EA040222B1 - Benzazepine derivatives - Google Patents

Description

The field of technology to which the invention belongs

The present invention relates to benzodiazepine derivatives and their salts. The present invention also relates to medicaments containing a benzadiazepine derivative and a salt thereof as an active ingredient, useful for the diagnosis, prevention and/or treatment of diseases associated with vasopressin receptors.

Prerequisites for the creation of the invention

Vasopressin is an antidiuretic hormone and is known to function in a way that raises blood pressure. The vasopressin V _1a receptor and the vasopressin V ₂ receptor are known as a subgroup of vasopressin receptors, each associated with vasoconstriction and water reabsorption in the collecting duct.

Tolvaptan has a benzoheterocyclic structure and is used to treat various diseases, especially as a vasopressin V ₂ receptor antagonist. It is known to be primarily metabolized by the hepatic metabolizing enzyme CYP3A4 (NPL 1-3). It is known that various compounds have a benzoheterocyclic structure (PTL 1-9), but among the benzoheterocycles there are no compounds containing difluoro and hydroxy groups in positions 4 and 5 of the benzazepine ring, respectively, which have an antagonistic effect against vasopressin as antagonists and vasopressin receptor V _1a , and vasopressin receptor V ₂ .

List of cited literature

Patent Literature

[PTL 1] W02011/052519

[PTL 2] JP 10-120592 A

[PTL 3] JP 9-221476 A

[PTL4] WO 1994/04525

[PTL5] WO 1994/01113

[PTL6] JP 4-321669 A

[PTL 7] WO 1991/05549

[PTL 8] WO 1995/34540

[PTL9] WO 1994/08582

Non-Patent Literature

[NPL 1] Shoaf S.E. et al., BrJ Clin Pharmacol. 2011, 73: 579-87

[NPL 2] Sorbera L.A. et al., Drugs of the Future. 2002, 27(4): 350-357

[NPL 3] Furukawa M. et al., Arch. Pharm. Res. 2014 37: 1578-87

Brief description of the essence of the invention Technical problem

The aim of the present invention is to provide novel benzazepine compounds or salts thereof having vasopressin V _1a and V ₂ receptor antagonistic activity and favorable metabolic stability and absorption capacity, and in medical applications of said compounds.

The solution of the problem

After extensive research, the inventors of the present invention came to the development of new benzazepine compounds and their salts having vasopressin antagonistic action and favorable metabolic stability and absorption capacity. The present invention has been realized on the basis of these discoveries.

According to one embodiment, the present invention relates to a benzazepine compound of formula (1) wherein R ¹ is deuterium or C _1-6 alkyl optionally substituted with 1-3 OH groups;

L is a direct bond or -C(=O)-NH-;

Ring A ¹ is a phenyl ring or a partially unsaturated or unsaturated 5-15-membered monocyclic, bicyclic or tricyclic heterocycle containing from 1 to 5 heteroatoms as ring atoms independently selected from the group consisting of nitrogen, oxygen and sulfur,

Ring A ² is a phenyl ring or a partially unsaturated or unsaturated 5-15-membered monocyclic, bicyclic or tricyclic heterocycle containing from 1 to 5 heteroatoms as ring atoms independently selected from the group consisting of nitrogen, oxygen and sulfur;

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Ring A ¹ may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C _1-6 alkyl, optionally substituted C ₁ - ₆ alkyl-O—, halo and oxo; And

Ring A ² may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyl-O-, optionally substituted C3-6 cycloalkyl, halogen, oxo, optionally substituted phenyl, and optionally substituted pyridyl , with the proviso that when Ring A ² contains more than one substituent on the ring carbon atoms, the substituents can be combined together with the carbon atoms to form C3-6 cycloalkyl; where in Ring A ¹ each substituent of optionally substituted C _1-6 alkyl or optionally substituted C _1-6 alkyl-O- independently represents 1-3 identical or different groups selected from the group consisting of halogen and C _1-6 alkyl- O-;

in Ring A ² each substituent of optionally substituted C _1-6 alkyl or optionally substituted C _1-6 αkyl-O- is independently the same or different 1-3 halogens, the substituent of optionally substituted C ₃ .6 cycloalkyl is 1-3 the same or different 1-3 halogen, the optionally substituted phenyl substituent is 1-3 groups independently selected from the group consisting of halogen, C _1-6 alkyl and C ₁ _ ₆ αkyl-O-, and the optionally substituted pyridyl substituent is the same or different 1-3 halo, or a salt thereof (referred to hereinafter as the compound of the present invention).

