ = 533.4, 535.2 0.04-0.10 (2H, m), 0.46-0.53 (4H, m), 0.78-0.85 (1H, m), 1.64-1.77 (4H, m), 1.93-2.16 (2H, m), 2.23 (2H, d, J = 6.7 Hz), 2.33- 2.40 (1H, m), 3.05-3.10 (2H, m), 3.73 (3H, s), 3.98 4.33 (2H, d, J = 5.9 Hz), 5.85 (1H, d, J = 14.6 Hz), 6.30-6.32 (1H, m), 6.66-6.67 (2H, m), 6.83 (1H, s), 6.90- 7.08 (3H, m), 7.22 (1H, s) 1070 H F Cl CH2CH2C(CH3)3 0 (APCI)+: 0.86 (9H, s), 1.34- [M + H]+ = 1.40 (2H, m), 581.4, 1.72-1.76 (4H, m), 583.4 1.88-1.95 (2H, m), 2.10-2.14 (1H, m), 2.28-2.34 (2H, m), 2.94-2.98 (2H, m), 3.64 (3H, s), 3.97 (1H, d, J = 14.6 Hz), 4.22 (2H, d, J = 5.7 Hz), 5.76 (1H, d, J = 14.6 Hz), 6.54 (1H, dd, J = 2.2, 8.4 Hz), 6.58-6.76 (4H, m), 6.96-7.03 (2H, m), 7.20 (1H, s) 1071 H F Cl 0 (APCI)+: [M + H]+ = 551.3, 553.3 0.07-0.09 (2H, m), 0.46-0.51 (2H, m), 0.80-0.84 (1H, m), 1.73-1.78 (4H, m), 1.93-1.99 (2H, m), 2.10-2.15 (1H, m), 2.24 (2H, d, J = 6.4 Hz), 2.51- 2.53 (1H, brs), 3.07-3.11 (2H, m), 3.66 (3H, s), 3.97 (1H, d, J = 14.6 Hz), 4.24 (2H, d, J = 5.9 Hz), 5.77 (1H, d, J = 14.6 Hz), 6.55-6.77 (5H, m), 6.96-7.04 (2H, m), 7.21 (1H, s) 1072 H F Me CH2CH2C(CH3)3 0 (APCI)+: 0.87 (9H, s), 1.35- [M + H]+ = 1.41 (2H, m), 561.4 1.73-1.81 (4H, m), 1.89-2.02 (2H, m), 2.10-2.14 (4H, m), 2.29-2.35 (2H, m), 2.94-2.98 (2H, m), 3.68 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.20-4.25 (2H, m), 5.79 (1H, d, J = 14.6 Hz), 6.42 (1H, dd, J = 1.2, 8.2 Hz), 6.52-7.00 (6H, m), 7.20 (1H, s) 1073 H F Me 0 (APCI)+: [M + H]+ = 531.4 0.05-0.10 (2H, m), 0.46-0.53 (2H, m), 0.79-0.83 (1H, m), 1.72-1.79 (4H, m), 1.95-2.04 (2H, m), 2.08-2.14 (4H, m), 2.22-2.26 (2H, m), 2.90-2.92 (1H, brs), 3.06-3.10 (2H, m), 3.66 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.18- 4.23 (2H, m), 5.76 (1H, d, J = 14.6 Hz), 6.43 (1H, dd, J = 1.2, 8.2 Hz), 6.57-6.97 (6H, m), 7.18 (1H, s) 1074 F H Me 0 (APCI)+: [M + H]+ = 531.4 0.09-0.15 (2H, m), 0.49-0.57 (2H, m), 0.79-0.92 (1H, m), 1.72-1.84 (4H, m), 1.99-2.19 (3H, m), 2.21 (3H, s), 2.26- 2.33 (2H, m), 3.10-3.16 (2H, m), 3.77 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.33 (2H, d, J = 5.9 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.24 (1H, brs), 6.36 (1H, s), 6.48- 6.58 (2H, m), 6.79 (1H, s), 6.87-7.01 (3H, m), 7.21 (1H, s) 1075 F H Me CH2CH2C(CH3)3 0 (APCI)+: 0.87 (9H, s), 1.36- [M + H]+ = 1.43 (2H, m), 561.4 1.62-1.81 (4H, m), 1.96-1.17 (3H, m), 2.20 (3H, s), 2.33- 2.40 (2H, m), 2.97-3.02 (2H, m), 3.76 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.32 (2H, d, J = 5.7 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.19 (1H, brs), 6.39 (1H, s), 6.47- 6.57 (2H, m), 6.78 (1H, s), 6.86-7.00 (3H, m), 7.21 (1H, s) 1076 H F H CH2CH2C(CH3)3 0 (APCI)+: 0.87 (9H, s), 1.34- [M + H]+ = 1.40 (2H, m), 547.4 1.68-1.77 (4H, m), 1.97-2.03 (2H, m), 2.03-2.19 (1H, m), 2.28-2.38 (2H, m), 2.52 (2H, s), 2.90- 3.00 (2H, m), 3.65 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 4.18 (1H, t, J = 6.2 Hz), 5.79 (1H, d, J = 14.6 Hz), 6.57- 6.72 (4H, m), 6.75 (1H, s), 6.90-7.02 (4H, m) 1077 H Cl H 0 (ESI)+: [M + H]+ = 533.5, 535.5 0.35-0.45 (3H, m), 0.68-0.80 (3H, m), 0.98-1.15 (2H, m), 1.81-2.10 (4H, m), 2.46-2.55 (1H, m), 2.91-3.00 (4H, m), 3.60-3.75 (3H, m), 3.78 (3H, s), 4.02 (1H, d, J = 14.6 Hz), 5.69 (1H, d, J = 14.6 Hz), 6.59- 6.70 (1H, m), 6.91-7.20 (6H, m), 7.25 (1H, s) 1078 H Cl H CH2CH2C(CH3)3 0 (ESI)+: 0.87 (9H, s), 1.31- [M + H]+ = 1.48 (3H, m), 563.5, 1.67-1.82 (4H, m), 565.7 1.93-2.22 (2H, m), 2.28-2.47 (3H, m), 2.90-3.10 (3H, m), 3.67 (3H, s), 4.03 (1H, d, J = 14.6 Hz), 4.10-4.21 (2H, m), 5.78 (1H, d, J = 14.6 Hz), 6.56- 6.70 (2H, m), 6.70-6.85 (1H, m), 6.85-6.95 (4H, m), 7.22 (1H, s) 1079 H Me H 0 (ESI)+: [M + H]+ = 513.5 0.05-0.07 (3H, m), 0.48-0.51 (3H, m), 0.83-0.85 (2H, m), 1.61-2.00 (7H, m), 2.22 (2H, d, J = 6.4 Hz), 2.31 (3H, s), 3.00-3.15 (2H, m), 3.71 (3H, s), 4.03 (1H, d, J = 14.6 Hz), 4.22 (2H, d, J = 5.7 Hz), 5.85 (1H, d, J = 14.6 Hz), 6.42 (1H, s), 6.60-6.87 (4H, m), 6.90-7.10 (2H, m) ppm. 1080 H Me H CH2CH2C(CH3)3 0 (ESI)+: δ 0.93 (9H, s), [M + H]+ = 1.28-1.37 (5H, m), 543.5 1.43-1.52 (2H, m), 1.71-1.91 (3H, m), 2.29 (3H, s), 2.30- 2.40 (2H, m), 2.60-2.68 (2H, m), 3.12-3.23 (2H, m), 3.62-3.73 (1H, m), 3.78 (3H, s), 4.00 (1H, d, J = 14.6 Hz), 5.73 (1H, d, J = 14.6 Hz), 6.59- 6.66 (1H, m), 6.78-6.85 (2H, m), 6.90-7.00 (2H, m), 7.01-7.15 (1H, m), 7.24 (1H, s), 7.25- 7.30 (1H, m) 1081 H Cl Cl 0 (APCI)+: [M + H]+ = 567.3 0.04-0.09 (2H, m), 0.46-0.51 (2H, m), 0.74-0.89 (1H, m), 1.63-1.84 (2H, m), 1.89-2.04 (2H, m), 2.05-2.21 (1H, m), 2.23 (2H, d, J = 6.4 Hz), 3.04- 3.15 (4H, m), 3.61 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 4.10-4.19 (2H, m), 4.31-4.38 (1H, m), 5.71 (1H, d, J = 14.6 Hz), 6.53 (1H, dd, J = 2.0, 8.4 Hz), 6.70-6.84 (3H, m), 6.96-7.11 (2H, m), 7.17 (1H, s), 7.73 (1H, s) 1082 H Me Cl 0 (APCI)+: [M + H]+ = 547.4, 549.4 0.03-0.09 (2H, m), 0.44-0.49 (2H, m), 0.78-0.84 (1H, m), 1.68-1.85 (4H, m), 1.94-2.10 (2H, m), 2.10-2.24 (1H, m), 2.22 (3H, s), 2.23 (2H, d, J = 8.2 Hz), 3.04-3.13 (2H, m), 3.61(3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.17 (2H, d, J = 5.7 Hz), 4.38 (1H, d, J = 5.7 Hz), 5.76 (1H, d, J = 14.6 Hz), 6.49- 6.65 (3H, m), 6.71-6.83 (2H, m), 6.87-7.02 (1H, m), 7.19 (1H, s), 7.57 (1H, s) 1083 H Cl Me 0 (APCI)+: [M + H]+ = 547.3, 549.3 d4-MeOH: 0.30- 0.36 (2H, m), 0.65-0.71 (2H, m), 0.96-1.10 (1H, m), 1.82-2.04 (4H, m), 2.15 (3H, s), 2.38- 2.49 (1H, m), 2.68-2.84 (4H, m), 3.49 (2H, brd, J = 12.6 Hz), 3.76 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 4.22 (2H, s), 5.67 (1H, d, J = 14.6 Hz), 6.46 (1H, dd, J = 1.5, 8.2 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.94- 7.11 (3H, m), 7.16 (1H, s), 7.22 (1H, s) 1084 H Me Me 0 (APCI)+: [M + H]+ = 527.4 0.05-0.09 (2H, m), 0.45-0.52 (2H, m), 0.72-0.86 (1H, m), 1.62-1.84 (4H, m), 1.97-2.11 (2H, m), 2.05 (3H, s), 2.11- 2.24 (1H, m), 2.25 (2H, d, J = 5.7 Hz), 2.26 (3H, s), 3.06- 3.17 (2H, m), 3.66 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.17 (2H, d, J = 5.7 Hz), 4.37 (1H, d, J = 5.7 Hz), 5.78 (1H, d, J = 14.6 Hz), 6.31-6.83 (7H, m), 7.19 (1H, s) 1085 H Cl Cl CH2CH2C(CH3)3 0 (APCI)+: 0.87 (9H, s), 1.33- [M + H]+ = 1.41 (2H, m), 597.3 1.63-1.98 (6H, m), 2.07-2.17 (1H, m), 2.26-2.32 (2H, m), 2.92-2.96 (2H, m), 3.61 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 4.08- 4.23 (2H, m), 4.34-4.37 (1H, m), 5.71 (1H, d, J = 14.6 Hz), 6.52 (1H, dd, J = 2.0, 8.4 Hz), 6.70-6.98 (5H, m), 7.17 (1H, s), 7.73 (1H, s) 1086 H Me Cl CH2CH2C(CH3)3 0 (APCI)+: 0.87 (9H, s), 1.33- [M + H]+ = 1.41 (2H, m), 577.4, 1.68-1.98 (6H, m), 579.3 2.03-2.17 (1H, m), 2.22 (3H, s), 2.27- 2.33 (2H, m), 2.93-2.97 (2H, m), 3.61 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.17-4.19 (2H, m), 4.37-4.39 (1H, m), 5.77 (1H, d, J = 14.6 Hz), 6.40- 7.17 (6H, m), 7.19 (1H, s), 7.47 (1H, s) ppm. 1087 H Cl Me CH2CH2C(CH3)3 0 (APCI)+: δ 0.88 (9H, s), [M + H]+ = 1.34-1.42 (2H, m), 577.4, 1.67-2.22 (7H, m), 579.4 2.07 (3H, s), 2.27- 2.33 (2H, m), 2.93-2.97 (2H, m), 3.65 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 4.13-4.20 (2H, m), 4.34-4.37 (1H, m), 5.75 (1H, d, J = 14.6 Hz), 6.43 (1H, dd, J = 1.2, 8.2 Hz), 6.67-6.80 (5H, m), 6.92-6.93 (1H, m), 7.19 (1H, s) 1088 H Me Me CH2CH2C(CH3)3 0 (APCI)+: 0.87 (9H, s), 1.33- [M + H]+ = 1.41 (2H, m), 557.4 1.65-2.04 (7H, m), 2.07 (3H, s), 2.22- 2.34 (5H, m), 2.92-3.00 (2H, m), 3.62 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.16-4.19 (2H, m), 4.36-4.39 (1H, m), 5.80 (1H, d, J = 14.6 Hz), 6.34- 7.14 (7H, m), 7.19 (1H, s) 1089 F H H 0 (ESI)+: [M + H]+ = 517.5 d4-MeOH: 0.14- 0.19 (2H, m), 0.53-0.59 (2H, m), 0.87-0.90 (1H, m), 1.73-1.81 (4H, m), 2.14-2.24 (3H, m), 2.35-2.37 (2H, m), 3.16-3.21 (2H, m), 3.79 (3H, s), 3.97 (1H, d, J = 14.6 Hz), 4.29 (2H, s), 5.75 (1H, d, J = 14.6 Hz), 6.65-6.77 (2H, m), 6.90-7.00 (2H, m), 7.07-7.15 (2H, m), 7.20-7.24 (2H, m) 1090 F H H CH2CH2C(CH3)3 0 (ESI)+: 0.86 (9H, s), 1.32- [M + H]+ = 1.39 (2H, m), 547.5 1.69-1.92 (3H, m), 2.04-2.10 (2H, m), 2.25-2.31 (1H, m), 2.58 (1H, m), 2.90-2.94 (2H, m), 3.67 (3H, s), 3.97 (1H, d, J = 14.6 Hz), 4.25-4.28 (2H, m), 5.83 (1H, d, J = 14.6 Hz), 6.37- 6.39 (1H, m), 6.65 (2H, m), 6.83-7.03 (5H, m), 7.14 (1H, s), 7.20 (1H, s) 1091 Cl H Me 0 (ESI)+: [M + H]+ = 547.4, 549.4 d4-MeOH: 0.14- 0.20 (2H, m), 0.52-0.60 (2H, m), 0.90 (1H, m), 1.76-1.84 (4H, m), 2.16-2.32 (6H, m), 2.36-2.39 (2H, m), 3.18-3.22 (2H, m), 3.78 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.32 (2H, s), 5.73 (1H, d, J = 14.6 Hz), 6.50 (1H, dd, J = 1.0, 8.0 Hz), 6.62 (1H, d, J = 8.0 Hz), 7.04 (1H, d, J = 1.0 Hz), 7.11 (2H, s), 7.20- 7.23 (2H, m) 1092 Cl H Me CH2CH2C(CH3)3 0 (APCI)+: 0.86 (9H, s), 1.33- [M + H]+ = 1.40 (2H, m), 577.3, 1.70-1.92 (6H, m), 579.3 2.12-2.14 (4H, m), 2.28-2.34 (2H, m), 2.93-2.96 (2H, m), 3.70 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.28-4.32 (2H, m), 5.79 (1H, d, J = 14.6 Hz), 6.45- 6.54 (2H, m), 6.79-6.89 (4H, m), 7.17 (1H, s), 7.22 (1H, s) 1093 Cl H Cl CH2CH2C(CH3)3 0 (APCI)+: 0.86 (9H, s), 1.33- [M + H]+ = 1.39 (2H, m), 597.2 1.68-1.90 (6H, m), 2.13 (1H, m), 2.26-2.32 (2H, m), 2.93-2.97 (2H, m), 3.67 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.32 (2H, m), 5.78 (1H, d, J = 14.6 Hz), 6.56 (2H, s), 6.87- 6.97 (2H, m), 7.02 (1H, s), 7.18 (1H, s), 7.21 (1H, d, J = 1.2 Hz), 7.64 (1H, s) 1094 F H Cl CH2CH2C(CH3)3 0 (APCI)+: 0.85 (9H, s), 1.35- [M + H]+ = 1.41 (2H, m), 1.76 581.3, (4H, m), 2.01-2.14 583.3 (3H, m), 2.34-2.40 (2H, m), 2.97-3.01 (2H, m), 3.68 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.27 (2H, m), 5.76 (1H, d, J = 14.6 Hz), 6.54 (2H, s), 6.81-6.97 (3H, m), 7.05 (1H, s), 7.17 (1H, s), 8.08 (1H, s) 1095 Me H Cl 0 (APCI)+: [M + H]+ = 547.4, 549.4 d6-DMSO: 0.15- 0.24 (2H, m), 0.48-0.59 (2H, m), 0.84-1.03 (1H, m), 1.61-1.88 (4H, m), 2.14 (3H, s), 2.20- 2.80 (4H, m), 3.16-3.46 (3H, m), 3.77 (3H, s), 3.90 (1H, d, J = 14.6 Hz), 4.06-4.23 (2H, m), 5.63 (1H, d, J = 14.6 Hz), 6.67 (1H, dd, J = 2.0, 8.4 Hz), 6.74 (1H, d, J = 8.4 Hz), 6.84 (1H, d, J = 7.8 Hz), 6.94 (1H, d, J = 7.8 Hz), 7.05 (1H, s), 7.18 (1H, s), 7.40 (1H, d, J = 2.0 Hz), 8.26 (1H, s), 8.82 (1H, s) 1096 Cl H Cl 0 (ESI)+: [M + H]+ = 567.2 d6-DMSO: 0.15- 0.22 (2H, m), 0.50-0.52 (2H, m), 0.89 (1H, m), 1.60-1.82 (6H, m), 2.13-2.34 (3H, m), 3.09-3.18 (2H, m), 3.76 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.25 (2H, m), 5.62 (1H, d, J = 14.6 Hz), 6.71 (1H, dd, J = 2.2, 8.4 Hz), 6.84 (1H, d, J = 8.4 Hz), 7.03- 7.11 (2H, m), 7.20 (2H, s), 7.38 (1H, d, J = 2.2 Hz), 8.34 (1H, m), 8.82 (1H, s) 1097 F H Cl 0 (ESI)+: [M + H]+ = 551.3, 553.3 d6-DMSO: 0.04- 0.06 (2H, m), 0.43-0.45 (2H, m), 0.78-0.81 (1H, m), 1.53-1.66 (5H, m), 1.90 (1H, m), 2.07-2.16 (3H, m), 2.98 (2H, m), 3.76 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.19 (2H, m), 5.61 (1H, d, J = 14.6 Hz), 6.69 (1H, dd, J = 2.2, 8.4 Hz), 6.82 (1H, d, J = 8.4 Hz), 6.90- 6.94 (2H, m), 7.05-7.11 (1H, m), 7.19 (1H, s), 7.37 (1H, d, J = 2.2 Hz), 8.25 (1H, m), 8.80 (1H, s) 1098 Me H Me 0 (APCI)+: [M + H]+ = 527.4 d4-MeOH: 0.32- 0.45 (2H, m), 0.68-0.80 (2H, m), 1.01-1.19 (1H, m), 1.78-2.15 (4H, m), 2.17 (3H, s), 2.24 (3H, s), 2.81-3.20 (4H, m), 3.51-3.78 (3H, m), 3.93 (1H, d, J = 14.6 Hz), 3.96 (3H, s), 4.26 (2H, s), 5.78 (1H, d, J = 14.6 Hz), 6.52- 6.71 (2H, m), 6.99-7.13 (4H, m), 7.61 (1H, s) 1099 Me H Cl CH2CH2C(CH3)3 0 (APCI)+: 0.88 (9H, s), 1.38- [M + H]+ = 1.45 (2H, m), 577.4, 1.72-1.94 (4H, m), 579.4 2.01-2.18 (2H, m), 2.11 (3H, s), 2.39- 2.45 (2H, m), 2.96-3.05 (2H, m), 3.09-3.22 (1H, m), 3.76 (3H, s), 3 .93 (1H, d, J = 14.6 Hz), 4.26 (2H, d, J = 4.5 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.13 (1H, brs), 6.57-6.61 (2H, m), 6.80-6.84 (3H, m), 7.03 (1H, s), 7.08 (1H, s), 7.21 (1H, s) 1100 Me H Me CH2CH2C(CH3)3 0 (APCI)+: 0.88 (9H, s), 1.38- [M + H]+ = 1.45 (2H, m), 557.5 1.67-1.83 (4H, m), 1.94-2.23 (2H, m), 2.07 (3H, s), 2.19 (3H, s), 2.35-2.44 (2H, m), 2.93-3.15 (3H, m), 3.74 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.19- 4.25 (2H, m), 5.83 (1H, d, J = 14.6 Hz) 6.19 (1H, brs), 6.45-6.55 (3H, m), 6.77-6.83 (3H, m), 7.06 (1H, s), 7.19 (1H, s)