Advantageous Effects of the Present Invention

The compound of the present invention with vasopressin antagonistic activity as both vasopressin V _1a receptor and vasopressin V ₂ receptor antagonists can be useful for the treatment, prevention and/or diagnosis of various diseases associated with vasopressin receptors. The compound according to the present invention may also have favorable metabolic stability with the possibility of increasing the duration of pharmacological effects and have a favorable absorption capacity.

Description of Embodiments

Examples of the terms halogen and halogen as used herein include fluorine, chlorine, bromine, and iodine. A preferred example is fluorine or chlorine.

Examples of the term C _1-6 alkyl as used herein include straight or branched alkyl groups having 1 to 6 carbon atoms, and more specifically include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and 3-methylpentyl.

The term halo-C _1-6 alkyl as used herein is C _1-6 alkyl substituted with the same or different 1-7, preferably 1-3, halogens, and includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2- chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2,2,2trifluoroethyl, 2,2,2-trifluoro-1-methylethyl, pentafluoroethyl, 2-trifluoromethylpropyl and 4-fluorobutyl.

Examples of the term C _3-6 cycloalkyl as used herein include saturated cyclic alkyl groups having 3 to 6 ring carbon atoms, and more specifically include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Examples of the term hydrocarbon ring as used herein include saturated and unsaturated 3-15 membered monocyclic, bicyclic or tricyclic hydrocarbon rings. Examples of a hydrocarbon ring include:

(a) saturated 3-8-membered, preferably 5- or 6-membered, monocyclic hydrocarbon rings; more specifically cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and benzene; and (b) saturated or unsaturated 7-15 membered bicyclic or tricyclic hydrocarbon rings, preferably saturated or unsaturated 7-12 membered bicyclic hydrocarbon rings; more specifically indene, dihydroindene, naphthalene, dihydronaphthalene, tetrahydronaphthalene, anthracene and phenanthrene.

Examples of the term heterocycle as used herein include saturated or unsaturated monocyclic or polycyclic heterocycles containing at least, for example, 1 to 5 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and include, for example, saturated or unsaturated 3-15 membered monocyclic, bicyclic or tricyclic heterocycles. Any ring in a bicyclic or tricyclic heterocycle may contain a heteroatom, or all rings contain a heteroatom. The term unsaturated ring refers to an aromatic ring or a saturated ring containing a partially unsaturated bond. Preferred heterocycles are saturated or unsaturated 5- to 10-membered heteromonocycles or heterobicycles containing at least one ring nitrogen atom. The ring atom in the heterocycle can be substituted with oxo to form an oxide. The term heterocycle includes, for example:

(a) saturated or unsaturated 3-8-membered, preferably 3-6-membered, more preferably 5- or 6-membered heteromonocycles containing at least one, for example 1 to 4,

- 2 040222 preferably 1 or 2 nitrogen atoms as ring heteroatoms; more specifically pyrrole, imidazole, pyrazole, pyridine, tetrahydropyridine, pyrimidine, pyrazine, pyridazine, triazole, tetrazol, dihydrotriazine, azetidine, pyrrolidine, imidazolidine, piperidine, pyrazolidine, piperazine, azepane and 1,4-diazepane;

(b) saturated or unsaturated 7-15-membered bicyclic or tricyclic heterocycles containing at least one, for example 1 to 5, nitrogen atoms as ring heteroatoms, preferably saturated or unsaturated 7-12-membered bicyclic or tricyclic heterocycles, containing from 1 to 3 nitrogen atoms as ring heteroatoms; more specifically indole, indoline (dihydroindole), isoindole, isoindoline (dihydroisoindole), benzimidazole, dihydrobenzimidazole, indazole, indazoline (dihydroindazole), quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, benzotriazole, tetrazolopyridine, tetrazolopyridazine, dihydrotriazolopyridazine, imidazolopyridazine, , naphthyridine, tetrahydronaphthyridine, hexahydronaphthyridine, cinnoline, quinoxaline, dihydroquinoxaline, tetrahydroquinoxaline, quinazoline, dihydroquinazoline, tetrahydroquinazoline, pyrazolopyridine, tetrahydropyridoindole, benzazepine, tetrahydrobenzazepine, carbazole, phenanthridine and dihydrophenanthridine;

(c) saturated or unsaturated 3-8-membered, preferably 5- or 6-membered, heteromonocycles containing 1 or 2 oxygen atoms as ring heteroatoms; more specifically furan, tetrahydropyran, tetrahydrofuran and dioxane;

(d) saturated or unsaturated 7-12-membered heterobicycles containing at least one, for example 1 to 3, nitrogen atoms as ring heteroatoms; more specifically, benzofuran, dihydrobenzofuran, chroman, benzodioxol and benzodioxane;

(e) saturated or unsaturated 3-8-membered, preferably 5- or 6-membered, heteromonocycles containing 1 or 2 sulfur atoms as ring heteroatoms; more specifically, thiophene, tetrahydrothiophene, thiopyran and tetrahydrothiopyran;

(f) saturated or unsaturated 7-12-membered heterobicycles containing at least one, for example from 1 to 3, sulfur atoms as ring atoms; more specifically benzothiophene;

(g) saturated or unsaturated 3-8-membered, preferably 5- or 6-membered, heteromonocycles containing 1 or 2 oxygen atoms and at least one, for example 1 to 3, nitrogen atoms as ring heteroatoms; more specifically oxazole, isoxazole, oxadiazole and morpholine;

(h) saturated or unsaturated 7-12-membered heterobicycles containing 1 or 2 oxygen atoms and at least one, for example from 1 to 3, nitrogen atoms as ring heteroatoms; more specifically benzoxazole, dihydrobenzoxazole, benzoxadiazole, benzisoxazole, benzoxazine, dihydrobenzooxazine, furopyridine, furopyrrole, benzoxazepine and tetrahydrobenzoxazepine;

(i) saturated or unsaturated 3-8-membered, preferably 5- or 6-membered, heteromonocycles containing 1 or 2 sulfur atoms and at least one, for example 1 to 3, nitrogen atoms as ring heteroatoms; more specifically thiazole, thiazoline (dihydrothiazole), thiadiazole, isothiazole and thiazolidine;

(j) saturated or unsaturated 7-12-membered heterobicycles containing 1 or 2 sulfur atoms and at least one, for example from 1 to 3, nitrogen atoms as ring heteroatoms; more specifically, benzothiazole, dihydrobenzothiazole, benzothiadiazole, thienopyridine, imidazothiazole, dihydroimidazothiazole, thienopyrazine, benzothiazine, dihydrobenzothiazine, benzothiazepine and tetrahydrobenzothiazepine; and (k) saturated or unsaturated 7-12-membered heterobicycles containing 1 or 2 oxygen atoms and at least one, for example from 1 to 3, sulfur atoms as ring heteroatoms; more specifically benzoxathiine.

Each group defined herein may form part of another group and may optionally be linked to another group via a linker such as -O- -CO-COO- -S-, -SO- -SO ₂ - -SO2-O- -O-CO- and -SO ₂ -NH-. For example, a group in which C ₁ . ₆ alkyl is linked to another group via -O-represented as C ₁ . ₆ αlkyl-O-. _C1 . ₆ alkyl group in the C ₁ group. ₆ alkyl-O- has the same definition as C ₁ . ₆ alkyl.

In some embodiments, R ¹ is deuterium or C ₁ . ₆ alkyl optionally substituted with 1-3 OH groups.

Particularly preferably R ¹ is C ₁ . ₆ alkyl substituted with OH.

In the formula (1), Ring A ¹ is a phenyl ring or a partially unsaturated or unsaturated 5 to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing 1 to 5 heteroatoms as ring atoms independently selected from the group consisting of nitrogen, oxygen and sulfur.

More preferably Ring A ¹ is: a phenyl ring or a partially unsaturated or unsaturated 5 to 15 membered monocyclic, bicyclic or tricyclic heterocycle containing 1 to 5 heteroatoms as ring atoms independently selected from the group consisting of nitrogen, oxygen and sulfur .

Especially preferably Ring A ¹ is benzene or pyridine.

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Ring A ¹ may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C1-6alkyl-O—, halo and oxo. In Ring A ¹ , each optionally substituted C1-6 alkyl or optionally substituted C _1-6 alkyl-O- substituent is independently 1-3 the same or different groups selected from the group consisting of halo and C _1-6 alkyl-O According to some embodiments implementation, Ring A ¹ is benzene, pyridine, pyrazine or tetrahydroisoquinoline, preferably benzene or pyridine, which may contain any of the above substituents.

In the formula (1), Ring A ² is a phenyl ring or a partially unsaturated or unsaturated 5 to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing 1 to 5 heteroatoms as ring atoms independently selected from the group consisting of nitrogen, oxygen and sulfur.