Compound number MS 1H NMR: δ (ppm) 1101 (ESI)+: 1.41(9H, s), 3.13-3.30(2H, m), 3.73 [M + H]+ = (2H, s), 3.80-4.15 (6H, m), 4.18-4.34 569.2 (2H, m), 5.77 (1H, m), 6.58 (2H, s), 6.73-6.87 (2H, m), 6.87-6.99 (1H, m), 7.08 (1H, s), 7.19 (1H, s), 7.82 (1H, s)

Com- pound number R1 R8 R9 R10 MS 1H NMR: δ (ppm) 1102 Me Me H H (ESI)+: 0.89 (9H, s), 1.46-1.56 (2H, [M + H]+ = m), 1.78-2.06 (7H, m), 557.6 2.20-2.62 (8H, m), 3.10- 3.20 (2H, m), 3.88 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.22 (2H, m), 5.90 (1H, d, J = 14.6 Hz), 6.28-6.40 (1H, m), 6.55-6.68 (2H, m), 6.79-6.88 (2H, m), 6.90- 7.04 (2H, m), 7.25 (1H, s) 1103 Me H Me H (ESI)+: 0.88 (9H, s), 1.36-1.46 (2H, [M + H]+ = m), 1.68-1.90 (4H, m), 2.03 557.4 (3H, s), 2.12 (3H, s), 2.26- 2.43 (4H, m), 2.95-3.05 (2H, m), 3.65-3.75 (1H, m), 3.78 (3H, s), 3.95 (1H, d, J = 14.7 Hz), 4.25-4.35 (2H, m), 5.86 (1H, d, J = 14.7 Hz), 6.02-6.12 (1H, m), 6.51 (1H, s), 6.82 (1H, s), 6.82- 6.94 (4H, m), 7.12 (1H, s) 1104 F Me H H (ESI)+: 0.91 (9H, s), 1.79-2.00 (2H, [M + H]+ = m), 2.10-2.34 (1H, m), 2.42 561.4 (3H, s), 2.50-2.73 (1H, m), 2.83-2.97 (2H, m), 2.98- 3.12 (3H, m), 3.13-3.33 (1H, m), 3.35-3.52 (1H, m), 3.53-3.70 (2H, m), 3.85 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.14-4.42 (2H, m), 5.81 (1H, d, J = 14.6 Hz), 6.08 (1H, s), 6.40-6.70 (2H, m), 6.72-7.06 (4H, m), 7.43 (1H, s)

Compound number b R11 MS 1H NMR: δ (ppm) 1105 3 Me 585.4 0.88 (9H, s), 0.97 (3H, t, J = 7.3 Hz), 1.03-1.05 (4H, m), 1.07-1.95 (6H, m), 2.00-2.25 (5H, m), 2.35-2.50 (2H, m), 3.00-3.12 (3H, m), 3.97 (1H, d, J = 14.6 Hz), 4.06 (2H, t, J = 6.8 Hz), 4.26 (2H, d, J = 4.7 Hz) 5.90 (1H, d, J = 14.6 Hz) 5.95-6.05 (1H, m) 6.24, (1H, s), 6.67-6.73 (2H, m), 6.80-6.98 (3H, m), 7.05-7.15 (2H, m) 1106 1 Me 557.4 0.87 (9H, s), 1.36-1.52 (5H, m), 1.68-1.90 (4H, m), 1.92-2.16 (6H, m), 2.32-2.42 (2H, m), 2.96-3.06 (2H, m), 3.97 (1H, d, J = 14.5 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.46 (2H, d, J = 4.9 Hz), 5.80-5.90 (1H, m), 5.90 (1H, d, J = 14.5 Hz), 6.63-6.74 (2H, m), 6.79-7.00 (3H, m), 7.02-7.12 (2H, m), 7.13 (1H, s), 7.24 (1H, s)

Compound number R1 R3 R8 n MS 1H NMR: δ (ppm) 1107 E 91 Me H H 1 (APCI)+: [M + H]+ = 473.5 d4-MeOH 1.35-1.54 (3H, m), 1.89 (2H, d, J = 13.6 Hz), 1.92- 2.11 (1H, m), 2.18 (3H, s), 2.18-2.24 (1H, m), 2.92-3.02 (2H, m), 3.29-3.39 (2H, m), 3.99-4.04 (1H, m), 4.04 (3H, s), 4.27 (2H, s), 5.88 (1H, d, J = 14.6 Hz), 6.84-6.86 (2H, m), 6.98-7.07 (3H, m), 7.20-7.27 (1H, m), 7.40 (1H, d, J = 8.2 Hz), 8.03 (1H, s) 1108 H Me Cl 2 (APCI)+: [M + H]+ = 521.6, 523.5 d4-MeOH 1.28-1.41 (1H, m), 1.42-1.67 (2H, m), 1.85-1.91 (2H, m), 2.20-2.33 (2H, m), 2.27 (3H, s), 2.78-2.94 (1H, m), 3.27-3.39 (5H, m), 3.79 (3H, s), 3.99 (1H, d, J = 14.6 Hz), 4.22 (2H, s), 5.71 (1H, d, J = 14.6 Hz), 6.53-6.61 (1H, m), 6.74-6.81 (1H, m), 6.83-6.94 (2H, m), 7.00-7.04 (1H, m), 7.22-7.25 (2H, m) 1109 Cl H H 0 (APCI)+: [M + H]+ = 479.4, 481.4 d4-MeOH 1.78-2.07 (2H, m), 2.52-2.71 (1H, m), 2.96-3.12 (2H, m), 3.19-3.32 (2H, m), 3.35-3.43 (2H, m), 4.04 (1H, d, J = 14.6 Hz), 4.05 (3H, s), 4.35 (2H, s), 5.87 (1H, d, J = 14.6 Hz), 6.86-6.90 (2H, m), 7.11-7.19 (2H, m), 7.22-7.28 (2H, m), 7.42-7.45 (1H, m), 8.05 (1H, s) 1110 F H Me 1 (ESI)+: [M + H]+ = 491.6 d4-MeOH 1.34-1.53 (2H, m), 1.85-1.91 (2H, m), 1.93-2.17 (1H, m), 2.20-2.23 (2H, m), 2.28 (3H, s), 2.91-3.02 (2H, m), 3.30-3.38 (2H, m), 3.99 (1H, d, J = 14.6 Hz), 4.02 (3H, s), 4.32 (2H, s), 5.84 (1H, d, J = 14.6 Hz), 6.67-6.78 (2H, m), 6.95-7.03 (2H, m), 7.12-7.23 (2H, m), 8.01 (1H, s) 1111 Me H H 2 (APCI)+: [M + H]+ = 487.4 d4-MeOH: 1.29-1.48 (2H, m), 1.50-1.64 (3H, m), 1.82-1.98 (2H, m), 2.18 (3H, s), 2.18-2.31 (2H, m), 2.85-2.99 (2H, m), 3.30-3.38 (2H, m), 3.94-4.05 (1H, m), 4.05 (3H, s), 4.26 (2H, s), 5.88 (1H, d, J = 14.6 Hz), 6.85 (2H, s), 7.00-7.09 (3H, m), 7.19-7.28 (1H, m), 7.40-7.43 (1H, m), 8.04 (1H, s)

Compound number MS 1H NMR: δ (ppm) 1112 (ESI)+: [M + H]+ = 469.2, 471.2 d4-MeOH 3.57-3.72 (1H, m), 3.98 (3H, s), 4.04 (1H, d, J = 15.3 Hz), 4.17 (4H, d, J = 8.2 Hz), 4.36-4.42 (2H, m), 5.83 (1H, d, J = 15.3 Hz), 6.82-6.92 (2H, m), 6.96-7.08 (2H, m), 7.18- 7.32 (1H, m), 7.41 (1H, s), 7.92 (1H, s), 8.56-8.64

Com- pound number R1 R3 R8 R13 n MS 1H NMR: δ (ppm) 1113 E92 Me H H CH2CH2C(CH3)3 1 (APCI)+: [M + H]+ = 557.5 0.86 (9H, s), 1.11-1.29 (2H, m), 1.34- 1.41 (2H, m), 1.58-1.64 (2H, m), 1.65- 1.86 (1H, m), 1.89-2.01 (2H, m), 2.04 (3H, s), 2.29-2.36 (2H, m), 2.80-2.91 (4H, m), 3.64 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.19 (2H, d, J = 4.0 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.51- 6.68 (3H, m), 6.75-6.81 (2H, m), 6.91- 7.02 (3H, m), 7.10-7.17 (2H, m) 1114 Me H H CH2CH2C(CH3)3 2 (APCI)+: [M + H]+ = 571.5 0.87 (9H, s), 1.13-1.28 (3H, m), 1.34- 1.40 (2H, m), 1.43-1.68 (4H, m), 1.78- 1.89 (2H, m), 2.06 (3H, s), 2.15 (2H, t, J = 7.4 Hz), 2.23-2.30 (2H, m), 2.88 (2H, d, J = 10.9 Hz), 3.66 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.22 (2H, d, J = 5.2 Hz), 5.87 (1H, d, J = 14.6 Hz), 6.08 (1H, t, J = 5.2 Hz), 6.61-6.68 (2H, m), 6.76-6.87 (3H, m), 6.95-7.05 (2H, m), 7.07 (1H, s), 7.20 (1H, s) 1115 Me H H CH2CH2C(CH3)3 0 (ESI)+: [M + H]+ = 543.4 0.88 (9H, s), 1.35-1.42 (2H, m), 1.57- 2.00 (6H, m), 2.12 (3H, s), 2.29-2.32 (2H, m), 2.92-3.03 (2H, m), 3.14-3.15 (1H, m), 3.80 (3H, s), 3.97 (1H, d, J = 14.6 Hz), 4.28 (2H, d, J = 5.2 Hz), 5.58-5.72 (1H, m), 5.90 (1H, d, J = 14.6 Hz), 6.11 (1H, s), 6.70 (2H, d, J = 4.2 Hz), 6.82-6.96 (3H, m), 7.03- 7.14 (1H, m), 7.14 (1H, s) 1116 Me H H 0 (ESI)+: [M + H]+ = 513.3 0.12-0.14 (2H, m), 0.53-0.56 (2H, m), 0.78-0.97 (1H, m), 1.48-2.01 (6H, m), 2.17 (3H, s), 2.18-2.24 (2H, m), 2.32 (2H, d, J = 6.7 Hz), 3.12-3.16 (2H, m), 3.80 (3H, s), 3.96 (1H, d, J = 15.1 Hz) 5.88 (1H, d, J = 15.1 Hz), 6.05- 6.18 (1H, m), 6.42-6.43 (1H, m), 6.68 (2H, d, J = 4.0 Hz), 6.80-6.89 (2H, m), 6.97-7.02 (1H, m), 7.03-7.13 (2H, m)

Compound number R13 MS 1117 E93 CH2CH2CH3 (ESI)+: [M + H]+ = 521.4 1118 (ESI)+: [M + H]+ = 569.3 1119 (ESI)+: [M + H]+ = 583.4 1120 (ESI)+: [M + H]+ = 603.3 1121 (ESI)+: [M + H]+ = 603.4 1122 CH2CH2CH2CH2CH3 (ESI)+: [M + H]+ = 549.4 1123 (ESI)+: [M + H]+ = 597.4 1124 CH2CH2CH(CH3)2 (ESI)+: [M + H]+ = 549.4 1125 CH2C(CH3)3 (ESI)+: [M + H]+ = 549.4 1126 (ESI)+: [M + H]+ = 589.4 1127 (ESI)+: [M + H]+ = 570.3 1128 (ESI)+: [M + H]+ = 575.3 1129 (ESI)+: [M + H]+ = 573.4 1130 (ESI)+: [M + H]+ = 583.3 1131 (ESI)+: [M + H]+ = 583.4 1132 (ESI)+: [M + H]+ = 583.4 1133 (ESI)+: [M + H]+ = 594.4 1134 (ESI)+: [M + H]+ = 594.4 1135 (ESI)+: [M + H]+ = 594.2 1136 (ESI)+: [M + H]+ = 659.4 1137 (ESI)+: [M + H]+ = 659.5

Compound number R1 R8 R13 n MS 1138 E94 F Me CH2(CH2)4CH3 1 (ESI)+: [M + H]+ = 575.7 1139 Cl H CH2(CH2)4CH3 0 (ESI)+: [M + H]+ = 563.3 1140 Cl H CH2(CH2)2CH3 0 (ESI)+: [M + H]+ = 535.3 1141 Cl H CH2(CH2)3OH 0 (ESI)+: [M + H]+ = 551.3 1142 Cl H CH2(CH2)2CN 0 (ESI)+: [M + H]+ = 546.3 1143 Cl H 0 (ESI)+: [M + H]+ = 597.3 1144 Cl H 0 (ESI)+: [M + H]+ = 589.3 1145 Cl H 0 (ESI)+: [M + H]+ = 587.3 1146 Cl H 0 (ESI)+: [M + H]+ = 625.4 1147 Cl H 0 (ESI)+: [M + H]+ = 653.3 1148 Cl H 0 (ESI)+: [M + H]+ = 627.3 1149 Cl H 0 (ESI)+: [M + H]+ = 575.3 1150 Cl H CH2CO2CH(CH3)2 0 (ESI)+: [M + H]+ = 579.3 1151 Cl H CH2CH2CN 0 (ESI)+: [M + H]+ = 532.2 1152 Cl H CH2CH2CH2OH 0 (ESI)+: [M + H]+ = 537.3 1153 Cl H CH2CN 0 (ESI)+: [M + H]+ = 518.2 1154 Cl H 0 (ESI)+: [M + H]+ = 614.3 1155 Cl H 0 (ESI)+: [M + H]+ = 619.3 1156 Cl H 0 (ESI)+: [M + H]+ = 519.2 1157 Cl H 0 (ESI)+: [M + H]+ = 595.3 1158 Cl H 0 (ESI)+: [M + H]+ = 645.4 1159 Cl H 0 (ESI)+: [M + H]+ = 577.3 1160 Cl H CH2COC(CH3)3 0 (ESI)+: [M + H]+ = 577.3 1161 Cl H CH2CONH2 0 (ESI)+: [M + H]+ = 536.2 1162 Cl H 0 (ESI)+: [M + H]+ = 604.3 1163 Cl H 0 (ESI)+: [M + H]+ = 611.3 1164 F Me CH2(CH2)2CH3 1 (ESI)+: [M + H]+ = 547.6 1165 F Me CH2(CH2)3OH 1 (ESI)+: [M + H]+ = 563.7 1166 F Me CH2(CH2)2CN 1 (ESI)+: [M + H]+ = 558.8 1167 F Me 1 (ESI)+: [M + H]+ = 609.8 1168 F Me 1 (ESI)+: [M + H]+ = 601.8 1169 F Me 1 (ESI)+: [M + H]+ = 599.7 1170 F Me 1 (ESI)+: [M + H]+ = 637.9 1171 F Me 1 (ESI)+: [M + H]+ = 665.7 1172 F Me 1 (ESI)+: [M + H]+ = 639.8 1173 F Me 1 (ESI)+: [M + H]+ = 581.7 1174 F Me 1 (ESI)+: [M + H]+ = 587.8 1175 F Me CH2CO2CH(CH3)2 1 (ESI)+: [M + H]+ = 591.7 1176 F Me CH2CH2CH(CH3)2 1 (ESI)+: [M + H]+ = 561.6 1177 F Me CH2CH2CH2OH 1 (ESI)+: [M + H]+ = 549.6 1178 F Me CH2CH2OCH2CH3 1 (ESI)+: [M + H]+ = 563.5 1179 F Me CH2CH2CH2F 1 (ESI)+: [M + H]+ = 551.5 1180 F Me 1 (ESI)+: [M + H]+ = 626.8 1181 F Me 1 (ESI)+: [M + H]+ = 545.6 1182 F Me 1 (ESI)+: [M + H]+ = 631.8 1183 F Me 1 (ESI)+: [M + H]+ = 607.7 1184 F Me 1 (ESI)+: [M + H]+ = 657.7 1185 F Me 1 (ESI)+: [M + H]+ = 589.7 1186 F Me 1 (ESI)+: [M + H]+ = 606.8 1187 F Me CH2COC(CH3)3 1 (ESI)+: [M + H]+ = 589.7 1188 F Me CH2CONH2 1 (ESI)+: [M + H]+ = 548.5 1189 F Me 1 (ESI)+: [M + H]+ = 616.7 1190 F Me 1 (ESI)+: [M + H]+ = 623.6