More preferably Ring A ² is a phenyl ring, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing from 1 to 4 nitrogen atoms as a ring heteroatom, a partially unsaturated or unsaturated 5- or 6-membered a heteroatom of 1 or 2 oxygen atoms, a partially unsaturated or unsaturated 7-12-membered heterobicycle containing from 1 to 3 oxygen atoms as a ring heteroatom, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing 1 or 2 as a ring heteroatom sulfur atoms, a partially unsaturated or unsaturated 7-15-membered heterobicycle containing from 1 to 5 nitrogen atoms as a ring heteroatom, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing 1 or 2 oxygen atoms as a ring heteroatom and at least one nitrogen atom, or a partially unsaturated or unsaturated 5- or 6-membered th heteromonocycle containing 1 or 2 sulfur atoms and at least one nitrogen atom as a ring heteroatom.

Particularly preferably Ring A ² is benzene.

Ring A ² may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyl-O-, optionally substituted C3-6 cycloalkyl, halogen, oxo, optionally substituted phenyl, and optionally substituted pyridyl , with the proviso that when Ring A ² contains multiple substituents on the ring carbon atoms, the substituents may be combined together with the carbon atoms to form C3-6 cycloalkyl; where in Ring A ² each substituent of optionally substituted C _1-6 alkyl or optionally substituted C _1-6 alkyl-O- independently represents the same or different 1-3 halogens, the substituent of optionally substituted C _3-6 cycloalkyl represents 1-3 identical or different 1-3 halogens, the optionally substituted phenyl substituent is 1-3 groups independently selected from the group consisting of halogen, C _1-6 alkyl and C _1-6 alkyl-O—, and the optionally substituted pyridyl substituent is the same or different 1-3 halogen-.

If Ring A ² contains multiple substituents on its carbon atoms, then the substituents can be combined together with the carbon atoms to form a C _3-6 cycloalkyl.

In some embodiments, Ring A ² is benzene, pyridine, furan, thiophene, or tetrahydroisoquinoline, preferably benzene, which may contain any of the above substituents.

If L is -C(=O)-NH-, then formula (1) includes both of the following embodiments:

where the wavy line represents the attachment point and the values of A ¹ and A ² are the same as defined above.

The present invention includes the following exemplary embodiments.

Item 1 Benzazepine Compound of Formula (1)

where R ¹ is deuterium or C _1-6 alkyl optionally substituted with 1-3 OH groups;

L is a direct bond or -C(=O)-NH-;

Ring A ¹ is a phenyl ring or a partially unsaturated or unsaturated 5-15-membered monocyclic, bicyclic or tricyclic heterocycle containing

- 4 040222 ve ring atoms from 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur,

Ring A ² is a phenyl ring or a partially unsaturated or unsaturated 5-15-membered monocyclic, bicyclic or tricyclic heterocycle containing from 1 to 5 heteroatoms as ring atoms independently selected from the group consisting of nitrogen, oxygen and sulfur;

Ring A ¹ may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C ₁ . ₆ alkyl optionally substituted with C ₁ . ₆ alkyl-O-, halo and oxo; And

Ring A ² may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C1.6αalkyl, optionally substituted C1.6αalkyl-O-, optionally substituted O3.6cycloalkyl, halogen, oxo, optionally substituted phenyl, and optionally substituted pyridyl , with the proviso that when Ring A ² contains multiple substituents on the ring carbon atoms, the substituents can be combined together with the carbon atoms to form C3. ₆ cycloalkyl; where in Ring A ¹ each substituent is an optionally substituted O^alkyl or an optionally substituted C ₁ . ₆ alkyl-O- independently represents 1-3 identical or different groups selected from the group consisting of halo and C ₁ . ₆ alkyl-C)-;

in Ring A ² each substituent is an optionally substituted O^alkyl or an optionally substituted C ₁ . ₆ αlkyl-O- independently represents the same or different 1-3 halo substituents of the optionally substituted C ₃ . ₆ cycloalkyl represents 1-3 identical or different 1-3 halogens, optionally substituted phenyl substituent represents 1-3 groups independently selected from the group consisting of halogen, C ₁ . ₆ alkyl and C ₁ . ₆ αalkyl-O-, and the optionally substituted pyridyl substituent is the same or different 1-3 halogens, or a salt thereof.

Item 2. The compound according to claim 1, where Ring A ¹ is a phenyl ring, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing from 1 to 4 nitrogen atoms as a ring heteroatom, a partially unsaturated or unsaturated 7- 15-membered heterobicycle containing from 1 to 5 nitrogen atoms as a ring heteroatom, partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing 1 or 2 oxygen atoms and at least one nitrogen atom as ring heteroatom, or partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing 1 or 2 sulfur atoms and at least one nitrogen atom as a ring heteroatom;

Ring A ² is a phenyl ring, a partially unsaturated or unsaturated 5 or 6-membered heteromonocycle containing from 1 to 4 nitrogen atoms as a ring heteroatom, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing 1 or 2 as a ring heteroatom oxygen atoms, a partially unsaturated or unsaturated 7-12-membered heterobicycle containing from 1 to 3 oxygen atoms as a ring heteroatom, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing 1 or 2 sulfur atoms as a ring heteroatom, partially unsaturated or an unsaturated 7-15-membered heterobicycle containing from 1 to 5 nitrogen atoms as a ring heteroatom, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing 1 or 2 oxygen atoms as a ring heteroatom and at least one nitrogen atom, or a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing having as a ring heteroatom 1 or 2 sulfur atoms and at least one nitrogen atom;

Ring A ¹ may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C ₁ . ₆ alkyl optionally substituted with C ₁ . ₆ alkyl-O-, halo and oxo; And

Ring A ² may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C1.6αalkyl, optionally substituted C1.6αalkyl-O-, optionally substituted O3.6cycloalkyl, halogen, oxo, optionally substituted phenyl, and optionally substituted pyridyl , with the proviso that when Ring A ² contains multiple substituents on the ring carbon atoms, the substituents can be combined together with the carbon atoms to form C3. ₆ cycloalkyl; where in Ring A ¹ each substituent is optionally substituted C ₁ . ₆ alkyl or optionally substituted C ₁ . ₆ alkyl-O- independently represents 1-3 identical or different groups selected from the group consisting of halo and C ₁ . ₆ alkyl-C)-;

in Ring A ² each substituent is an optionally substituted C ₁ . ₆ alkyl or optionally substituted C ₁ . ₆ αlkyl-O- independently represents the same or different 1-3 halo substituent of optionally substituted O ₃ . ₆ cycloalkyl represents 1-3 identical or different 1-3 halogens, optionally substituted phenyl substituent represents 1-3 groups independently selected from the group consisting of halogen, C ₁ . ₆ alkyl and C ₁ . ₆ αalkyl-O-, and the optionally substituted pyridyl substituent is the same or different 1-3 halogens, or a salt thereof.

Item 3. A compound according to any one of claims 1 or 2, or a salt thereof, wherein Ring A ¹ is benzene, pyridine, pyrazine or tetrahydroisoquinoline and Ring A ¹ may contain from 1 to 4

- 5,040,222 substituents independently selected from the group consisting of optionally substituted C1-balkyl, optionally substituted _C1-6 alkyl-O-, halo and oxo;

Ring A ² is benzene, pyridine, furan, thiophene, or tetrahydroisoquinoline, and Ring A ² may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkyl-O -, optionally substituted C _3-6 cycloalkyl, halogen, oxo, optionally substituted phenyl and optionally substituted pyridyl, wherein in Ring A ¹ each substituent of optionally substituted C _1-6 alkyl or optionally substituted C _1-6 alkyl-O- is independently 1-3 identical or different groups selected from the group consisting of halo and _C1-6 alkyl-O-;

in Ring A ² each optionally substituted C1-6alkyl or optionally substituted C1-6αalkyl-O- substituent is independently the same or different 1-3 halogens, the optionally substituted C3.6cycloalkyl substituent is 1-3 identical or different 1-3 halogens, the optionally substituted phenyl substituent is 1-3 groups independently selected from the group consisting of halogen, C1-6alkyl and C1_6αkyl-O-, and the optionally substituted pyridyl substituent is the same or different 1-3 halogens, provided that, if Ring A ² contains many substituents on its carbon atoms, the substituents can combine together with carbon atoms to form C3_ ₆ cycloalkyl; or its salt.

Item 4. A compound according to any one of claims 1-3, wherein R ¹ is C _1-6 alkyl substituted with 1-3 OH groups, or a salt thereof.

Item 5. A compound according to claim 4, wherein Ring A ¹ is benzene optionally substituted with halogen, C _1-6 alkyl, halo-C _1-6 alkyl, C ₁ . ₆ alkyl-O-, halo-C ₁ . ₆ alkyl-O-, C ₁ _ ₆ alkyl-O-C ₁ _ ₆ alkyl-O-, halogen-C ₁ _ ₆ alkyl-O-C ₁ _ ₆ alkyl-O-,

C ₁ _ ₆ alkyl-O-halogen-C ₁ _ ₆ alkyl-O- or halo-C ₁ . ₆ alkyl-O-halo-C ₁ . ₆ alkyl-O-; pyridine optionally substituted with halogen; pyrazine; or tetrahydroisoquinoline optionally substituted with oxo; And