Compound number R16 MS 1191 E95 CH2CH3 (ESI)+: [M + H]+ = 577.4 1192 (ESI)+: [M + H]+ = 660.7 1193 (ESI)+: [M + H]+ = 660.4 1194 (ESI)+: [M + H]+ = 659.5 1195 (ESI)+: [M + H]+ = 655.5 1196 (ESI)+: [M + H]+ = 660.6 1197 (ESI)+: [M + H]+ = 626.3 1198 (ESI)+: [M + H]+ = 631.4 1199 (ESI)+: [M + H]+ = 643.3 1200 CH2CH2CH3 (ESI)+: [M + H]+ = 591.3 1201 (ESI)+: [M + H]+ = 589.4 1202 C(CH3)3 (ESI)+: [M + H]+ = 605.2 1203 CH2(CH2)3CH3 (ESI)+: [M + H]+ = 619.3 1204 CH(CH2CH3)CH2CH2CH2CH3 (ESI)+: [M + H]+ = 648.7 1205 (ESI)+: [M + H]+ = 639.4 1206 (ESI)+: [M + H]+ = 665.5 1207 (ESI)+: [M + H]+ = 645.3 1208 (ESI)+: [M + H]+ = 655.4 1209 CH2CH2CH2CO2CH2CH3 (ESI)+: [M + H]+ = 663.5

Compound number R16 MS 1210 E96 CH2CH3 1211 (ESI)+: [M + H]+ = 661.2 1212 (ESI)+: [M + H]+ = 686.2 1213 (ESI)+: [M + H]+ = 729.3 1214 (ESI)+: [M + H]+ = 718.4 1215 (ESI)+: [M + H]+ = 701.2 1216 (ESI)+: [M + H]+ = 776.4 1217 CH2CH2CH2CH3 (ESI)+: [M + H]+ = 641.4

Compound number R16 MS 1218 E97 1219 (ESI)+: [M + H]+ = 689.4, 691.4 1220 (ESI)+: [M + H]+ = 703.6, 705.6 1221 (ESI)+: [M + H]+ = 686.3, 688.3 1222 (ESI)+: [M + H]+ = 605.4, 607.4 1223 (ESI)+: [M + H]+ = 671.3 1224 (ESI)+: [M + H]+ = 603.4, 605.4 1225 (ESI)+: [M + H]+ = 641.5 1226 (ESI)+: [M + H]+ = 675.4, 677.4 1227 (ESI)+: [M + H]+ = 655.5, 657.5 1228 (ESI)+: [M + H]+ = 621.3, 623.3 1229 (ESI)+: [M + H]+ = 593.4 1230 (ESI)+: [M + H]+ = 725.4, 1231 CH3 (ESI)+: [M + H]+ = 579.4, 581.4 1232 (ESI)+: [M + H]+ = 591.1 1233 (ESI)+: [M + H]+ = 699.5, 701.5

Compound number R1 R3 R4 R8 MS 1H NMR: δ (ppm) 1234 E98 F H CH2CH2CH3 Me (APCI)+: [M + H]+ = 472.4 0.96 (3H, t, J = 7.4 Hz), 1.65-1.78 (2H, m), 2.21 (3H, s), 2.83 (2H, t, J = 7.7 Hz), 3.75 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.21 (2H, d, J = 6.2 Hz), 4.90 (1H, brs), 5.83 (1H, d, J = 14.6 Hz), 6.24 (1H, s), 6.48-6.58 (2H, m), 6.77 (1H, s), 6.93-7.02 (2H, m), 7.06- 7.12 (1H, m), 7.21 (1H, s) 1235 Cl H CH2CH2CH3 Cl (APCI)+: [M + H]+ = 508.3 0.97 (3H, t, J = 7.4 Hz), 1.68- 1.83 (2H, m), 2.86 (2H, t, J = 7.4 Hz), 3.69 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.26 (2H, d, J = 6.4 Hz), 5.56 (1H, t, J = 6.4 Hz), 5.80 (1H, d, J = 14.6 Hz), 6.58-6.62 (2H, m), 6.94 (1H, dd, J = 1.5, 7.9 Hz), 7.04 (1H, s), 7.09 (1H, s), 7.16-7.20 (2H, m), 7.33 (1H, d, J = 1.5 Hz) 1236 F H CH2CH2CH3 Cl (APCI)+: [M + H]+ = 492.3, 494.3 0.97 (3H, t, J = 7.4 Hz), 1.68-1.79 (2H, m), 2.85, (2H, t, J = 7.4 Hz), 3.77 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.25 (2H, d, J = 6.2 Hz), 4.80 (1H, t, J = 6.2 Hz), 5.84 (1H, d, J = 14.6 Hz), 6.38 (1H, s), 6.60-6.66 (2H, m), 6.94-7.03 (3H, m), 7.17-7.24 (2H, m)

Compound number R1 R3 R4 R8 MS 1H NMR: δ (ppm) 1237 E99 F H H Me (ESI)+: [M + H]+ = 394.2 2.20 (3H, s), 3.75 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.30-4.40 (2H, m), 5.82 (1H, d, J = 14.6 Hz), 6.31- 6.42 (1H, m), 6.46 (1H, s), 6.47-6.59 (2H, m), 6.78 (1H, s), 6.88-7.03 (3H, m), 7.21 (1H, s), 8.16 (1H, s) 1238 Cl H H Cl (ESI)+: [M + H]+ = 430.2 3.69 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.40-4.55 (2H, m), 5.83 (1H, d, J = 14.6 Hz), 6.28-6.41 (1H, m), 6.56- 6.68 (2H, m), 6.78 (1H, s), 6.90-7.14 (3H, m), 7.23 (1H, s), 7.30 (1H, s), 8.20 (1H, s) 1239 F H H Cl (ESI)+: [M + H]+ = 414.2, 416.2 3.72 (3H, s), 3.96 (1H, d, J = 14.6 Hz), 4.33-4.40 (2H, m), 5.81 (1H, d, J = 14.6 Hz), 6.52-6.56 (1H, m), 6.61 (2H, s), 6.87-6.94 (2H, m), 7.01-7.07 (2H, m), 7.13 (1H, s), 7.21 (1H, s), 8.16 (1H, s)

Compound number R1 R3 R4 R8 MS 1H NMR: δ (ppm) 1240 E100 F H Me (APCI)+: [M + H]+ = 434.2 0.65-0.69 (2H, m), 0.85-0.88 (2H, m), 1.37-1.43 (1H, m), 2.08 (3H, s), 3.64 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.28-4.31 (2H, m), 5.81 (1H, d, J = 14.6 Hz), 6.46 (1H, d, J = 8.4 Hz), 6.53 (1H, d, J = 7.9 Hz), 6.78-6.96 (4H, m), 7.15 (1H, s), 7.17 (1H, s) 1241 E101 Me H Me (ESI)+: [M + H]+ = 430.4 0.62-0.71 (2H, m), 0.81-0.89 (2H, m), 1.39-1.50 (1H, m), 2.04 (3H, s), 2.12 (3H, s), 3.66 (3H, s), 3.91 (1H, d, J = 14.6 Hz), 4.22 (2H, d, J = 2.0 Hz), 5.82 (1H, d, J = 14.6 Hz), 6.46 (2H, q, J = 7.9 Hz), 6.68-6.87 (4H, m), 7.06 (2H, s) 1242 E102 F H Cl (APCI)+: [M + H]+ = 454.2, 456.2 0.62-0.80 (2H, m), 0.88-1.00 (2H, m), 1.31-1.47 (1H, m), 3.69 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.35 (2H, d, J = 5.4 Hz), 5.82 (1H, d, J = 14.6 Hz), 6.51 (1H, t, J = 5.4 Hz), 6.61 (2H, s), 6.82- 7.08 (4H, m), 7.17 (1H, s), 7.21 (1H, s) 1243 E103 F H CH2CH3 Cl (ESI)+: [M + H]+ = 442.1, 444.2 1.12 (3H, t, J = 7.7 Hz), 2.21 (2H, q, J = 7.7 Hz), 3.76 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.37 (2H, d, J = 5.7 Hz), 5.83 (1H, d, J = 14.6 Hz), 5.94 (1H, t, J = 5.7 Hz), 6.58-6.67 (3H, m), 6.89-7.00 (3H, m), 7.07 (1H, t, J = 7.4 Hz), 7.23 (1H, s) 1244 E104 F H CH2CH2CH3 Cl (APCI)+: [M + H]+ = 456.3, 458.3 0.88 (3H, t, J = 7.4 Hz), 1.56-1.69 (2H, m), 2.15 (2H, t, J = 7.2 Hz), 3.71 (3H, s), 3.96 (1H, d, J = 14.6 Hz), 4.35 (2H, d, J = 5.7 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.23 (1H, t, J = 5.7 Hz), 6.59-6.64 (2H, m), 6.87-6.94 (2H, m), 7.01-7.06 (2H, m), 7.19 (1H, s), 7.22 (1H, s) 1245 E105 F H CH(CH3)2 Cl (APCI)+: [M + H]+ = 456.3, 458.2 1.11 (6H, d, J = 6.9 Hz), 2.29-2.42 (1H, m), 3.73 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.35 (2H, d, J = 5.7 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.06 (1H, t, J = 5.7 Hz), 6.60-6.63 (2H, m), 6.88-7.08 (5H, m), 7.22 (1H, s) 1246 E106 Cl H Cl (APCI)+: [M + H]+ = 470.2 0.71-0.74 (2H, m), 0.90- 0.91 (2H, m), 1.40-1.43 (1H, m), 3.67 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.38 (2H, d, J = 5.4 Hz), 5.81 (1H, d, J = 14.6 Hz), 6.56 (3H, m), 6.90-7.04 (4H, m), 7.21 (1H, s), 7.26 (1H, s) 1247 E107 Cl H CH2CH2CH3 Cl (APCI)+: [M + H]+ = 472.3 0.87 (3H, t, J = 7.4 Hz), 1.60-1.65 (2H, m), 2.16 (2H, t, J = 7.7 Hz), 3.67 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.36 (2H, t, J = 3.5 Hz), 5.79 (1H, d, J = 14.6 Hz), 6.59 (2H, s), 6.91 (1H, d, J = 7.7 Hz), 6.98 (1H, d, J = 7.7 Hz), 7.03 (2H, s), 7.20 (1H, s), 7.23 (1H, s), 7.60 (1H, s) 1248 E108 Cl H CH(CH3)2 Cl (APCI)+: [M + H]+ = 472.3 1.09-1.13 (6H, m), 2.30- 2.50 (1H, m), 3.70 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.37 (2H, d, J = 4.0 Hz), 5.81 (1H, d, J = 14.6 Hz), 6.25 (1H, t, J = 5.9 Hz), 6.60 (2H, s), 6.85-7.04 (3H, m), 7.22 (1H, s), 7.26 (2H, s) 1249 Me H CH(CH3)2 Cl (ESI)+: [M + H]+ = 452.2, 454.2 1.14 (6H, d, J = 6.7 Hz), 2.14 (3H, s), 2.27-2.42 (1H, m), 3.74 (3H, s), 3.94 (1H, d, J = 14.5 Hz), 4.30 (2H, d, J = 5.2 Hz), 5.70 (1H, s), 5.87 (1H, d, J = 14.5 Hz), 6.57-6.67, (3H, m), 6.88 (2H, s), 6.98 (2H, s), 7.13 (1H, s) 1250 Me H CH2CH2CH3 Cl (ESI)+: [M + H]+ = 452.2, 454.2 0.92 (3H, t, J = 7.3 Hz), 1.64 (2H, q, J = 7.3 Hz), 2.12-2.24 (5H, m), 3.75 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.32 (2H, d, J = 5.0 Hz), 5.64 (1H, s), 5.87 (1H, d, J = 14.6 Hz), 6.40 (1H, s), 6.62 (2H, s), 6.89 (2H, s), 6.97 (2H, s), 7.14 (1H, s) 1251 Me H CH2CH3 Cl (ESI)+: [M + H]+ = 438.2, 440.2 1.14 (3H, t, J = 7.3 Hz), 2.15 (3H, s), 2.23 (2H, q, J = 7.3 Hz), 3.74 (3H, s), 3.93 (1H, d, J = 14.9 Hz), 4.31 (2H, d, J = 5.2 Hz), 5.71 (1H, s), 5.87 (1H, d, J = 14.9 Hz), 6.55 (1H, s), 6.62 (2H, s), 6.88 (2H, s), 6.98 (2H, s), 7.13 (1H, s) 1252 Me H CH2CH2CH3 Me (ESI)+: [M + H]+ = 433.2 0.91 (3H, t, J = 7.4 Hz), 1.65 (2H, q, J = 7.4 Hz), 2.13 (3H, s), 2.11-2.30 (2H, m), 2.21 (3H, s), 3.76 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.29 (2H, d, J = 5.2 Hz), 5.55-5.70 (1H, m), 5.87 (1H, d, J = 14.6 Hz), 6.09 (1H, s), 6.52 (2H, q, J = 7.7 Hz), 6.74 (1H, s), 6.80-6.93 (2H, m), 7.14 (1H, s), 7.23 (1H, s) 1253 Me H CH(CH3)2 Me (ESI)+: [M + H]+ = 433.2 1.12 (6H, d, J = 6.7 Hz), 2.13 (3H, s), 2.21 (3H, s), 2.25-2.42 (1H, m), 3.76 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.29 (2H, d, J = 5.4 Hz), 5.55-5.70 (1H, m), 5.88 (1H, d, J = 14.6 Hz), 6.10 (1H, s), 6.52 (2H, q, J = 7.9 Hz), 6.74 (1H, s), 6.75-6.93 (2H, m), 7.14 (1H, s), 7.23 (1H, s) 1254 Me H CH2CH3 Me (ESI)+: [M + H]+ = 418.2 1.13 (3H, t, J = 7.4 Hz), 2.12 (3H, s), 2.18-2.28 (5H, m), 3.76 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.29 (2H, d, J = 5.2 Hz), 5.57- 5.70 (1H, m), 5.87 (1H, d, J = 14.6 Hz), 6.07 (1H, s), 6.52 (2H, q, J = 7.9 Hz), 6.74 (1H, s), 6.80-6.92 (2H, m), 7.14 (1H, s), 7.23 (1H, s) 1255 Me H CH2CH3 F (APCI)+: [M + H]+ = 422.4 1.13 (3H, t, J = 7.4 Hz), 2.12 (3H, s), 2.20 (2H, q, J = 7.4 Hz), 3.70 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.28 (1H, d, J = 5.2 Hz), 5.83 (1H, s), 5.85 (1H, d, J = 14.6 Hz), 6.33-6.39 (1H, m), 6.61-6.70 (2H, m), 6.77-6.86 (3H, m), 7.10 (1H, s), 7.23 (1H, s) 1256 Me H CH2CH2CH3 F (APCI)+: [M + H]+ = 436.4 0.91 (3H, t, J = 7.4 Hz), 1.59-1.68 (2H, m), 2.10- 2.20 (5H, m), 3.71 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.29 (2H, d, J = 5.2 Hz), 5.79 (1H, s), 5.86 (1H, d, J = 14.6 Hz), 6.33-6.42 (1H, m), 6.61-6.72 (3H, m), 6.83-6.88 (2H, m), 7.11 (1H, s), 7.23 (1H, s) 1257 Me H CH(CH3)2 F (APCI)+: [M + H]+ = 436.4 1.12 (6H, d, J = 6.4 Hz), 2.12 (3H, s), 2.30-2.41 (1H, m), 3.71 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.28 (2H, d, J = 5.2 Hz), 5.75 (1H, s), 5.86 (1H, d, J = 14.6 Hz), 6.33-6.39 (1H, m), 6.62-6.73 (3H, m), 6.80-6.92 (2H, m), 7.10 (1H, s), 7.23 (1H, s) 1258 Me H F (APCI)+: [M + H]+ = 434.4 0.71-0.74 (2H, m), 0.91- 0.96 (2H, m), 1.35-1.37 (1H, m), 2.13 (3H, s), 3.70 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.30 (2H, d, J = 5.2 Hz), 5.86 (1H, d, J = 14.6 Hz), 5.99 (1H, s), 6.34-6.40 (1H, m), 6.62- 6.70 (3H, m), 6.83-6.91 (2H, m), 7.11 (1H, s) 1259 F H F (APCI)+: [M + H]+ = 438.4 0.71-0.75 (2H, m), 0.91- 0.95 (2H, m), 1.31-1.37 (1H, m), 3.74 (3H, s), 3.96 (1H, d, J = 14.6 Hz), 4.38 (2H, d, J = 5.7 Hz), 5.84 (1H, d, J = 14.6 Hz), 6.14 (1H, s), 6.37-6.43 (1H, m), 6.64-6.69 (3H, m), 6.89-6.95 (2H, m), 7.04- 7.10 (1H, m) 1260 F H CH(CH3)2 F (APCI)+: [M + H]+ = 440.4 1.11 (6H, d, J = 6.7 Hz), 2.34 (1H, septet, J = 6.7 Hz), 3.76 (3H, s), 3.96 (1H, d, J = 14.6 Hz), 4.36 (2H, d, J = 5.9 Hz), 5.84 (1H, d, J = 14.6 Hz), 5.87 (1H, s), 6.37-6.43 (1H, m), 6.51 (1H, s), 6.64-6.69 (2H, m), 6.91- 6.95 (2H, m), 7.04-7.10 (1H, m) 1261 F H CH2CH2CH3 F (APCI)+: [M + H]+ = 440.4 0.88 (3H, t, J = 7.2 Hz), 1.58-1.66 (2H, m), 2.14 (2H, t, J = 7.4 Hz), 3.74 (3H, s), 3.96 (1H, d, J = 14.6 Hz), 4.36 (2H, d, J = 5.2 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.01 (1H, s), 6.36-6.41 (1H, m), 6.63- 6.71 (2H, m), 6.79 (1H, s), 6.91-6.94 (2H, m), 7.03- 7.09 (1H, m) 1262 F H CH2CH3 F (APCI)+: [M + H]+ = 426.4 1.12 (3H, t, J = 7.4 Hz), 2.20 (2H, q, J = 7.4 Hz), 3.76 (3H, s), 3.96 (1H, d, J = 14.6 Hz), 4.37 (2H, d, J = 5.4 Hz), 5.83 (1H, d, J = 14.6 Hz), 5.87 (1H, s), 6.37-6.47 (2H, m), 6.64- 6.69 (2H, m), 6.92-6.95 (2H, m), 7.05-7.11 (1H, m) 1263 F H Me (APCI)+: [M + H]+ = 448.4 1.72-1.91 (3H, m), 2.05- 2.28 (4H, m), 2.92-3.06 (1H, m), 3.46 (2H, s), 3.72 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.31 (2H, d, J = 5.7 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.05 (1H, t, J = 5.7 Hz), 6.47 (1H, d, J = 7.7 Hz), 6.54 (1H, d, J = 7.7 Hz), 6.68 (1H, s), 6.78 (1H, s), 6.82-7.00 (3H, m), 7.20 (1H, s) 1264 F H Me (APCI)+: [M + H]+ = 476.4 1.10-1.48 (5H, m), 1.60- 1.70 (1H, m), 1.70-1.84 (4H, m), 2.00-2.14 (1H, m), 2.19 (3H, s), 3.74 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.32 (2H, d, J = 5.9 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.03 (1H, t, J = 6.0 Hz), 6.44-6.59 (3H, m), 6.77 (1H, s), 6.88- 7.02 (3H, m), 7.21 (1H, s) 1265 F H CH2CH2CH3 Me (APCI)+: [M + H]+ = 436.4 0.86 (3H, t, J = 7.4 Hz), 1.53-1.68 (2H, m), 2.13 (2H, q, J = 7.4 Hz), 2.17 (3H, s), 3.71 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.31 (2H, d, J = 5.4 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.29 (1H, t, J = 6.7 Hz), 6.47 (1H, d, J = 8.2 Hz), 6.55 (1H, d, J = 8.2 Hz), 6.76 (2H, d, J = 6.4 Hz), 6.87- 6.97 (3H, m), 7.20 (1H, s) 1266 F H Me Me (APCI)+: [M + H]+ = 408.4 1.92 (3H, s), 2.17 (3H, s), 3.70 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.29 (2H, d, J = 5.4 Hz), 5.81 (1H, d, J = 14.6 Hz), 6.42-6.61 (3H, m), 6.85 (2H, d, J = 6.9 Hz), 6.87-7.00 (3H, m), 7.20 (1H, s) 1267 F H CH(CH3)2 Me (APCI)+: [M + H]+ = 436.4 1.08-1.11 (6H, m), 2.16 (3H, s), 2.28-2.42 (1H, m), 3.71 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.31 (2H, d, J = 4.2 Hz), 5.82 (1H, d, J = 14.6 Hz), 6.23 (1H, t, J = 5.9 Hz), 6.47(1H, d, J = 7.9 Hz), 6.55 (1H, d, J = 7.9 Hz), 6.77 (2H, d, J = 2.5 Hz), 6.85-7.03 (3H, m), 7.20 (1H, s) 1268 F H C(CH3)3 Me (APCI)+: [M + H]+ = 450.4 1.15 (9H, s), 2.16 (3H, s), 3.71 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.32 (2H, d, J = 5.7 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.10-6.23 (1H, m), 6.46 (1H, d, J = 7.9 Hz), 6.55 (1H, d, J = 7.9 Hz), 6.68 (1H, s), 6.76 (1H, s), 6.85-7.05 (3H, m), 7.20 (1H, s) 1269 Cl H Cl (APCI)+: [M + H]+ = 484.3 1.78-2.04 (2H, m), 2.04- 2.32 (4H, m), 2.92-3.10 (1H, m), 3.73 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.39 (2H, d, J = 3.2 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.01 (1H, t, J = 5.7 Hz), 6.62 (2H, s), 6.85-7.10 (4H, m), 7.23 (1H, s), 7.27 (1H, s) 1270 Cl H Cl (APCI)+: [M + H]+ = 512.4 1.23 (2H, t, J = 7.2 Hz), 1.26-1.50 (3H, m), 1.59- 1.71 (1H, m), 1.71-1.83 (5H, m), 2.12-2.28 (1H, m), 3.79 (3H, s), 3.97 (1H, d, J = 14.6 Hz), 4.33 (2H, d, J = 1.5 Hz), 5.74 (1H, d, J = 14.6 Hz), 6.63-6.68 (2H, m), 7.08-7.13 (2H, m), 7.20 (1H, s), 7.21-7.23 (2H, m) 1271 Cl H Cl (APCI)+: [M + H]+ = 498.3 1.43-1.58 (1H, m), 1.58- 1.78 (5H, m), 1.58-1.90 (2H, m), 2.46-2.60 (1H, m), 3.72 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.30-4.50 (2H, m), 5.83 (1H, d, J = 14.6 Hz), 6.12 (1H, t, J = 5.9 Hz), 6.61 (2H, s), 6.84-7.11 (4H, m), 7.22 (1H, s), 7.27 (1H, s) 1272 Cl H Me Cl (APCI)+: [M + H]+ = 444.3 1.97 (3H, s), 3.67 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.33 (2H, t, J = 5.2 Hz), 5.79 (1H, d, J = 14.6 Hz), 6.59 (2H, s), 6.60-6.70 (1H, m), 6.90 (1H, d, J = 7.9 Hz), 6.97 (1H, d, J = 7.9 Hz), 7.04 (1H, s), 7.19 (1H, s), 7.23 (1H, s), 7.58 (1H, s) 1273 F H Me (APCI)+: [M + H]+ = 462.4 1.41-1.84 (8H, m), 2.13 (3H, s), 2.46-2.57 (1H, m), 3.67 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.28 (2H, d, J = 5.2 Hz), 5.81 (1H, d, J = 14.6 Hz), 6.43-6.55 (3H, m), 6.79 (1H, s), 6.83- 6.96 (3H, m), 7.12 (1H, s), 7.17 (1H, s) 1274 F H CH2CH3 Me (APCI)+: [M + H]+ = 422.4 1.08 (3H, t, J = 7.7 Hz), 2.15 (3H, s), 2.17 (2H, q, J = 7.7 Hz), 3.69 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.30 (2H, d, J = 5.2 Hz), 5.81 (1H, d, J = 14.6 Hz), 6.38-6.57 (3H, m), 6.80- 6.98 (5H, m), 7.19 (1H, s) 1275 Cl H C(CH3)3 Cl (APCI)+: [M + H]+ = 486.3 1.17 (9H, s), 3.72 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.38 (2H, d, J = 5.9 Hz), 5.82 (1H, d, J = 14.6 Hz), 6.21 (1H, t, J = 5.7 Hz), 6.61 (2H, s), 6.85-7.08 (4H, m), 7.22-7.27 (2H, m) 1276 Cl H CH2CH3 Cl (APCI)+: [M + H]+ = 458.2 1.11 (3H, t, J = 7.7 Hz), 2.22 (2H, q, J = 7.7 Hz), 3.45 (1H, d, J = 5.2 Hz), 3.67 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.23-4.45 (2H, m), 5.80 (1H, d, J = 14.6 Hz), 6.53 (1H, t, J = 5.9 Hz), 6.59 (2H, s), 6.85-6.92 (1H, m), 6.98 (1H, s), 6.99-7.04 (1H, m), 7.20 (1H, s), 7.59 (1H, s) 1277 F H Cl (APCI)+: [M + H]+ = 496.3, 498.3 1.17-1.25 (2H, m), 1.25- 1.42 (2H, m), 1.65-1.81 (6H, m), 2.02-2.18 (1H, m), 3.73 (3H, s), 3.96 (1H, d, J = 14.6 Hz), 4.34 (2H, d, J = 5.7 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.08 (1H, t, J = 5.7 Hz), 6.59-6.64 (2H, m), 6.87-6.94 (2H, m), 7.00-7.04 (2H, m), 7.06 (1H, s), 7.22 (1H, s) 1278 F H Cl (APCI)+: [M + H]+ = 468.3, 470.3 1.80-2.02 (2H, m), 2.03- 2.31 (4H, m), 2.95-3.08 (1H, m), 3.71 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.34 (2H, d, J = 5.7 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.06 (1H, t, J = 5.7 Hz), 6.59- 6.63 (2H, m), 6.87-6.94 (2H, m), 6.99-7.06 (2H, m), 7.22 (2H, s) 1279 F H Me Cl (APCI)+: [M + H]+ = 428.2, 430.2 1.96 (3H, s), 3.73 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.35 (2H, d, J = 5.7 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.23 (1H, t, J = 5.7 Hz), 6.58-6.66 (2H, m), 6.87- 7.05 (5H, m), 7.22 (1H, s) 1280 F H C(CH3)3 Cl (APCI)+: [M + H]+ = 470.3, 472.3 1.16 (9H, s), 3.74 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.36 (2H, d, J = 5.7 Hz), 5.84 (1H, d, J = 14.6 Hz), 6.07 (1H, t, J = 5.7 Hz), 6.60-6.64 (2H, m), 6.79 (1H, s), 6.90-6.98 (3H, s), 7.02-7.08 (1H, m), 7.23 (1H, s) 1281 F H Cl (ESI)+: [M + H]+ = 482.2, 484.2 1.31-1.88 (8H, m), 2.48- 2.58 (1H, m), 3.72 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.34 (2H, d, J = 5.7 Hz), 5.81 (1H, d, J = 14.6 Hz), 6.25 (1H, t, J = 5.7 Hz), 6.59 (2H, s), 6.87-6.93 (2H, m), 7.01 (1H, t, J = 7.4 Hz), 7.08 (1H, s), 7.21 (1H, s), 7.44 (1H, s) 1282 H Cl Me (APCI)+: [M + H]+ = 450.2, 452.3 0.70-0.74 (2H, m), 0.91- 0.94 (2H, m), 1.39 (1H, m), 2.13 (3H, s), 3.70 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 4.25 (2H, m), 5.79 (1H, d, J = 14.6 Hz), 6.32 (1H, s), 6.45-6.49 (2H, m), 6.65 (1H, s), 6.74-6.83 (3H, m), 7.04 (1H, s), 7.23 (1H, s) 1283 H Me Cl (APCI)+: [M + H]+ = 450.2, 452.2 0.68-0.73 (2H, m), 0.90- 0.94 (2H, m) 1.31-1.43 (1H, m), 2.25 (3H, s), 3.63 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.23 (2H, d, J = 5.6 Hz), 4.41 (1H, d, J = 5.6 Hz), 5.80 (1H, d, J = 14.6 Hz), 6.39-6.46 (1H, m), 6.56-7.23 (7H, m) 1284 H Me Me (APCI)+: [M + H]+ = 430.2 0.69-0.74 (2H, m), 0.93- 0.96 (2H, m), 1.28-1.36 (1H, m), 2.15 (3H, s), 2.31 (3H, s), 3.47 (2H, d, J = 5.6 Hz), 3.72 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.27 (1H, d, J = 5.6 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.11 (1H, s), 6.41-6.46 (1H, m), 6.58-6.91 (6H, m) 1285 H Cl Cl (APCI)+: [M + H]+ = 470.2 0.68-0.76 (2H, m), 0.88- 0.97 (2H, m), 1.42 (1H, m), 3.60 (3H, s), 3.98 (1H, d, J = 14.6 Hz), 4.19 (2H, m), 4.38 (1H, m), 5.73 (1H, d, J = 14.6 Hz), 6.52- 6.56 (1H, m), 6.71-7.18 (6H, m), 7.60 (1H, brs) 1286 H F Cl (APCI)+: [M + H]+ = 454.2, 456.3 0.69-0.75 (2H, m), 0.91- 0.94 (2H, m), 1.32-1.44 (1H, m), 3.66 (3H, s), 3.96 (1H, d, J = 14.6 Hz), 4.28 (2H, d, J = 5.9 Hz), 5.80 (1H, d, J = 14.6 Hz), 6.51- 6.62 (2H, m), 6.69 (2H, t, J = 8.4, 18.3 Hz), 6.79 (1H, d, J = 6.4 Hz), 6.92 (2H, s), 6.98-7.09 (1H, m), 7.22 (1H, s) 1287 H F Me (APCI)+: [M + H]+ = 434.2 0.69-0.74 (2H, m), 0.91- 0.96 (2H, m), 1.31-1.42 (1H, m), 2.15 (3H, s), 3.69 (3H, s), 3.96 (1H, d, J = 14.6 Hz), 4.27 (2H, t, J = 5.7, 11.1 Hz), 5.81 (1H, d, J = 14.6 Hz), 6.32 (1H, s), 6.42-6.47 (2H, m), 6.62-6.79 (3H, m), 7.02 (1H, t, J = 7.4, 14.8 Hz), 7.21 (1H, s) 1288 Cl H Me (APCI)+: [M + H]+ = 450.3, 452.4 0.94 (2H, m), 1.37-1.46 (1H, m), 2.15 (3H, s), 3.68 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.24-4.42 (2H, m), 5.81 (1H, d, J = 14.6 Hz), 6.47 (1H, d, J = 8.2 Hz), 6.54 (1H, d, J = 8.2 Hz), 6.74-6.79 (2H, m), 6.90-6.96 (2H, m), 7.19-7.23 (1H, m) 1289 Me H Cl (ESI)+: [M + H]+ = 450.3, 452.4 0.66-0.78 (2H, m), 0.82- 0.94 (2H, m), 1.34-1.46 (1H, m), 2.08 (3H, s), 3.63 (3H, s), 3.93 (1H, d, J = 14.6 Hz), 4.26 (2H, d, J = 4.0 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.47-6.62 (2H, m), 6.78-6.86 (2H, m), 7.01-7.08 (1H, m), 7.19 (1H, s), 7.39 (1H, s)

Com- pound num- ber R1 R4 R8 R9 R10 MS 1H NMR: δ (ppm) 1290 Me CH(CH3)2 Me H H (ESI)+: 1.13 (6H, d, J = 6.5 Hz), [M + 2.15 (3H, s), 2.26- H]+ = 2.38 (1H, m), 2.39 433.2 (3H, s), 3.82 (3H, s), 3.95 (1H, d, J = 14.6 Hz, 4.29 (2H, d, J = 5.2 Hz), 5.43 (1H, s), 5.77 (1H, s), 5.93 (1H, d, J = 14.6 Hz), 6.62 (2H, s), 6.87 (2H, s), 6.96-7.06 (1H, m), 7.16 (1H, s), 7.25 (1H, s) 1291 Me CH2CH2CH3 Me H H (ESI)+: 0.91 (3H, t, J = 7.2 Hz), [M + 1.56-1.74 (2H, m), H]+ = 2.09 (3H, s), 2.10- 433.2 2.20 (2H, m), 2.39 (3H, s), 3.81 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.25 (2H, d, J = 4.7 Hz), 5.65 (1H, s), 5.85-6.05 (2H, m), 6.60-6.63 (2H, m), 6.82 (2H, s), 7.00 (1H, d, J = 5.7 Hz), 7.07 (1H, s), 7.20 (1H, s) 1292 Me CH2CH3 Me H H (ESI)+: 1.34 (3H, t, J = 7.4 Hz), [M + 2.12 (3H, s), 2.20 (2H, H]+ = q, J = 7.4 Hz), 2.39 (3H, 418.2 s), 3.82 (3H, s), 3.94 (1H, d, J = 14.7 Hz), 4.27 (2H, d, J = 5.2 Hz), 5.52 (1H, s), 5.85 (1H, s) 5.92 (1H, d, J = 14.7 Hz), 6.56-6.68 (2H, m), 6.86 (2H, s), 7.00 (1H, d, J = 5.7 Hz), 7.12 (1H, s), 7.25 (1H, s) 1293 Me CH(CH3)2 H Me H (ESI)+: 1.08-1.24 (6H, m), [M + 2.02 (3H, s), 2.13 (3H, H]+ = s), 2.26-2.44 (1H, m) 433.2 3.74 (3H, s), 3.94 (1H, d, J = 14.4 Hz), 4.28 (2H, d, J = 5.2 Hz), 5.62 (1H, s), 5.88 (1H, d, J = 14.4 Hz), 6.12 (1H, s), 6.52 (1H, s), 6.78- 6.96 (4H, m), 7.14 (1H, s), 7.22 (1H, s) 1294 Me CH2CH2CH3 H Me H (ESI)+: 0.88-1.02 (3H, m), [M + 2.02 (3H, s), 2.08- H]+ = 2.22 (7H, m), 3.72 433.2 (3H, s), 3.93 (1H, d, J = 14.5 Hz), 4.28 (2H, d, J = 5.2 Hz), 5.73 (1H, s), 5.86 (1H, d, J = 14.5 Hz), 6.21 (1H, s), 6.51 (1H, s), 6.79- 6.96 (4H, m), 7.12 (1H, s), 7.22 (1H, s) 1295 Me CH2CH3 H Me H (ESI)+: 1.12 (3H, t, J = 7.4 Hz), [M + 2.02 (3H, s), 2.12 (3H, H]+ = s), 2.19 (2H, q, 418.2 J = 7.4 Hz), 3.73 (3H, s), 3.94 (1H, d, J = 14.4 Hz), 4.28 (2H, d, J = 5.0 Hz), 5.68 (1H, s), 5.87 (1H, d, J = 14.4 Hz), 6.15 (1H, s), 6.51 (1H, s), 6.78- 6.98 (4H, m), 7.13 (1H, s), 7.22 (1H, s) 1296 Me H H Me (ESI)+: [M + H]+ = 430.1 0.69-0.79 (2H, m), 0.91-1.03 (2H, m), 1.32-1.41 (1H, m), 1.97 (3H, s), 2.07 (3H, s), 3.71 (3H, s), 3.86 (1H, d, J = 14.6 Hz), 4.26 (2H, d, J = 5.5 Hz), 5.89 (1H, d, J = 14.6 Hz), 5.99-6.08 (1H, m), 6.64 (1H, d, J = 7.4 Hz), 6.69-6.83 (2H, m), 6.90-7.03 (2H, m), 7.13 (1H, s), 7.23 (1H, s) 1297 Me CH(CH3)2 H H Me (ESI)+: 1.10-1.21 (6H, m), [M + 1.99 (3H, s), 2.10 (3H, H]+ = s), 2.33-2.42 (1H, m), 432.2 3.76 (3H, s), 3.86 (1H, d, J = 14.6 Hz), 4.27 (2H, d, J = 5.5 Hz), 5.61 (1H, s), 5.89 (1H, d, J = 14.6 Hz), 6.65 (1H, d, J = 7.4 Hz), 6.76-6.85 (2H, m), 6.94-7.04 (2H, m), 7.17 (1H, s), 7.22 (1H, s) 1298 Me CH2CH2CH3 H H Me (ESI)+: 0.87-0.99 (3H, m), [M + 1.56-1.72 (2H, m), H]+ = 1.98 (3H, s), 2.10 (3H, 432.2 s), 2.13-2.25 (2H, m), 3.76 (3H, s), 3.86 (1H, d, J = 14.6 Hz), 4.27 (2H, d, J = 5.7 Hz), 5.66 (1H, s), 5.90 (1H, d, J = 14.6 Hz), 6.65 (1H, d, J = 7.4 Hz), 6.76-6.85 (3H, m), 6.94-7.04 (3H, m), 7.16 (1H, s) 1299 Me CH2CH3 H H Me (ESI)+: 1.09-1.22 (3H, m), [M + 1.98 (3H, s), 2.08 (3H, H]+ = s), 2.14-2.29 (2H, m) 418.2 3.74 (3H, s), 3.86 (1H, d, J = 14.6 Hz), 4.26 (2H, d, J = 5.5 Hz), 5.75 (1H, s), 5.89 (1H, d, J = 14.6 Hz), 6.61-6.66 (1H, m), 6.74-6.83 (2H, m), 6.94-7.04 (2H, m), 7.15 (1H, s), 7.22 (1H, s) 1300 Me H Me H (ESI)+: [M + H]+ = 430.2 0.68-0.79 (2H, m), 0.90-0.98 (2H, m), 1.30-1.40 (1H, m), 2.03 (3H, s), 2.12 (3H, s), 3.73 (3H, s), 3.94 (1H, d, J = 14.6 Hz), 4.27-4.33 (2H, m), 5.87 (1H, d, J = 14.6 Hz), 5.90-5.97 (1H, m), 6.24 (1H, s), 6.51 (1H, s), 6.79- 6.94 (4H, m), 7.13 (1H, s) 1301 Me Me H H (ESI)+: [M + H]+ = 430.3 0.68-0.80 (2H, m), 0.90-1.02 (2H, m), 1.28-1.40 (1H, m), 2.14 (3H, s), 2.39 (3H, s), 3.82 (3H, m), 3.95 (1H, d, J = 14.6 Hz), 4.30 (2H, d, J = 5.4 Hz), 5.69 (1H, brs), 5.82 (1H, s), 5.93 (1H, d, J = 14.6 Hz), 6.58-6.70 (2H, m), 6.85-6.96 (2H, m), 6.96-7.08 (1H, m), 7.14 (1H, s)