Ring A ² is benzene optionally substituted with 1-3 groups independently selected from the group consisting of halogen, C _1-6 alkyl, halo-C ₁ _ ₆ alkyl, C ₁ . ₆ alkyl-O-, halo-C ₁ _ ₆ αalkyl-O-, C _3-6 cycloalkyl, optionally substituted phenyl and pyridyl, where optionally substituted phenyl is phenyl optionally substituted with halogen, C ₁₆ alkyl, halo-C ₁ _ ₆ alkyl, C ₁ _ ₆ alkyl-O- or halo-C ₁ _ ₆ alkyl-O-; pyridine optionally substituted with C ₁ _ ₆ alkyl, halo-C ₁ _ ₆ alkyl or phenyl; furan optionally substituted with C ₁ _ ₆ alkyl; thiophene optionally substituted with C1. ₆ alkyl; or tetrahydroisoquinoline optionally substituted with 1-3 groups independently selected from the group consisting of halogen, C _1-6 alkyl and oxo, provided that if the tetrahydroisoquinoline contains a plurality of C _1-6 alkyl groups on its ring carbon atoms, then C^ alkyl groups can combine together with carbon atoms to form C3-bcycloalkyl, or a salt thereof.

Clause 6. A compound according to any one of claims 1-5, wherein R ¹ is C _1-6 alkyl substituted with 1-3 OH groups,

Ring A ¹ is benzene optionally substituted with halogen, C _1-6 alkyl _, C _1-6 alkyl-O-, or C _{1_6} alkyl-O-C _{1_6} alkyl-O- _; or pyridine optionally substituted with halogen, and

Ring A ² is benzene optionally substituted with 1-3 groups independently selected from the group consisting of halo, _C1-6 alkyl, halo- _C1-6 alkyl, _C1-6 alkyl-O-, halo- _C1-6 alkyl -O-, C _3-6 cycloalkyl, optionally substituted phenyl and pyridyl, wherein the optionally substituted phenyl is phenyl optionally substituted with halogen, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkyl-O- or halogen _-C1-6 alkyl-O-, or a salt thereof.

Item 7. A compound according to any one of claims 1-6, wherein R ¹ is C _1-6 alkyl substituted with 1-3 OH groups,

Ring A ¹ is benzene optionally substituted with halo, _C1-6 alkyl-O- or halo- _C1-6 alkyl-O-; or pyridine, and

Ring A ² is benzene optionally substituted with 1-3 groups independently selected from the group consisting of halogen, C _1-6 alkyl, halo-C _1-6 alkyl and phenyl optionally substituted with halogen; pyridine optionally substituted with phenyl or halo- _C1-6 alkyl; or tetrahydroisoquinoline optionally substituted with 1-3 groups independently selected from the group consisting of halogen and oxo, or a salt thereof.

Item 8. A compound according to any one of claims 1 to 7, wherein L is -C(=O)-NH-, or a salt thereof.

Item 9. A compound or salt thereof selected from the following group of compounds:

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but ho) _f CkOO fX _f XXy but ho) _f Cixy^A+F yl HO hq/f θ ^! γΟΑ aa F HO hq/f Cl^yy Cl θ ^X D γυ%Χο Y ⁷ h 1 F ^F HO HQ A ClyA/y yA HO ^H 4>F CIxyyHj-F yl HO HQ ) _F Clxyy*4-F “X?/ HO ^H< V f С1уу+-р УУ HO H0 ₆ > F GlyOy-F HO H.Q. / F _ Sk/V-F O XX J HO ^h qA f ^C|s ^4/HF EF 1 A ) y ^F ₀ νΧα XVA) Η N HQ HQ> fe _ ciy/y O kA / Yo ^'N ⁷ O^n-OA y ⁷ H ^N F HO HQ,> F ____ Cix^i\>ryF 0 xo NvA αύχ h ^N HO hq > r _c p F ΤΪ / Y ^F 0 ^^N- ⁷ CyVOA y ⁷ HF HQ αΑξψ y _o Όζΐ y _H y HQ ^HO 'J f = c ^, x^O ^t y- ^F O kA ) JTyK Il Г νΆ^/ ^υ y ⁷ Η F HO αχ3ψ y AO AAaAb n g Γ ^F

- 7 040222

Item 10. A vasopressin receptor antagonist comprising a compound according to any one of claims 1 to 9 or a salt thereof.

Item 11. Pharmaceutical composition for the treatment and/or prevention of a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, inappropriate vasopressin secretion syndrome, liver cirrhosis, hyponatremia , hypokalemia, diabetes, circulatory failure, kinesia, water metabolism disorders and ischemic disorders, comprising as an active ingredient, containing a compound according to any one of claims 1 to 9 or a salt thereof.

Item 12. Pharmaceutical composition for diagnosing a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, syndrome of inappropriate vasopressin secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes , circulatory failure, kinesia, water metabolism disorder and ischemic disorder, comprising as an active ingredient a compound according to any one of claims 1 to 9 or a salt thereof.

Item 13. A method of treating and/or preventing a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, syndrome of inappropriate vasopressin secretion, liver cirrhosis, hyponatremia, hypokalemia , diabetes, circulatory failure, kinesia, disorders of water metabolism and ischemic disorders, including the introduction to the subject of the connection in accordance with any of Mon. 1-9 or its salts.

Item 14. Method for diagnosing a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, inappropriate vasopressin secretion syndrome, liver cirrhosis, hyponatremia, hypokalemia, diabetes, insufficiency circulation, kinesia, water metabolism disorders and ischemic disorders, including the introduction to the subject of the compounds in accordance with any one of paragraphs. 1-9 or its salts.

Item 15. The use of a compound according to any one of claims 1 to 9 or a salt thereof for the treatment and/or prevention of a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, syndrome of inappropriate vasopressin secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, kinesia, water metabolism disorders and ischemic disorders.

Item 16. The use of a compound according to any one of claims 1 to 9 or a salt thereof for diagnosing a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, syndrome of inappropriate secretion of vasopressin, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, kinesia, water metabolism disorders and ischemic disorders.

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Item 17. Use of a compound according to any one of claims 1 to 9 or a salt thereof for the manufacture of a medicament for the treatment and/or prevention of a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction , renal failure, polycystic kidney disease, inappropriate vasopressin secretion syndrome, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, kinesia, water metabolism disorders and ischemic disorders.

Item 18. The use of a compound according to any one of claims 1 to 9 or a salt thereof for the manufacture of a medicament for diagnosing a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, syndrome of inappropriate vasopressin secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, kinesia, water metabolism disorders and ischemic disorders.

The present invention also embraces any combination of preferred embodiments or choices for the various elements and features presented herein as well as the embodiments illustrated above, provided that such combinations are not incompatible.

General method of obtaining

The compound of the present invention can be produced, for example, according to the general production method below, but the production method of the compound of the present invention is not limited thereto.

The starting materials used in the context of this document may be commercially available or may be obtained in accordance with known methods or any methods in accordance with them.

Any non-limiting solvents, acids, bases, protecting groups, and leaving groups that are commonly used in the field of organic synthesis chemistry can be used in the preparation of a compound of the present invention.

The products in the process for preparing the compound of the present invention can be used in the subsequent reaction either dissolved in the reaction solutions or in the form of crude products. Products can also be isolated from reaction mixtures according to traditional methods and easily purified according to traditional purification methods. Such purification methods include, for example, filtration, extraction, concentration, evaporation, crystallization, recrystallization, distillation, chromatography, and optical resolution.

Alkylation, hydrolysis, amination, esterification, amidation, esterification, oxidation and reduction to obtain the compound of the present invention can be carried out in accordance with known methods.

Reagents and methods commonly used in the context of this document are described, for example, in ORGANIC FUNCTIONAL GROUP PREPARATIONS 2 ^nd edition, ACADEMIC PRESS, INC. 1989; Comprehensive Organic Transformations, VCH Publishers Inc., 1989, PGM Wuts; TW Greene Greene's Protective Groups in Organic Synthesis 4 ^th edition, 2006; and John Wiley & Sons, New York, 1991, p. 309.

Reaction Scheme 1

In the diagram, the values of R ¹ , A ¹ , A ² and L are the same as defined above.

The compound according to the present invention can be obtained by amidation using compound (2) and compound (3). More specifically, the compound (1) can be obtained by reacting the compound (2) or its reactive derivative at the carboxy group and the compound (3) or its reactive derivative at the imino group.

Preferred reactive derivatives of compound (2) at the carboxy group include, for example, acid halides, acid azides, acid anhydrides, activated amides, and activated esters. More preferred reactive derivatives include acid chlorides; acid azides; mixtures of acid anhydrides with acids such as substituted phosphates (e.g. dialkyl phosphates, phenyl phosphates, diphenyl phosphates, dibenzyl phosphates and halogenated phosphates), dialkyl phosphite, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (e.g. methanesulfonic acid), aliphatic carboxylic acid (e.g. , acetic acid, propionic acid, butyric acid, isobutyric acid, trimethylacetic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, and trichloroacetic acid) and an aromatic carboxylic acid (eg, benzoic acid); symmetrical acid anhydrides;

- 9 040222 activated amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; activated esters (eg, cyanomethyl ether, methoxymethyl ether, dimethyliminomethyl ether, vinyl ether, propargyl ether, p-nitrophenyl ether, 2,4-dinitrophenyl ether, trichlorophenyl ether, pentachlorophenyl ether, and mesylphenyl ether); and esters with N-hydroxy compounds (eg N,N-dimethylhydroxylamine, 1hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide and HOBt). Such reactive derivatives may be selected from these derivatives depending on the type of compound (2) to be used.