Com- pound num- ber R1 R4 R8 b R11 MS 1302 F CH2CH2CH3 F 0 (ESI)+: [M + H]+ = 502.4 1303 F CH(CH3)2 F 0 (ESI)+: [M + H]+ = 502.2 1304 F F 0 (ESI)+: [M + H]+ = 500.2 1305 F CH2CH3 F 0 (ESI)+: [M + H]+ = 488.2 1306 F CH2CH2CH3 F 1 CH3 (ESI)+: [M + H]+ = 454.3 1307 F CH(CH3)2 F 1 CH3 (ESI)+: [M + H]+ = 454.3 1308 F F 1 CH3 (ESI)+: [M + H]+ = 452.3 1309 F CH2CH3 F 1 CH3 (ESI)+: [M + H]+ = 440.3 1310 Me CH2CH2CH3 F 0 C(CH3)3 (ESI)+: [M + H]+ = 478.4 1311 Me CH2CH3 F 0 C(CH3)3 (ESI)+: [M + H]+ = 464.4 1312 Me CH(CH3)2 F 0 C(CH3)3 (ESI)+: [M + H]+ = 478.4 1313 Me F 0 C(CH3)3 (ESI)+: [M + H]+ = 476.4 1314 F CH2CH2CH3 F 0 (ESI)+: [M + H]+ = 508.3 1315 F CH2CH3 F 0 (ESI)+: [M + H]+ = 494.2 1316 F CH(CH3)2 F 0 (ESI)+: [M + H]+ = 508.3 1317 F F 0 (ESI)+: [M + H]+ = 506.2 1318 F CH2CH2CH3 F 0 C(CH3)3 (ESI)+: [M + H]+ = 482.2 1319 F CH2CH3 F 0 C(CH3)3 (ESI)+: [M + H]+ = 468.2 1320 F CH(CH3)2 F 0 C(CH3)3 (ESI)+: [M + H]+ = 482.2 1321 F F 0 C(CH3)3 (ESI)+: [M + H]+ = 480.2 1322 F CH(CH3)2 Cl 1 CH3 (ESI)+: [M + H]+ = 436.4 1323 F CH2CH2CH3 Cl 1 CH3 (ESI)+: [M + H]+ = 436.4 1324 F CH2CH3 Cl 1 CH3 (ESI)+: [M + H]+ = 422.4 1325 F Cl 1 CH3 (ESI)+: [M + H]+ = 434.4 1326 Me CH2CH3 H 2 CH2CH3 (ESI)+: [M + H]+ = 446.3 1327 Me CH2CH2CH3 H 2 CH2CH3 (ESI)+: [M + H]+ = 460.3 1328 Me CH(CH3)2 H 2 CH2CH3 (ESI)+: [M + H]+ = 460.2 1329 Me H 2 CH2CH3 (ESI)+: [M + H]+ = 458.2 1330 F CH2CH3 H 2 CH2CH3 (ESI)+: [M + H]+ = 450.2 1331 F CH2CH2CH3 H 2 CH2CH3 (ESI)+: [M + H]+ = 464.2 1332 F CH(CH3)2 H 2 CH2CH3 (ESI)+: [M + H]+ = 464.2 1333 F H 2 CH2CH3 (ESI)+: [M + H]+ = 462.4 1334 F Cl 0 (ESI)+: [M + H]+ = 517.2, 519.2 1335 F CH(CH3)2 Cl 0 (ESI)+: [M + H]+ = 519.2, 521.2 1336 F CH2CH2CH3 Cl 0 (ESI)+: [M + H]+ = 519.2, 521.2 1337 F CH2CH3 Cl 0 (ESI)+: [M + H]+ = 505.2, 507.2 1338 Me CH(CH3)2 H 1 CH3 (ESI)+: [M + H]+ = 433.2 1339 Me CH2CH2CH3 H 1 CH3 (ESI)+: [M + H]+ = 433.2 1340 Me CH2CH3 H 1 CH3 (ESI)+: [M + H]+ = 418.2 1341 Me H 1 CH3 (ESI)+: [M + H]+ = 430.2 1342 F CH2CH2CH3 Cl 0 (ESI)+: [M + H]+ = 524.3, 526.3 1343 F CH(CH3)2 Cl 0 (ESI)+: [M + H]+ = 524.3, 526.3 1344 F Cl 0 (ESI)+: [M + H]+ = 522.2, 524.2 1345 F CH2CH3 Cl 0 (ESI)+: [M + H]+ = 510.3, 512.3 1346 F CH2CH2CH3 Cl 0 (ESI)+: [M + H]+ = 518.3, 520.3 1347 F Cl 0 (ESI)+: [M + H]+ = 530.2, 532.2 1348 F CH2CH3 Cl 0 (ESI)+: [M + H]+ = 504.2, 506.2 1349 F CH(CH3)2 Cl 0 (ESI)+: [M + H]+ = 518.2, 520.2 1350 F CH2CH2CH3 Cl 0 C(CH3)3 (ESI)+: [M + H]+ = 498.2, 500.2 1351 F Cl 0 C(CH3)3 (ESI)+: [M + H]+ = 510.4, 512.4 1352 F CH2CH3 Cl 0 C(CH3)3 (ESI)+: [M + H]+ = 484.4, 486.4 1353 F CH(CH3)2 Cl 0 C(CH3)3 (ESI)+: [M + H]+ = 498.4, 500.4 1354 F CH2CH2CH3 Cl 1 CH3 (ESI)+: [M + H]+ = 470.3, 472.3 1355 F Cl 1 CH3 (ESI)+: [M + H]+ = 482.3, 484.3 1356 F CH2CH3 Cl 1 CH3 (ESI)+: [M + H]+ = 456.2, 458.2 1357 F CH(CH3)2 Cl 1 CH3 (ESI)+: [M + H]+ = 470.2, 472.2 1358 F CH2CH2CH3 Cl 2 CH2CH3 (ESI)+: [M + H]+ = 498.3, 500.3 1359 F Cl 2 CH2CH3 (ESI)+: [M + H]+ = 510.3, 512.3 1360 F CH2CH3 Cl 2 CH2CH3 (ESI)+: [M + H]+ = 484.3, 486.3 1361 F CH(CH3)2 Cl 2 CH2CH3 (ESI)+: [M + H]+ = 498.3, 500.3 1362 F Cl 0 (ESI)+: [M + H]+ = 516.2, 518.2 1363 F Cl 0 C(CH3)3 (ESI)+: [M + H]+ = 496.2, 498.2 1364 F Cl 1 CH3 (ESI)+: [M + H]+ = 468.1, 470.2 1365 F Cl 2 CH2CH3 (ESI)+: [M + H]+ = 496.3, 498.3

Compound number R4 MS 1366 E109 (ESI)+: [M + H]+ = 402.4 1367 (APCI)+: [M + H]+ = 522.3

Com- pound num- ber c R12 MS 1368 1 NHCO2C(CH3)3 (ESI)+: [M + H]+ = 543.2, 545.2 E113 1369 1 N(CH3)2 (ESI)+: [M + H]+ = 471.2 1370 1 N(CH3)CO2C(CH3)3 (ESI)+: [M + H]+ = 557.1, 559.1 1371 1 NH2 (ESI)+: [M + H]+ = 443.0 E114 1372 1 NHCH3 (ESI)+: [M + H]+ = 457.1

Compound number R4 MS 1373 E115 (ESI)+: [M + H]+ = 427.2 1374 (APCI)+: [M + H] = 357.3, 359.3 1375 (APCI)+: [M + H]+ = 413.2, 415.2 1376 (APCI)+: [M + H]+ = 399.2, 401.2 1377 CH2CH2CH2CH2CH3 (APCI)+: [M + H]+ = 387.2, 389.2 1378 (APCI)+: [M + H]+ = 427.1, 429.1 1379 (APCI)+: [M + H]+ = 427.1, 429.1 1380 (APCI)+: [M + H]+ = 393.2, 395.2

Com- pound number R1 R10 R13 X2 MS 1381 Me Me S (ESI)+: [M + H]+ = 573.3

Com- pound number R1 R10 R13 X2 MS 1382 E122 Me H NH (APCI)+: [M + H]+ = 542.4 1383 Me Cl NH (ESI)+: [M + H]+ = 576.4 1384 Me Me NH (ESI)+: [M + H]+ = 556.4

Compound number R1 R4 R10 X2 MS 1385 E124 Me H S (APCI)+: [M + H]+ = 432.3 1386 Cl Me S (ESI)+: [M + H]+ = 446.2

Compound number R1 R3 R4 R10 X2 MS 1387 H F CH2CH2CH3 Me NH (ESI)+: [M + H]+ = 435.2

Compound number 1H NMR: δ (ppm) 1314 0.89 (3H, t, J = 7.4 Hz), 1.20-1.53 (3H, m), 1.54-1.70 (2H, m), 1.71- 1.82 (1H, m), 1.80-2.10 (6H, m), 2.14 (2H, t, J = 7.4 Hz), 2.77-3.93 (1H, m), 3.97 (1H, d, J = 14.6 Hz), 4.38 (2H, d, J = 6.2 Hz), 5.70-5.79 (1H, m), 5.86 (1H, d, J = 14.6 Hz), 6.10 (1H, s), 6.34-6.46 (1H, m), 6.62-6.75 (2H, m), 6.95 (2H, d, J = 8.6 Hz), 7.11 (1H, t, J = 7.4 Hz), 7.28 (1H, s) 1315 1.13 (3H, t, J = 7.4 Hz), 1.30-1.54 (3H, m), 1.72-1.80 (1H, m), 1.89- 2.11 (6H, m), 2.19 (2H, q, J = 7.4 Hz), 3.78-3.92 (1H, m), 3.97 (1H, d, J = 14.6 Hz), 4.38 (2H, d, J = 5.7 Hz), 5.69-5.80 (1H, m), 5.87 (1H, d, J = 14.6 Hz), 6.07 (1H, s), 6.38-6.48 (1H, m), 6.62-6.71 (2H, m), 6.94 (2H, d, J = 8.6 Hz), 7.11 (1H, t, J = 7.2 Hz), 7.28 (1H, s) 1316 1.11 (6H, d, J = 6.9 Hz), 1.30-1.49 (3H, m), 1.74-1.80 (1H, m), 1.94- 1.99 (6H, m), 2.31-2.36 (1H, m), 3.79-3.92 (1H, m), 3.97 (1H, d, J = 14.8 Hz), 4.37 (2H, d, J = 5.9 Hz), 5.70-5.81 (1H, m), 5.87 (1H, d, J = 14.8 Hz), 6.10 (1H, s), 6.36-6.43 (1H, m), 6.62-6.70 (2H, m), 6.95 (2H, d, J = 8.9 Hz), 7.10 (1H, t, J = 7.4 Hz), 7.28 (1H, s) 1317 0.72-0.77 (2H, m), 0.92-1.00 (2H, m), 1.25-1.50 (4H, m), 1.74-1.80 (1H, m), 1.95-2.00 (6H, m), 3.78-3.90 (1H, m), 3.97 (1H, d, J = 14.8 Hz), 4.40 (2H, d, J = 5.7 Hz), 5.84-5.94 (2H, m), 6.04 (1H, s), 6.36-6.45 (1H, m), 6.64-6.70 (2H, m), 6.95 (2H, d, J = 8.9 Hz), 7.12 (1H, t, J = 7.7 Hz), 7.28 (1H, s) 1318 0.89 (3H, t, J = 7.4 Hz), 1.59-1.64 (2H, m), 1.74 (9H, s), 2.14 (2H, t, J = 7.7 Hz), 3.97 (1H, d, J = 14.6 Hz), 4.38 (2H, d, J = 5.7 Hz), 5.62- 5.77 (1H, m), 5.85 (1H, d, J = 14.6 Hz), 6.36-6.48 (2H, m), 6.58-6.70 (2H, m), 6.92-7.00 (2H, m), 7.13 (1H, t, J = 7.7 Hz), 7.21 (1H, s) 1319 1.13 (3H, t, J = 7.4 Hz), 1.74 (9H, s), 2.18 (2H, q, J = 7.4 Hz), 3.97 (1H, d, J = 14.6 Hz), 4.39 (2H, d, J = 5.9 Hz), 5.63-5.75 (1H, m), 5.85 (1H, d, J = 14.6 Hz), 6.37-6.45 (2H, m), 6.60-6.70 (2H, m), 6.90-7.00 (2H, m), 7.12 (1H, t, J = 7.4 Hz), 7.22 (1H, s) 1320 1.11 (6H, d, J = 6.7 Hz), 1.74 (9H, s), 2.22-2.40 (1H, m), 3.97 (1H, d, J = 14.8 Hz), 4.38 (2H, d, J = 5.7 Hz), 5.65-5.73 (1H, m), 5.85 (1H, d, J = 14.8 Hz), 6.34-6.48 (2H, m), 6.56-6.70 (2H, m), 6.90-7.00 (2H, m), 7.12 (1H, t, J = 7.7 Hz), 7.22 (1H, s) 1321 0.68-0.81 (2H, m), 0.92-1.01 (2H, m), 1.24-1.35 (1H, m), 1.74 (9H, s), 3.97 (1H, d, J = 14.4 Hz), 4.40 (2H, d, J = 6.2 Hz), 5.77-5.95 (2H, m), 6.36 (1H, s), 6.37-6.48 (1H, m), 6.58-6.70 (2H, m), 6.90-7.03 (2H, m), 7.13 (1H, t, J = 7.2 Hz), 6.22 (1H, s) 1322 1.11 (6H, d, J = 6.9 Hz), 1.47 (3H, t, J = 7.2 Hz), 2.32 (1H, septet, J = 6.9 Hz), 3.99 (1H, d, J = 14.6 Hz), 4.09 (2H, q, J = 7.2 Hz), 4.34 (2H, d, J = 5.9 Hz) 5.79 (1H, s), 5.88 (1H, d, J = 14.6 Hz), 6.14 (1H, s), 6.69-6.71, (2H, m), 6.91-7.11 (5H, m), 7.25-7.26 (1H, m) 1323 0.89 (3H, t, J = 7.4 Hz), 1.48 (3H, t, J = 7.2 Hz), 1.57-1.60, (2H, m), 2.13 (2H, q, J = 7.6 Hz), 3.99 (1H, d, J = 14.6 Hz), 4.09 (2H, q, J = 7.2 Hz), 4.36 (2H, d, J = 5.9 Hz), 5.74 (1H, s), 5.87 (1H, d, J = 14.6 Hz), 6.05 (1H, s), 6.69-6.71 (2H, m), 6.90-6.97 (3H, m), 7.03-7.12 (2H, m), 7.25-7.26 (1H, m) 1324 1.11 (3H, t, J = 7.7 Hz), 1.46 (3H, t, J = 7.2 Hz), 2.18 (2H, q, J = 7.7 Hz), 3.99 (1H, d, J = 14.6 Hz), 4.09 (2H, q, J = 7.2 Hz), 4.35 (2H, d, J = 5.9 Hz), 5.82 (1H, s), 5.88 (1H, d, J = 14.6 Hz), 6.19 (1H, s), 6.69- 6.71 (2H, m), 6.91-7.13 (5H, m), 7.25-7.26 (1H, m) 1325 0.70-0.74 (2H m), 0.91 -0.95 (2H, m), 1.25-1.35 (1H, m), 1.48 (3H, t, J = 7.2 Hz), 3.98 (1H, d. J = 14.6 Hz), 4.09 (2H, q, J = 7.2 Hz), 4.37 (2H, d. J = 5.9 Hz), 5.89 (1H, d, J = 14.6 Hz), 5.96 (1H, s), 6.10 (1H, s), 6.70-6.72, (2H, m), 6.90-7.12 (5H, m), 7.25-7.26 (1H, m) 1326 0.96 (3H, t, J = 7.4 Hz), 1.12 (3H, t, J = 7.4 Hz), 1.33-1.44 (2H, m), 1.79-1.88 (2H, m), 2.10-2.25 (5H, m), 3.95-4.04 (3H, m), 4.27 (2H, d, J = 5.4 Hz), 5.67 (1H, s), 5.90 (1H, d, J = 14.6 Hz), 6.21 (1H, s), 6.68-6.70 (2H, m), 6.83-7.12 (5H, m), 7.24 (1H, s) 1327 0.87-0.99 (6H, m), 1.33-1.44 (2H, m), 1.58-1.67 (2H, m), 1.77-1.87 (2H, m), 2.10-2.16 (5H, m), 3.95-4.04 (3H, m), 4.27 (2H, d, J = 5.7 Hz), 5.65 (1H, s), 5.90 (1H, d, J = 14.6 Hz), 6.18 (1H, s), 6.68- 6.70 (2H, m), 6.86-7.12 (5H, m), 7.24 (1H, s) 1328 0.97 (3H, t, J = 7.2 Hz), 1.12 (6H, d, J = 6.2 Hz), 1.37-1.45 (2H, m), 1.78-1.87 (2H, m), 2.13 (3H, s), 2.30-2.36 (1H, m), 3.95-4.06 (3H, m), 4.28 (2H, d, J = 5.4 Hz), 5.53 (1H, s), 5.91 (1H, d, J = 14.6 Hz), 6.05 (1H, s), 6.68-6.70 (2H, m), 6.85-7.14 (5H, m), 7.24 (1H, s) 1329 0.70-0.74 (2H, m), 0.94-1.00 (5H, m), 1.30-1.45 (3H, m), 1.81-1.87 (2H, m), 2.13 (3H, s), 3.95-4.05 (3H, m), 4.30 (2H, d, J = 5.7 Hz), 5.74 (1H, s), 5.91 (1H, d, J = 14.6 Hz), 6.06 (1H, s), 6.70-6.72 (2H, m), 6.89-6.93 (3H, m), 7.03-7.14 (2H, m), 7.24 (1H, s) 1330 0.96 (3H, t, J = 7.4 Hz), 1.10 (3H, t, J = 7.4 Hz), 1.35-1.44 (2H, m), 1.77-1.85 (2H, m), 2.17 (2H, q, J = 7.4 Hz), 3.96-4.06 (3H, m), 4.33 (2H, d, J = 5.4 Hz), 5.87 (1H, d, J = 14.6 Hz), 5.90 (1H, s), 6.26 (1H, s), 6.68 = 6.70 (2H, m), 6.86-7.10 (5H, m), 7.24 (1H, s) 1331 0.87 (3H, t, J = 7.4 Hz), 0.95 (3H, t, J = 7.4 Hz), 1.35-1.43 (2H, m), 1.56-1.64 (2H, m), 1.76-1.84 (2H, m), 2.09-2.15 (2H, m), 3.96-4.05 (3H, m), 4.33 (2H, d, J = 5.7 Hz), 5.87 (1H, d, J = 14.6 Hz), 5.93 (1H, s), 6.28 (1H, s), 6.68-6.70 (2H, m), 6.86-7.10 (5H, m), 7.24 (1H, s) 1332 0.96 (3H, t, J = 7.2 Hz), 1.09 (6H, d, J = 6.2 Hz), 1.32-1.46 (2H, m), 1.77-1.88 (2H, m), 2.27-2.37 (1H, m), 3.96-4.06 (3H, m), 4.32 (2H, d, J = 5.4 Hz), 5.87 (1H, d, J = 14.6 Hz), 5.90 (1H, s), 6.27 (1H, s), 6.68-6.70 (2H, m), 6.85-7.10 (5H, m), 7.24 (1H, s) 1333 0.70-0.74 (2H, m), 0.94-1.01 (5H, m), 1.29-1.45 (3H, m), 1.78-1.87 (2H, m), 3.96-4.05 (3H, m), 4.36 (2H, d, J = 5.7 Hz), 5.88 (1H, d, J = 14.6 Hz), 5.97 (1H, s), 6.06 (1H, s), 6.70-6.72 (2H, m), 6.89-6.97 (3H, m), 7.03-7.09 (2H, m), 7.24 (1H, s) 1334 0.63-0.80 (2H, m), 0.80-1.08 (2H, m), 1.21-1.45 (1H, m), 4.00 (1H, d, J = 15.1 Hz), 4.40 (2H, d, J = 5.7 Hz), 5.80-5.94 (2H, m), 6.55-6.70 (2H, m), 6.89-7.21 (5H, m), 7.46 (1H, s), 7.80-7.90 (1H, m), 8.04 (1H, d, J = 8.7 Hz), 8.44 (1H, d, J = 4.5 Hz), 11.26 (1H, s) 1335 1.11 (6H, d, J = 6.7 Hz), 2.32 (1H, sept, J = 6.7 Hz), 4.00 (1H, d, J = 14.6 Hz), 4.38 (2H, d, J = 5.7 Hz), 5.62-5.78 (1H, m), 5.92 (1H, d, J = 14.6 Hz), 6.50-6.70 (2H, m), 6.90-7.21 (5H, m), 7.46 (1H, s), 7.83-7.89 (1H, m), 8.04 (1H, d, J = 8.4 Hz), 8.44 (1H, d, J = 4.2 Hz), 11.26 (1H, s) 1336 0.89 (3H, t, J = 7.4 Hz), 1.62 (2H, m), 2.14 (2H, t, J = 7.7 Hz), 4.00 (1H, d, J = 14.6 Hz), 4.39 (2H, d, J = 5.7 Hz), 5.50-5.65 (1H, m), 5.92 (1H, d, J = 14.6 Hz), 6.50-6.70 (2H, m), 6.91 -7.21 (5H, m), 7.46 (1H, s), 7.82-7.91 (1H, m), 8.05 (1H, d, J = 8.4 Hz), 8.44 (1H, d, J = 4.2 Hz), 11.26 (1H, s) 1337 1.12 (3H, t, J = 7.5 Hz), 2.18 (2H, q, J = 7.5 Hz), 4.00 (1H, d, J = 14.8 Hz), 4.39 (2H, d, J = 5.7 Hz), 5.60-5.85 (1H, m), 5.92 (1H, d, J = 14.8 Hz), 6.58-6.69 (2H, m), 6.98-7.20 (5H, m), 7.46 (1H, s), 7.83-7.90 (1H, m), 8.04 (1H, d, J = 8.7 Hz), 8.44 (1H, d, J = 4.7 Hz), 11.26 (1H, s) 1338 1.12 (6H, d, J = 6.7 Hz), 1.47 (3H, t, J = 7.0 Hz), 2.13 (3H, s), 2.33 (1H, sept, J = 6.7 Hz), 3.98 (1H, d, J = 14.9 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.28 (2H, d, J = 5.2 Hz), 5.50-5.60 (1H, m), 5.92 (1H, d, J = 14.9 Hz), 6.10 (1H, s), 6.62-6.76 (2H, m), 6.82-7.00 (3H, m), 7.02-7.10 (1H, m), 7.14 (1H, s) 1339 0.90 (3H, t, J = 7.3 Hz), 1.46 (3H, t, J = 7.2 Hz), 1.54-1.71 (2H, m), 2.06-2.20 (5H, m), 3.97 (1H, d, J = 14.6 Hz), 4.07 (2H, q, J = 7.2 Hz), 4.28 (2H, d, J = 4.9 Hz), 5.56-5.66 (1H, m), 5.86 (1H, d, J = 14.6 Hz), 6.17 (1H, s), 6.62-6.74 (2H, m), 6.84-6.98 (3H, m), 7.02-7.12 (1H, m), 7.13 (1H, s) 1340 1.13 (3H, t, J = 7.7 Hz), 1.47 (3H, t, J = 7.1 Hz), 2.13 (3H, s), 2.19 (2H, q, J = 7.7 Hz), 3.97 (1H, d, J = 14.9 Hz), 4.08 (2H, q, J = 7.1 Hz), 4.28 (2H, d, J = 5.4 Hz), 5.54-5.64 (1H, m), 5.91 (1H, d, J = 14.9 Hz), 6.14 (1H, s), 6.66-6.76 (2H, m), 6.82-6.98 (3H, m), 7.02-7.12 (1H, m), 7.14 (1H, s) 1341 0.68-0.78 (2H, m), 0.94 (2H, s), 1.26-1.38 (1H, m), 1.46 (3H, t, J = 7.2 Hz), 2.13 (3H, s), 3.97 (1H, d, J = 14.6 Hz), 4.07 (2H, q, J = 7.2 Hz), 4.29 (2H, d, J = 5.2 Hz), 5.76-5.86 (1H, m), 5.92 (1H, d, J = 14.6 Hz), 6.18 (1H, s), 6.64-6.74 (2H, m), 6.86-6.96 (3H, m), 7.02-7.12 (1H, m), 7.14 (1H, s) 1342 0.90 (3H, t, J = 7.4 Hz), 1.20-1.71 (5H, m), 1.70 (1H, m), 1.81-2.10 (6H, m), 2.15 (2H, t, J = 7.4 Hz), 3.76-3.90 (1H, m), 3.95 (1H, d, J = 14.4 Hz), 4.39 (2H, d, J = 5.9 Hz), 5.65-5.79 (1H, m), 5.87 (1H, d, J = 14.4 Hz), 6.64 (2H, q, J = 7.2 Hz), 6.58-6.70 (3H, m), 7.12 (1H, t, J = 7.7 Hz), 7.27 (1H, s) 1343 1.12 (6H, d, J = 6.7 Hz), 1.14-1.50 (3H, m), 1.77 (1H, m), 1.81-2.11 (6H, m), 2.28-2.40 (1H, m), 3.73-3.91 (1H, m), 3.95 (1H, d, J = 14.6 Hz), 4.38 (2H, d, J = 6.2 Hz), 5.64-5.76 (1H, m), 5.98 (1H, d, J = 14.6 Hz), 6.64 (2H, q, J = 6.9 Hz), 6.95-6.98 (3H, m), 7.12 (1H, t, J = 7.9 Hz), 7.28 (1H, s) 1344 0.60-0.81 (2H, m), 0.90-1.00 (2H, m), 1.20-1.48 (4H, m), 1.76 (1H, m), 1.82-2.10 (6H, m), 3.73-3.90 (1H, m), 3.95 (1H, d, J = 14.6 Hz), 4.41 (2H, d, J = 6.2 Hz), 5.84-5.90 (2H, m), 6.60-6.72 (2H, m), 6.88- 7.03 (3H, m), 7.12 (1H, t, J = 7.2 Hz), 7.28 (1H, s) 1345 1.13 (3H, t, J = 7.5 Hz), 1.16-1.63 (3H, m), 1.76 (1H, m), 1.85-2.13 (6H, m), 2.22 (2H, q, J = 7.5 Hz), 3.72-3.90 (1H, m), 3.95 (1H, d, J = 15.1 Hz), 4.39 (2H, d, J = 5.9 Hz), 5.66-5.80 (1H, m), 5.86 (1H, d, J = 15.1 Hz), 6.60-6.87 (2H, m), 6.92-7.05 (3H, m), 7.12 (1H, t, J = 7.2 Hz), 7.27 (1H, s) 1346 0.88-0.98 (3H, m), 1.60-1.71 (2H, m), 2.10-2.21 (2H, m), 4.08 (1H, d, J = 14.6 Hz), 4.40 (2H, d, J = 5.4 Hz), 5.70 (1H, brs), 5.95 (1H, d, J = 14.6 Hz), 6.27 (1H, s), 6.62-6.70 (2H, m), 6.80 (1H, s), 6.85-7.08 (2H, m), 7.12-7.19 (1H, m), 7.45-7.65 (6H, m) 1347 1.80-2.02 (2H, m), 2.08-2.30 (4H, m), 2.97 (1H, t, J = 9.2 Hz), 4.01 (1H, d, J = 14.9HZ), 4.39 (2H, d, J = 6.2 Hz), 5.60 (1H, brs), 5.96 (1H, d, J = 14.9 Hz), 6.27 (1H, s), 6.62-6.72 (2H, m), 6.80 (1H, s), 6.96- 7.06 (2H, m), 7.10-7.20 (1H, m), 7.45-7.65 (6H, m) 1348 1.13 (3H, t, J = 7.5 Hz), 2.19 (2H, q, J = 7.5 Hz), 4.04 (1H, d, J = 14.9 Hz), 4.39 (2H, d, J = 5.9 Hz), 5.69 (1H, brs), 5.96 (1H, d, J = 14.9 Hz), 6.27 (1H, s), 6.61-6.71 (2H, m), 6.80 (1H, s), 6.96-7.02 (2H, m), 7.10-7.18 (1H, m), 7.42-7.66 (6H, m) 1349 1.20 (6H, d, J = 6.7 Hz), 2.30-2.40 (1H, m), 4.05 (1H, d, J = 14.6 Hz), 4.39 (1H, d, J = 5.7 Hz), 5.72 (1H, brs), 5.96 (1H, d, J = 14.6 Hz), 6.29 (1H, s), 6.61-6.72 (2H, m), 6.72 (1H, s), 6.95-7.15 (2H, m), 7.10- 7.20 (1H, m), 7.45-7.70 (6H, m) 1350 0.88-1.00 (3H, m), 1.59-1.71 (2H, m), 1.74 (9H, s), 2.12-2.20 (2H, m), 3.95 (1H, d, J = 14.6 Hz), 4.39 (2H, d, J = 5.2 Hz), 5.70 (1H, brs), 5.84 (1H, d, J = 14.6 Hz), 6.36 (1H, s), 6.58-6.62 (2H, m), 6.88-7.02 (3H, m), 7.10-7.20 (1H, m), 7.20-7.22 (1H, s) 1351 1.74 (9H, s), 1.82-2.03 (2H, m), 2.04-2.35 (4H, m), 2.90-3.05 (1H, m), 3.95 (1H, d, J = 14.6 Hz), 4.39 (2H, d, J = 5.9 Hz), 5.59 (1H, brs), 5.85 (1H, d, J = 14.6 Hz), 6.36 (1H, s), 6.60-6.72 (2H, m), 6.90-7.08 (3H, m), 7.10-7.20 (1H, m), 7.25 (1H, s) 1352 1.13 (3H, t, J = 7.4 Hz), 1.74 (9H, s), 2.19 (2H, q, J = 7.4 Hz), 3.98 (1H, d, J = 14.6 Hz), 4.40 (2H, d, J = 5.4 Hz), 5.70 (1H, brs), 5.88 (1H, d, J = 14.6 Hz), 6.36 (1H, s), 6.58-6.70 (2H, m), 6.89-7.04 (3H, m), 7.10-7.20 (1H, m), 7.25 (1H, s) 1353 1.12 (6H, d, J = 6.7 Hz), 1.74 (9H, s), 2.33 (1H, q, J = 6.9 Hz), 3.95 (1H, d, J = 14.9 Hz), 4.39 (2H, d, J = 5.9 Hz), 5.70 (1H, brs), 5.85 (1H, d, J = 14.9 Hz), 6.36 (1H, s), 6.59-6.71 (2H, m), 6.90-7.05 (3H, m), 7.21 (1H, s), 7.25 (1H, s) 1354 0.89 (3H, t, J = 7.4 Hz), 1.48 (3H, t, J = 7.2 Hz), 1.56-1.68 (2H, m), 2.15 (2H, t, J = 7.4 Hz), 3.95 (1H, d, J = 14.8 Hz), 4.06 (2H, q, J = 7.2 Hz), 4.39 (2H, d, J = 5.9 Hz), 5.72-5.80 (1H, m), 5.85 (1H, d, J = 14.8 Hz), 6.11 (1H, s), 6.65 (2H, dd, J = 8.4, 14.1 Hz), 6.89-6.98 (3H, m), 7.12 (1H, t, J = 7.7 Hz), 7.27 (1H, s) 1355 1.45 (3H, t, J = 7.2 Hz), 1.75-2.03 (2H, m), 2.04-2.31 (4H, m), 2.88- 3.07 (1H, m), 3.95 (1H, d, J = 14.6 Hz), 4.07 (2H, q, J = 7.4 Hz), 4.38 (2H, d, J = 5.9 Hz), 5.58-5.72 (1H, m), 5.85 (1H, d, J = 14.6 Hz), 6.17 (1H, s), 6.65 (2H, dd, J = 8.4, 13.6 Hz), 6.88-6.98 (3H, m), 7.10 (1H, t, J = 8.2 Hz), 7.26 (1H, s) 1356 1.13 (3H, t, J = 7.7 Hz), 1.47 (3H, t, J = 7.4 Hz), 2.21 (2H, q, J = 7.7 Hz), 3.98 (1H, d, J = 14.6 Hz), 4.07 (2H, q, J = 7.4 Hz), 4.39 (2H, d, J = 7.4 Hz), 5.70-5.91 (2H, m), 6.17 (1H, s), 6.65 (2H, dd, J = 8.4, 14.1 Hz), 6.88-7.00 (3H, m), 7.11 (1H, t, J = 7.7 Hz), 7.26 (1H, s) 1357 1.12 (6H, d, J = 6.9 Hz), 1.47 (3H, t, J = 7.2 Hz), 2.25-2.43 (1H, m), 3.95 (1H, d, J = 14.6 Hz), 4.06 (2H, q, J = 7.2 Hz), 4.38 (2H, d, J = 5.9 Hz), 5.73-5.92 (2H, m), 6.22 (1H, s), 6.64 (2H, dd, J = 8.1, 12.4 Hz), 6.88-6.99 (3H, m), 7.09 (1H, t, J = 7.7 Hz), 7.26 (1H, s) 1358 0.90 (3H, t, J = 7.4 Hz), 0.98 (3H, t, J = 7.4 Hz), 1.33-1.52 (1H, m), 1.56-1.70 (2H, m), 1.73-1.90 (2H, m), 2.15 (2H, t, J = 7.7 Hz), 3.88- 4.04 (3H, m), 4.39 (2H, d, J = 7.2 Hz), 5.69-5.80 (1H, m), 5.85 (1H, d, J = 14.6 Hz), 6.06 (1H, s), 6.59-6.72 (2H, m), 6.89-7.01 (3H, m), 7.12 (1H, t, J = 7.4 Hz), 7.25 (1H, s) 1359 0.98 (3H, t, J = 7.2 Hz), 1.33-1.48 (2H, m), 1.56 (2H, s), 1.78-2.00 (4H, m), 2.03-2.30 (3H, m), 2.90-3.06 (1H, m), 3.88-4.05 (3H, m), 4.38 (2H, d, J = 5.7 Hz), 5.58-5.68 (1H, m), 5.85 (1H, d, J = 14.6 Hz) 6.06 (1H, s), 6.57-6.70 (2H, m), 6.90-7.02 (3H, m), 7.11 (1H, t, J = 7.7 Hz) 1360 0.97 (3H, t, J = 7.4 Hz), 1.13 (3H, t, J = 7.4 Hz), 1.31-1.49 (2H, m), 1.72-1.91 (2H, m), 2.13-2.28 (2H, m), 3.00-3.15 (1H, m), 3.90-4.10 (3H, m), 4.38 (2H, d, J = 6.2 Hz), 5.83-5.90 (2H, m), 6.20 (1H, s), 6.56-6.70 (2H, m), 6.90-7.03 (3H, m), 7.07-7.14 (1H, m) 1361 0.98 (3H, t, J = 7.4 Hz), 1.12 (6H, d, J = 6.9 Hz), 1.33-1.48 (2H, m), 1.77-1.91 (2H, m), 2.28-2.41 (1H, m), 3.90-4.10 (3H, m), 4.38 (2H, d, J = 5.9 Hz), 5.70-5.90 (2H, m), 6.14 (1H, s), 6.64 (2H, dd, J = 7.9, 12.1 Hz), 6.90-7.00 (3H, m), 7.10 (1H, t, J = 7.2 Hz), 7.25 (1H, s) 1362 0.66-0.78 (2H, m), 0.90-0.99 (2H, m), 1.28-1.52 (2H, m), 4.03 (1H, d, J = 14.6 Hz), 4.40 (2H, d, J = 5.9 Hz), 5.90-6.00 (2H, m), 6.29 (1H, s), 6.60-6.74 (2H, m), 6.80 (1H, d, J = 1.7 Hz), 6.91-7.03 (2H, m), 7.13 (1H, t, J = 7.7 Hz), 7.42-7.66 (5H, m) 1363 0.66-0.78 (2H, m), 0.91-1.00 (2H, m), 1.21-1.46 (2H, m), 1.74 (9H, s), 3.95 (1H, d, J = 14.8 Hz), 4.40 (2H, d, J = 5.7 Hz), 5.85 (1H, d, J = 14.8 Hz), 5.92-6.00 (1H, m), 6.39 (1H, s), 6.59-6.69 (2H, m), 6.89-7.02 (2H, m), 7.13 (1H, t, J = 7.4 Hz), 7.25 (1H, s) 1364 0.67-0.85 (2H, m), 0.94 (2H, s), 1.25-1.55 (5H, m), 3.95 (1H, d, J = 14.6 Hz), 4.07 (2H, q, J = 7.2 Hz), 4.39 (2H, d, J = 5.7 Hz), 5.85 (1H, d, J = 14.6 Hz), 6.11 (1H, s), 6.52 (1H, s), 6.65 (2H, dd, J = 8.6, 13.3 Hz), 6.80-7.00 (3H, m), 7.09 (1H, t, J = 7.2 Hz) 1365 0.67-0.80 (2H, m), 0.86-1.06 (5H, m), 1.28-1.46 (4H, m), 1.75-1.90 (2H, m), 3.89-4.08 (3H, m), 4.39 (2H, d, J = 7.2 Hz), 5.85 (1H, d, J = 14.6 Hz), 5.95-6.07 (1H, m), 6.25 (1H, s), 6.64 (2H, dd, J = 8.4, 13.1 Hz), 6.85-7.00 (3H, m), 7.05-7.15 (1H, m) 1366 0.37-0.11 (2H, m), 0.42-0.47 (2H, m), 0.87-1.10 (1H, m), 1.32- 1.69 (1H, m), 2.16 (3H, s), 2.37-2.43 (2H, m), 3.64 (2H, s), 3.77 (3H, s), 3.99 (1H, d, J = 14.6 Hz), 5.90 (1H, d, J = 14.6 Hz), 6.20-6.34 (1H, m), 6.58-6.72 (2H, m), 6.80-7.09 (4H, m), 7.16 (1H, s), 7.24(1H, d, J = 4.7 Hz) 1367 1.46-1.63 (2H, m), 2.15 (3H, s), 3.64 (2H, s), 3.79 (4H, s), 3.96 (1H, d, J = 14.6 Hz), 5.92 (1H, d, J = 14.6 Hz), 6.07 (1H, s), 6.61-6.73 (2H, m), 6.87-6.96 (2H, m), 6.99-7.10 (2H, m), 7.17 (1H, s), 7.20- 7.30 (4H, m), 7.36-7.48 (1H, m) 1368 1.38 (9H, s), 3.66 (3H, s), 3.70-3.80 (2H, m), 3.94 (1H, d, J = 14.6 Hz), 4.28-4.38 (2H, m), 5.52-5.61 (1H, m), 5.78 (1H, d, J = 14.6 Hz), 6.58 (2H, s), 6.82-7.20 (6H, m), 7.62 (1H, s) 1369 2.23 (6H, s), 2.96 (2H, s), 3.78 (3H, s), 3.95 (1H, d, J = 14.5 Hz), 4.41 (2H, d, J = 5.9 Hz), 5.85 (1H, d, J = 14.5 Hz), 6.44 (1H, s), 6.58- 6.70 (2H, m), 6.90-7.10 (3H, m), 7.11 (1H, t, J = 7.0 Hz), 7.51 (1H, s) 1370 1.38 (9H, s), 2.85 (3H, s), 3.68 (3H, s), 3.84 (2H, s), 3.93 (1H, d, J = 14.6 Hz), 4.30-4.41 (2H, m), 5.78 (1H, d, J = 14.6 Hz), 6.57 (2H, s), 6.75-7.25 (6H, m), 7.70 (1H, s) 1371 3.30 (1H, s), 3.68 (2H, s), 4.00 (3H, s), 4.00-4.10 (1H, m), 4.41 (2H, s), 5.84 (1H, d, J = 15.1 Hz), 6.82-6.92 (2H, m), 7.00 (1H, d, J = 8.9 Hz), 7.26 (1H, t, J = 7.5 Hz), 7.43 (1H, s), 7.95 (1H, s), 8.55- 8.65 (1H, m) 1372 2.70 (3H, s), 3.30 (1H, s), 3.79 (2H, s), 4.01 (3H, s), 4.01-4.10 (1H, m), 4.41 (2H, s), 5.84 (1H, d, J = 15.1 Hz), 6.82-6.96 (2H, m), 6.98-7.06 (2H, m), 7.26 (1H, t, J = 7.7 Hz), 7.44 (1H, s), 7.98 (1H, s), 8.70-8.80 (1H, m) 1373 2.21 (3H, s), 3.43 (3H, s), 4.51 (2H, d, J = 5.7 Hz), 6.40-6.52 (1H, m), 6.87-6.98 (4H, m), 7.17-7.21 (3H, m), 7.28-7.38 (1H, m), 7.42- 7.48 (1H, m), 7.61-7.67 (1H, m), 7.76 (1H, s) 1374 0.68-0.79 (2H, m), 0.92-1.00 (2H, m), 1.27-1.40 (1H, m), 2.21 (3H, s), 3.44 (3H, s), 4.36 (2H, d, J = 5.7 Hz), 5.61-5.68 (1H, m), 6.95- 7.04 (4H, m), 7.18-7.25 (3H, m) 1375 2.12 (3H, s), 3.42 (3H, s), 3.85 (2H, s), 4.31 (2H, d, J = 5.7 Hz), 5.72-5.77 (1H, m), 6.84-6.99 (6H, m), 7.12-7.25 (4H, m) 1376 2.27 (3H, s), 3.44 (3H, s), 4.52 (2H, d, J = 5.7 Hz), 6.00-6.16 (1H, m), 6.92-6.99 (3H, m), 7.04-7.11 (2H, m), 7.21-7.30 (3H, m), 7.45- 7.48 (2H, m) 1377 0.85 (3H, t, J = 7.2 Hz), 1.20-1.37 (4H, m), 1.53-1.70 (2H, m), 2.12- 2.29 (2H, m), 2.21 (3H, s), 3.43 (3H, s), 4.34 (2H, d, J = 5.4 Hz), 5.44-5.54 (1H, m), 6.91-6.99 (4H, m), 7.17-7.24 (3H, m) 1378 2.28 (3H, s), 3.44 (3H, s), 4.57 (2H, d, J = 5.4 Hz), 6.19-6.30 (1H, m), 6.92-7.01 (2H, m), 7.09-7.11 (1H, m), 7.11-7.29 (4H, m), 7.31- 7.42 (3H, m), 7.62-7.70 (1H, m) 1379 2.21 (3H, s), 3.42 (3H, s), 4.50 (2H, d, J = 5.4 Hz), 6.41-6.51 (1H, m), 6.87-7.03 (4H, m), 7.13-7.22 (3H, m), 7.37 (2H, d, J = 6.7 Hz), 7.69 (2H, d, J = 6.7 Hz) 1380 2.23 (3H, s), 3.43 (3H, s), 4.53 (2H, d, J = 5.7 Hz), 6.29-6.42 (1H, m), 6.89-7.07 (4H, m), 7.13-7.25 (3H, m), 7.37-7.50 (3H, m), 7.74- 7.77 (2H, m) 1381 0.87 (9H, s), 1.34-1.41 (2H, m), 1.68-2.10 (7H, m), 2.14 (3H, s), 2.27-2.32 (2H, m), 2.33 (3H, s), 2.74 (3H, s), 2.94-3.18 (4H, m), 3.48-3.55 (1H, m), 4.30 (2H, d, J = 5.4 Hz), 5.12-5.18 (1H, m), 5.51 (1H, s), 6.55 (1H, d, J = 7.9 Hz), 6.67 (1H, d, J = 7.9 Hz), 6.76-6.81 (2H, m), 7.16 (1H, s), 8.16 (1H, s) 1382 0.86 (9H, s), 1.33-1.40 (2H, m), 1.66-1.92 (6H, m), 2.04-2.11 (1H, m), 2.08 (3H, s), 2.24-2.32 (2H, m), 2.45 (3H, s), 2.69-3.43 (5H, m), 4.25 (2H, d, J = 4.4 Hz), 4.98-5.06 (1H, brd), 5.76-5.84 (1H, brd), 6.62 (2H, t, J = 6.4, 13.6 Hz), 6.76-6.85 (2H, m), 7.06 (1H, s), 7.07-7.24 (1H, m), 8.11-8.23 (1H, m), 10.04-10.19 (1H, m) 1383 (CD3OD): 0.89-0.99 (10H, m), 1.48-1.54 (2H, m), 1.77-1.80 (1H, m), 1.80-1.91 (4H, m), 2.15 (3H, s), 2.30-2.43 (1H, m), 2.43 (3H, s), 2.44-2.50 (1H, m), 2.64-2.73 (1H, m), 2.91-3.10 (2H, m), 3.22- 3.39 (4H, m), 4.26, (2H, s), 4.95-5.08 (1H, m), 6.63-6.75 (2H, m), 6.78-6.87 (2H, m), 6.90-7.00 (2H, m), 7.95 (1H, s) 1384 0.75-0.98 (11H, m), 1.33-1.50 (2H, m), 1.51-1.67 (1H, m), 1.68- 1.90, (4H, m), 2.09 (3H, s), 2.11-2.33 (6H, m), 2.36-2.58 (4H, m), 2.77-2.92 (1H, m), 2.93-3.16 (2H, m), 3.17-3.30 (1H, m), 4.14- 4.30 (2H, m), 4.90-5.09 (1H, m), 6.36-6.53 (1H, m), 6.53-6.70 (1H, m), 6.70-6.78 (1H, m), 7.04 (1H, s), 7.20-7.30 (2H, m), 7.88(1Hs) 1385 0.69-0.73 (2H, m), 0.81-0.97 (2H, m), 1.23-1.28 (1H, m), 2.14 (3H, s), 2.73 (3H, s), 3.09-3.19 (2H, m), 3.48-3.60 (1H, m), 4.30 (2H, d, J = 5.4 Hz), 5.13-5.23 (1H, m), 5.72 (1H, brs), 6.67 (2H, m), 6.86 (1H, d, J = 7.9 Hz), 6.95 (1H, m), 7.12-7.24 (2H, m), 8.37 (1H, dd, J = 1.5, 8.1 Hz) 1386 0.68-0.75 (2H, m), 0.93-0.98 (2H, m), 1.25-1.42 (1H, m), 2.16 (3H, s), 2.33 (3H, s), 2.74 (3H, s), 3.04-3.18 (2H, m), 3.48-3.57 (1H, m), 4.32 (2H, d, J = 5.4 Hz), 5.12-5.19 (1H, m), 5.64 (1H, s), 6.55 (1H, d, J = 7.9 Hz), 6.69 (1H, d, J = 7.6 Hz), 6.77 (1H, d, J = 7.6 Hz), 6.86 (1H, d, J = 7.9 Hz), 7.16 (1H, s), 8.16(1H, s) 1387 0.90 (3H, t, J = 7.4 Hz), 1.56-1.70 (2H, m), 2.14 (2H, t, J = 7.2 Hz), 2.25 (3H, s), 2.46 (3H, s), 2.81-2.87 (1H, m), 2.98-3.10 (1H, m), 3.25-3.34 (1H, m), 4.28 (2H, d, J = 5.9 Hz), 4.93-5.00 (1H, m), 6.06 (1H, bs), 6.57-6.84 (6H. m), 7.82 (1H, bs) Compound number 1H NMR: δ(ppm) MS 1388 E48 δ 0.32-0.47 (4H, m), 1.50-1.61 (1H, m), 1.83-2.00 (APCI)+: (2H, m), 2.31-2.52 (4H, m), 2.52-2.73 (4H, m), 3.45 [M + H]+ = (2H, s), 3.76 (3H, s), 3.89-4.06 (3H, m), 5.87 (1H, d, 505.4 J = 14.3 Hz), 6.37 (1H, s), 6.61-6.80 (3H, m), 6.86- 7.00 (2H, m), 7.00-7.13 (2H, m), 7.20 (1H, s) ppm. 1389 E55 δ 1.10-1.35 (4H, m), 1.62-1.82 (4H, m), 2.11 (3H, s), (ESI)+: 2.36-2.50 (2H, m), 2.70-2.90 (2H, m), 3.73 (3H, s), [M + H]+ = 3.80-4.00 (5H, m), 4.50-4.65 (2H, m), 5.87 (1H, d, 530.3 J = 14.6 Hz), 6.60-7.25 (9H, m) ppm. 1390 E68 δ 0.88 (9H, s), 1.22-1.46 (7H, m), 1.64-1.77 (4H, m), (APCI)+: 1.93 (2H, t, J = 10.9 Hz), 2.02 (3H, s), 2.31-2.38 (2H, [M + H]+ = m), 2.95-2.99 (2H, m), 3.78 (3H, s), 3.78-3.92 (2H, 544.6 m), 3.95 (1H, d, J = 14.6 Hz), 5.91 (1H, d, J = 14.6 Hz), 6.16 (1H, s), 6.43-6.49 (1H, m), 6.68-6.73 (2H, m), 6.92-7.11 (4H, m), 7.21 (1H, s) ppm. 1391 E69 δ 0.86 (9H, s), 1.33-1.40 (2H, m), 1.84-1.94 (2H, m), (APCI)+: 2.26-2.33 (2H, m), 2.42 (3H, s), 2.33-2.51 (10H, m), [M + H]+ = 2.85 (1H, d, J = 15.6 Hz), 2.91-3.05 (1H, m), 3.26- 548.4 3.42 (1H, m), 3.91 (2H, t, J = 6.2 Hz), 5.06 (1H, dd, J = 4.2, 12.6 Hz), 6.56 (1H, t, J = 8.2 Hz), 6.62-6.73 (2H, m), 6.83-6.94 (2H, m), 7.18 (1H, t, J = 7.4 Hz), 8.08-8.22 (1H, brs), 10.25-10.55 (1H, brs) ppm. 1392 E70 δ 0.87 (9H, s), 1.37-1.45 (2H, m), 1.83-1.94 (2H, m), (APCI)+: 2.00 (3H, s), 2.29-2.40 (2H, m), 2.43 (3H, s), 2.44- [M + H]+ = 2.63 (10H, m), 2.83 (1H, d, J = 15.3 Hz), 2.91-3.08 544.5 (1H, m), 3.22-3.41 (1H, m), 3.83 (2H, t, J = 5.9 Hz), 5.09 (1H, dd, J = 4.2, 12.9 Hz), 6.35 (1H, d, J = 8.4 Hz), 6.63-6.69 (2H, m), 6.85 (1H, t, J = 7.4 Hz), 7.07 (1H, s), 7.16 (1H, t, J = 7.4 Hz), 8.10 (1H, d, J = 6.4 Hz) ppm. 1393 E71 δ 0.89 (9H, s), 1.42-1.49 (2H, m), 1.88-2.02 (2H, m), (APCI)+: 2.46-2.58 (4H, m), 2.58-2.78 (8H, m), 3.42 (3H, s), [M + H]+ = 4.01 (2H, t, J = 6.2 Hz), 6.72 (1H, t, J = 8.4 Hz), 6.93- 490.3/492.3 6.99 (3H, m), 7.04 (1H, dd, J = 2.0, 11.6 Hz), 7.19- 7.25 (2H, m) ppm. 1394 E72 δ 0.89 (9H, s), 1.42-1.53 (2H, m), 1.58-1.82 (4H, m), (APCI)+: 2.40-2.58 (3H, m), 2.58-2.79 (4H, m), 3.46 (3H, s), [M + H]+ = 3.81 (3H, s), 3.88-3.97 (3H, m), 5.87 (1H, d, 563.4 J = 14.8 Hz), 6.55 (1H, s), 6.60-6.69 (4H, m), 6.93 (1H, d, J = 11.4 Hz) 6.99-7.12 (4H, m), 7.21 (1H, s) ppm. 1395 E73 δ 0.88 (9H, s), 1.32-1.46 (2H, m), 1.47-1.83 (2H, m), (ESI)+: 2.03 (3H, s), 2.30-2.40 (2H, m), 2.40-2.57 (2H, m), [M + H]+ = 2.57-2.69 (2H, m), 2.80 (2H, t, J = 4.9 Hz), 3.80 (3H, 531.4 s), 3.95-4.08 (2H, m), 5.91-6.01 (2H, m), 6.50 (1H, d, J = 7.7 Hz), 6.63-7.78 (2H, m), 6.92 (1H, d, J = 7.9 Hz), 6.92-7.01 (1H, m), 7.06-7.18 (2H, m), 7.21-7.28 (3H, m) ppm. 1396 E74 δ 0.86 (9H, s), 1.33-1.39 (2H, m), 2.09 (3H, s), 2.24- (ESI)+: 2.37 (6H, m), 3.50-3.60 (4H, m), 3.75 (3H, s), 3.95 [M + H]+ = (1H, d, J = 14.6 Hz), 4.60 (2H, s), 5.91 (1H, d, 545.4 J = 14.6 Hz), 6.10 (1H, s), 6.51 (1H, d, J = 8.1 Hz), 6.70 (2H, s), 6.88-6.99 (2H, m), 7.01-7.10 (1H, m), 7.20- 7.24 (2H, m) ppm. 1397 E75 δ 0.88 (9H, s), 1.37 (2H, t, J = 8.4 Hz), 2.24-2.37 (6H, (ESI)+: m), 3.50-3.60 (4H, m), 3.75 (3H, s), 3.95 (1H, d, [M + H]+ = J = 14.6 Hz), 4.60 (2H, s), 5.93 (1H, d, J = 14.6 Hz), 531.5 6.39 (1H, s), 6.61-6.73 (4H, m), 6.93 (1H, d, J = 7.9 Hz), 7.01-7.10 (1H, m), 7.20-7.24 (2H, m) ppm. 1398 E76 δ 0.87 (9H, s), 1.30-1.36 (2H, m), 1.86-1.91 (2H, (ESI)+: m), 1.99 (3H, s), 2.22-2.28 (6H, m), 2.40-2.45 (2H, [M + H]+ = m), 3.34-3.39 (4H, m), 3.77 (3H, s), 3.84-3.90 (3H, 573.5 m), 5.68 (2H, d, J = 14.3 Hz), 6.63-6.69 (3H, m), 6.91 (1H, d, J = 8.4 Hz), 7.01 (1H, s), 7.13-7.16 (2H, m), 7.30 (1H, d, J = 8.2 Hz), 8.60 (1H, s) ppm. 1399 E77 δ 1.18-1.38 (2H, m), 1.48-1.76 (2H, m), 1.87 (2H, t, (ESI)+: J = 10.6 Hz), 2.15 (3H, s), 2.42-2.48 (2H, m), 2.71- [M + H]+ = 2.88 (4H, m), 2.91-3.01 (1H, m), 3.78 (3H, s), 3.86- 488.4 3.90 (2H, m), 3.95 (1H, d, J = 14.6 Hz), 5.90 (1H, d, J = 14.6 Hz), 6.68 (2H, brs), 6.79-6.96 (3H, m), 7.02- 7.10 (1H, m), 7.13-7.24 (2H, m) ppm. 1400 E78 δ 2.15 (3H, s), 3.72 (3H, s), 3.75 (3H, s), 3.96 (1H, (APCI)+: d, J = 14.6 Hz), 4.50 (2H, s), 5.80 (1H, d, J = 14.6 Hz), [M + H]+ = 6.12 (1H, s), 6.45-6.51 (2H, m), 6.64 (1H, s), 6.74- 441.2, 6.92, (3H, m), 7.23(1H, s) 443.2 1401 E79 δ 0.42-1.38 (3H, m), 2.16 (3H, s), 2.28-2.66 (4H, m), (ESI)+: 2.71-3.01 (4H, m), 3.28-3.76 (4H, m), 3.78 (3H, s), [M + H]+ = 3.96 (1H, d, J = 14.6 Hz), 4.60-4.73 (1H, m), 5.89 488.5 (1H, d, J = 14.6 Hz), 6.15 (1H, d, J = 9.1 Hz), 6.71 (2H, s), 6.77-6.98 (3H, m), 7.01-7.21 (3H, m) ppm. 1402 E80 δ 0.88 (9H, s), 1.33-1.40 (2H, m), 2.17-2.58 (11H, (ESI)+: m), 2.79-2.98 (2H, m), 3.18-3.41 (5H, m), 3.60 (2H, [M + H]+ = brs), 3.87 (3H, s), 3.88-4.01 (1H, m), 5.92-6.11 (1H, 557.5 m), 6.78-7.42 (8H, m) ppm. 1403 E82 δ 0.89 (9H, s), 1.35-1.41 (2H, m), 1.64 (2H, brs), (ESI)+: 1.74-1.84 (2H, m), 2.14 (3H, s), 2.23 (2H, t, [M + H]+ = J = 7.4 Hz), 2.28-2.38 (6H, m), 2.54 (2H, t, J = 7.4 Hz), 506.5 3.34 (2H, t, J = 4.9 Hz), 3.59 (2H, t, J = 4.9 Hz), 6.58- 6.78 (4H, m), 6.81-6.92 (1H, m), 7.04-7.09 (3H, m) ppm. 1404 E83 δ 0.87 (9H, s), 1.30-1.70 (4H, m), 2.09 (3H, s), 2.20- (ESI)+: 2.50 (10H, m), 3.41 (2H, brs), 3.58 (4H, brs), 3.74 [M + H]+ = (3H, s), 3.88-3.98 (1H, m), 5.85-5.95 (1H, m), 6.60- 571.5 7.22 (9H, m) ppm. 1405 E84 δ 1.08-1.47 (2H, m), 1.61-1.86 (4H, m), 2.15 (3H, s), (ESI)+: 2.35-2.48 (2H, m), 2.78-2.84 (2H, m), 2.94-3.11 [M + H]+ = (2H, m), 3.44-3.62 (1H, m), 3.77 (3H, s), 3.72-3.88 474.5 (1H, m), 3.95 (1H, d, J = 14.6 Hz), 4.01-4.12 (1H, m), 5.89 (1H, d, J = 14.6 Hz), 6.34 (1H, d, J = 4.7 Hz), 6.66- 6.71 (2H, m), 6.76-6.94 (3H, m), 7.01-7.18 (2H, m) ppm. 1406 E85 δ 1.36-1.55 (6H, m), 1.71-1.80 (2H, m), 1.82-1.96 (ESI)+: (1H, m), 2.02-2.10 (4H, m), 2.68 (3H, s), 2.97-3.10 [M + H]+ = (2H, m), 3.40-3.55 (4H, m), 3.63 (3H, s), 3.81 (1H, 513.8 d, J = 14.6 Hz), 5.83 (1H, d, J = 14.6 Hz), 6.42-6.56 (1H, m), 6.61-6.89 (2H, m), 6.95-7.05 (1H, m), 7.17- 7.25 (3H, m), 7.33 (1H, s) ppm. 1407 E86 δ 0.20-0.27 (2H, m), 0.31-0.42 (2H, m), 0.83-1.10 (ESI)+: (2H, m), 1.44-1.83 (4H, m), 2.02-2.10 (1H, m), 2.13 [M + H]+ = (3H, s), 2.29-2.58 (6H, m), 2.71-2.89 (2H, m), 3.55- 527.7 3.74 (2H, m), 3.75 (3H, s), 3.95 (1H, d, J = 14.6 Hz), 4.50-4.60 (1H, m), 5.90 (1H, d, J = 14.6 Hz), 6.48- 6.75 (3H, m), 6.79-7.22 (5H, m) ppm. 1408 E87 δ 0.55-0.64 (2H, m), 0.71-0.81 (2H, m), 1.11-1.24 (ESI)+: (2H, m), 1.53-1.62 (2H, m), 1.70-1.91 (1H, m), 2.15 [M + H]+ = (3H, s), 2.62-2.84 (4H, m), 3.12-3.25 (4H, m), 3.86 527.6 (3H, s), 3.90-4.15 (5H, m), 5.67 (1H, d, J = 14.6 Hz), 6.61-6.75 (2H, m), 6.76-6.94 (2H, m), 7.07-7.17 (2H, m), 7.35-7.43 (1H, m), 7.47 (1H, s) ppm. 1409 E110 δ 1.91-1.99 (1H, m), 3.32 (2H, s), 3.52-3.85 (8H, (ESI)+: m), 3.93 (1H, d, J = 14.6 Hz), 5.81 (1H, d, J = 14.6 Hz), [M + H]+ = 6.59 (2H, s), 6.80-7.10 (4H, m), 7.10-7.38, (2H, m) 530.2, ppm 532.2 1410 E111 δ 3.47 (4H, s), 3.67 (6H, s), 3.79 (3H, s), 3.87 (2H, (ESI)+: s), 3.95 (1H, d, J = 14.6 Hz), 5.85 (1H, d, J = 14.6 Hz), [M + H]+ = 6.14 (1H, s), 6.60-6.70 (2H, m), 6.90-7.02 (3H, m), 458.1 7.20-7.38 (2H, m) ppm 1411 E112 δ 1.28 (1H, s), 2.71 (2H, t, J = 5.3 Hz), 3.64 (2H, t, (ESI)+: J = 5.3 Hz), 3.81 (3H, s), 3.95 (2H, s), 4.00 (1H, d, [M + H]+ = J = 14.7 Hz), 5.74 (1H, d, J = 14.7 Hz), 6.66 (1H, d, 430.1 J = 8.3 Hz), 6.78 (1H, d, J = 8.3 Hz), 7.02-7.10 (2H, m), 7.22-7.38(3H, m) ppm 1412 E116 (270 MHz, d4-MeOH): δ 0.37-0.48 (2H, m), 0.70- (APCI)+: 0.81 (2H, m), 1.02-1.18 (1H, m), 1.86-2.11 (4H, m), [M + H]+ = 2.22 (3H, s), 2.49-2.64 (1H, m), 3.01 (2H, d, J = 7.4 454.3/456.3 Hz), 3.17-3.30 (2H, m), 3.42 (3H, s), 3.49-3.76 (2H, m), 4.30 (2H, s), 7.06-7.17 (5H, m), 7.23-7.27 (2H, m)ppm. 1413 E117 δ 0.91 (9H, s), 1.48-1.58 (2H, m), 1.60-1.79 (4H, (ESI)+: m), 2.16 (3H, s), 2.22-2.35 (1H, m), 2.51-2.65 (2H, [M + H]+ = m), 2.71-2.82 (2H, m), 3.11-3.27 (2H, m), 3.43 (3H, 484.4/486.4 s), 4.25 (2H, d, J = 5.5 Hz), 6.52-6.63 (1H, m), 6.95- 7.09 (5H, m), 7.20 (2H, d, J = 8.6 Hz) ppm. 1414 E118 δ 0.87 (9H, s), 1.34-1.41 (2H, m), 1.62-1.96 (6H, (APCI)+: m), 2.04-2.19 (1H, m), 2.17 (3H, s), 2.26-2.33 (2H, [M + H]+ = m), 2.94-2.99 (2H, m), 3.48 (3H, s), 4.34 (2H, d, 518.4 J = 5.4 Hz), 6.95 (2H, d, J = 1.0 Hz), 7.14 (2H, d, J = 8.2 Hz), 7.19 (1H, s), 7.49 (2H, d, J = 8.4 Hz) ppm. 1415 E119 δ 0.64-0.73 (2H, m), 0.90-1.00 (2H, m), 1.25-1.40 (ESI)+: (1H, m), 2.12 (3H, s), 2.55 (3H, s), 2.80-2.90 (1H, [M + H]+ = m), 2.90-2.94 (1H, m), 3.45 (1H, s), 4.30 (2H, d, 416.3 J = 5.4 Hz), 5.09-5.22 (1H, m), 5.77-5.88 (1H, m), 6.60-6.73 (2H, m), 6.86-6.93 (2H, m), 7.01 (1H, s), 7.14-7.24 (1H, m), 7.76 (1H, dd, J = 1.2, 7.9 Hz) ppm. 1416 E120 δ 0.87 (9H, s), 1.36-1.45 (2H, m), 1.73-1.82 (2H, m), (APCI)+: 1.90-2.07 (2H, m), 2.11 (3H, s), 2.36-2.42 (2H, m), 2.55 [M + H]+ = (3H, s), 2.80-2.90 (1H, m), 2.90-2.98 (1H, m), 3.10-3.16 543.4 (2H, m), 4.28 (2H, d, J = 5.2 Hz), 5.11-5.19 (1H, m), 5.72- 5.82 (1H, m), 6.49 (2H, dd, J = 1.5, 6.7 Hz), 6.61-6.72 (2H, m), 6.80-6.97 (2H, m), 7.00 (1H, s), 7.13-7.25 (1H, m), 7.77 (1H, dd, J = 1.5, 7.9 Hz), 8.15 (2H, dd, J = 1.7, 5.2 Hz) ppm. 1417 E121 δ 0.88 (9H, s), 1.37-1.53 (5H, m), 1.63-1.70 (2H, (APCI)+: m), 2.11 (3H, s), 2.45 (3H, s), 2.63-3.46 (8H, m), [M + H]+ = 2.87-2.94 (2H, m), 4.23 (2H, brd), 5.08 (2H, d, 632.4 J = 7.9 Hz), 4.96-5.11 (1H, m), 6.60 (2H, t, J = 7.9, 15.1 Hz), 6.81-6.86 (2H, m), 6.95 (2H, d, J = 7.9 Hz), 7.04 (1H, s), 7.12-7.33 (4H, m), 8.22 (1H, dd, J = 1.2, 7.9 Hz) ppm. 1418 E123 δ 0.64-0.71 (2H, m), 0.89-0.95 (2H, m), 1.33-1.39 (APCI)+: (1H, m), 2.10 (3H, s), 2.43 (3H, s), 2.74-2.81 (1H, [M + H]+ = m), 2.92-3.04 (1H, m), 3.07-3.26 (1H, m), 4.18-4.34 415.3 (2H, m), 4.97-5.05 (1H, m), 6.60 (2H, d, J = 7.9 Hz), 6.79-6.84 (2H, m), 7.05 (1H, s), 7.11 (1H, t, J = 7.4, 14.8 Hz), 7.96-8.21 (1H, brs), 10.10-10.60 (1H, brs) ppm. 1419 E125 δ 1.13 (6H, d, J = 6.9 Hz), 2.15 (3H, s), 2.30-2.40 (1H, (ESI)+: m), 2.48 (3H, s), 2.86-3.03 (2H, m), 3.20-3.38 (1H, [M + H]+ = m), 4.20-4.36 (2H, m), 5.04-5.11 (1H, m), 5.63 (1H, 451.2, s), 6.53 (1H, d, J = 8.2 Hz), 6.62 (1H, d, J = 7.9 Hz), 453.2 6.70-6.90 (2H, m), 7.10 (1H, s), 8.21 (1H, s), 9.39 (1H, s) ppm.

Claims

1-73. (canceled)

74. A method of treatment of a disorder selected among dysmenorrhoea, pre-term labour, hypertension, Raynaud's disease, brain oedema, motion sickness, hyperlipemia, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure, comprising the administration to a person in need of such treatment of an effective amount of a compound according to general formula 1a, or a compound which is a tautomer or a pharmaceutically acceptable salt thereof, wherein G is a group selected among general formula 2a, 3a, 4a, 5a, and 6a, wherein:

A1 is selected among CH2, CH(OH), NH, N-alkyl, O and S;
A2 is selected among CH2, CH(OH), C(═O) and NH;
A3 and A12 are independently selected among S, NH, N-alkyl, —C(R8)═CH—, —C(R8)═N—, —N═C(R8)— and —CH═C(R8)—;
A4 and A13 are independently selected among C(R9) and N;
A5 and A14 are independently selected among C(R10) and N;
A6 is selected among CH2, NH, N-alkyl and O;
A7 and A11 are independently selected among C and N;
A8 and A9 are independently selected among CH, N, NH, N(CH2)bR11 and S;
A10 is selected among —CH═CH—, CH, N, NH, N—(CH2)b—R11 and S;
wherein the ring constituted by A7, A8, A9, A10 and A11 is aromatic;
R1, R2 and R3 are independently selected among H, alkyl, O-alkyl, NO2, F, Cl and Br;
R4 is selected among H, alkyl, aryl, heteroaryl, —(CH2)c—R12 and
R5 and R6 are independently selected among alkyl, aryl, —(CH2)f-aryl and —CH2)f-heteroaryl;
R7 is selected among H, alkyl, heteroaryl and —(CH2)g—R14;
R8, R9 and R10 are independently selected among H, alkyl, alkoxy, F, Cl, Br, CN, NH2, NO2, NH(alkyl), N(alkyl)2:
with the provisos that when G is 3a, and R4 is H, alkyl, aryl, heteroaryl or —(CH2)c—R2, then the ring containing A3, A4 and A5 is substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, NHS, NO2, NH(alkyl) or N(alkyl)2; and
when G is 4a, R4 is H, alkyl, aryl, heteroaryl or —(CH2)c—R12, and A8 is NH, NCH3 or S, then the ring containing A3, A4 and A5 is substituted in at least one position by alkyl, alkoxy, F, Cl, Br, CN, or NH2, NO2, NH(alkyl) or N(alkyl)2;
R11 and R12 are independently selected among H, alkyl, aryl; heteroaryl, F, OH, O-alkyl, S-alkyl, O-acyl NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)-acyl, CO2H, CO2-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, CN and CF3;
R13 is selected among H, alkyl, aryl, heteroaryl, —(CH2)h—R15 and Z—R16;
R14 and R15 are independently selected among H, alkyl, alkenyl, aryl, heteroaryl, F, OH, O-alkyl, S-alkyl, O-acyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)-acyl, CO2H, CO2-alkyl, CO-alkyl, CO-aryl, CONH2, CONH-alkyl, CON(alkyl)2, alkenyl-CO2-alkyl, alkenyl-aryl, CN and CF3;
R16 is selected among H, alkyl, alkenyl, aryl, heteroaryl, O-aryl, —(CH2)i—R17, cyclopropyl-aryl and O—(CH2)i—R17;
R17 is selected among H, alkyl, aryl, heteroaryl, F, OH, O-alkyl, S-alkyl, O-acyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)-acyl, CO2H, CO2-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, CN and CF3;
W is selected among O and NH;
X is selected among (CH2)m, C(═O) and S(═O)j;
Y is selected among O, S, NH and N-alkyl;
Z is selected among —C(═O), —C(═O)—O and —S(═O)k;
a is selected among 1 and 2;
b and c are independently selected among 0, 1, 2 and 3;
d, e and f are independently selected among 1 and 2;
g, h and i are independently selected among 1, 2 and 3;
j and k are independently selected among 1 and 2; and
m and n are independently selected among 0, 1 and 2.

75. The method of claim 74, wherein G is selected among:

76. The method of claim 74, wherein G is selected among:

77. The method of claim 74, wherein at least one of R1, R2 and R3 is other than hydrogen.

78. The method of claim 77, wherein one of R1, R2 and R3 is selected among methyl, chlorine and fluorine, and the others are hydrogen

79. The method of claim 74, wherein W is NH.

80. The method of claim 74, wherein R4 is alkyl.

81. The method of claim 74, wherein d is 2 and e is 2.

82. The method of claim 74, wherein R13 is alkyl.

83. The method of claim 74, wherein n is 0.

84. The method of claim 74, wherein R2 is H, R4 is a piperidine where d is 2 and e is 2, W is NH, X is C(═O) and n is 0, as shown in formula 18a: wherein R1 is selected among methyl, chlorine and fluorine, and R3 is H; or R1 is H, and R3 is selected among methyl, chlorine and fluorine, and R13 is alkyl.

85. The method of claim 74, wherein X is C(═O), n is 0 and R4 is a piperidine where d is 2 and e is 2, as shown in formula 19a: wherein G is selected among general formulae 7a to 17a, and R13 is alkyl:

86. The method of claim 74, wherein R2 is H and W is NH as shown in formula 20a: wherein either R1 is selected among methyl, chlorine and fluorine, and R3 is H; or R1 is H, and R3 is selected among methyl, chlorine and fluorine; and G is selected from general formulae 7a to 17a:

87. The method of claim 74, wherein R2 is H, W is NH and X is C(═O) as shown in formula 21a: wherein R1 is selected among methyl, chlorine and fluorine, and R3 is H; or R1 is H, and R3 is selected among methyl, chlorine and fluorine; and R4 is alkyl.

88. The method of claim 74, wherein X is C(═O) as shown in formula 22a: wherein G is selected among general formulae 7a to 17a, and R4 is alkyl:

89. The method of claim 74, wherein R2 and R3 are both H, W is NH and X is C(═O) as shown in formula 23a: wherein G is selected among general formulae 9a, 10a, 15a, 16a and 17a, R1 is selected among methyl, chlorine and fluorine, and R4 is alkyl:

90. The method of claim 74, wherein R2 and R3 are both H, R4 is a piperidine where d is 2 and e is 2, W is NH, X is C(═O) and n is 0 as shown in formula 24a: wherein G is selected among general formulae 9a, 10a, 15a, 16a and 17a, R1 is selected among methyl, chlorine and fluorine, and R13 is alkyl:

91. The method of claim 74, wherein the compound is selected among the group consisting of:

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo-[f]azulene-9-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-methyl-4-(2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulene-6-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 3-chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 3-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 3-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo-[f]azulene-9-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide;
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-[(4-chloro-phenyl)-methyl-carbamoyl]-2-methyl-benzylamide;
1-Cyclopropyl-methyl-piperidine-4-carboxylic acid 2-chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 3-chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 3-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 3-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide;
1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-[(4-chloro-phenyl)-methyl-carbamoyl]-2-methyl-benzylamide;
Cyclobutanecarboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
Cyclobutanecarboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;
Cyclobutanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;
Cyclopentanecarboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
Cyclopentanecarboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;
Cyclopentanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;
Cyclopropanecarboxylic acid 2-chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
Cyclopropanecarboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
Cyclopropanecarboxylic acid 3-chloro-4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
Cyclopropanecarboxylic acid 3-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;
Cyclopropanecarboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;
Cyclopropanecarboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;
Cyclopropanecarboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide;
Cyclopropanecarboxylic acid 4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide;
Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;
Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide;
Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;
Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide;
N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-propionamide;
N-[-2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-2,2-dimethyl-propionamide;
N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-isobutyramide;
N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-butyramide;
N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-propionamide;
N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-2,2-dimethyl-propionamide;
N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-isobutyramide;
N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-butyramide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-propionamide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-2,2-dimethyl-propionamide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-isobutyramide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-acetamide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-butyramide;
N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-formamide;
N-[4-(6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-propionamide;
Cyclopropane-carboxylic acid 4-(6-chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;
N-[2-Fluoro-4-(6-fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-propionamide;
N-[2-Fluoro-4-(6-fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-isobutyramide;
Cyclopropanecarboxylic acid 2-fluoro-4-(6-fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; and
N-[4-(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzyl]-isobutyramide.
Patent History
Publication number: 20120101082
Type: Application
Filed: Dec 19, 2011
Publication Date: Apr 26, 2012
Inventors: ANDRZEJ ROMAN BATT (SOUTHAMPTON), MARTIN LEE STOCKLEY (LORDSHILL), MICHAEL BRYAN ROE (SOUTHAMPTON), CELINE Marguerite Simone HEENEY (PORTSWOOD), ANDREW JOHN BAXTER (WOODLEY), PETER HUDSON (COPENHAGEN S), RACHEL HANDY (HAMPSHIRE)
Application Number: 13/329,476