When the compound (2) is used in the form of a free acid or a salt thereof in Reaction Scheme 1, the reaction can be carried out in the presence of a condensing agent. Such a condensing agent may be any known agent commonly used in the art and includes, for example, DCC; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; WSC or its hydrochloride; N,N'-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene, 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; an alkyl haloformate such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; intramolecular salt of 2-ethyl-5-(meta-sulfophenyl)isoxazolium hydroxide; benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate; 1-(para-chlorobenzenesulfonyloxy)-6-chloro-1Hbenzotriazole; and the so-called Vilsmeier reagents, prepared by reactions of DMF with an agent such as thionyl chloride, phosgene, trichloromethyl chloroformate, and phosphorus oxychloride. The reaction can also be carried out in the presence of the condensing agent mentioned above and an active esterifying agent such as N-hydroxysuccinimide, N-hydroxyphthalimide and HOBt.

Preferred imino reactive derivatives of compound (3) include, for example, its imino-enamino tautomers of Schiff bases obtained by reactions of compound (3) with carbonyl compounds such as aldehydes and ketones; silyl derivatives obtained by reacting compound (3) with silyl compounds such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide and bis(trimethylsilyl)urea; and derivatives obtained by reactions of compound (3) with phosphorus trichloride or phosgene.

Reaction Scheme 1 is usually carried out in a conventional solvent which does not adversely affect the reaction. Such a solvent includes, for example, water; alcohol solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; ether solvents such as THF, dioxane, Et ₂ O, diisopropyl ether and diglyme; ester solvents such as AcOMe and AcOEt; aprotic polar solvents such as MeCN, DMF, and DMSO; hydrocarbon solvents such as n-pentane, n-hexane, n-heptane and cyclohexane; halogenated hydrocarbon solvents such as DCM and ethylene chloride; and other organic solvents; and their mixtures.

Reaction Scheme 1 can be carried out in the presence of a base. Such a base may be any of the known inorganic and organic bases commonly used in the art. Such inorganic bases include, for example, alkali metals (for example, sodium or potassium), alkali metal hydrogen carbonates (for example, lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate), alkali metal hydroxides (for example, LiOH, NaOH and KOH), alkali carbonates metals (eg Li ₂ CO ₃ , Na ₂ CO ₃ , K2CO3 and Cs ₂ CO ₃ ), alkali metal lower alkoxides (eg sodium methoxide and sodium ethoxide) and alkali metal hydrides (eg NaH and KH). Such organic bases include, for example, trialkylamine (eg, trimethylamine, triethylamine, and N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. Bases in the form of a liquid can also act as a solvent. In the context of this document, the base is used alone or in a mixture of two or more bases. The amount of base used in the context of this document is usually 0.1 to 10 moles, preferably 0.1 to 3 moles, per 1 mole of compound (2).

The ratio of compound (2) and compound (3) used in Reaction Scheme 1 is usually at least 1 mol, preferably 1 to 5 mol, of the first of said compounds per 1 mol of the latter.

The reaction temperature is not limited, and in general, the reaction proceeds under any conditions such as cooling, room temperature, and heating. The reaction may preferably be carried out at room temperature to 100° C. for 30 minutes to 30 hours, preferably 30 minutes to 5 hours.

- 10 040222

Reaction Scheme 2

(4) (1a)

In the scheme, the meanings of A ¹ , A ² and L are the same as defined above, R ¹ is hydroxyalkyl in which OH is protected by a protective group, and R ^la is C ₁ . ₆ alkyl substituted with OH.

Reaction Scheme 2 is a method for preparing a compound of the present invention, wherein R ¹ of compound (3) is hydroxyalkyl in which OH is protected by a protecting group. By removing the OH-protecting group on R ¹ of compound (4) in the absence of a solvent or in the presence of an inert solvent, compound (1a) can be obtained.

Any non-limiting hydroxy protecting groups that are commonly used in the field of organic synthesis chemistry can be used as the OH protecting group. Such an OH protecting group includes, for example, alkyl groups (eg, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, and acetylmethyl); alkyl(alkenyl)carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, and (E)-2 -methyl-2-butenoyl); arylcarbonyl groups (e.g. benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoyl, 4-anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl , 2-(methoxycarbonyl)benzoyl and 4-phenylbenzoyl); tetrahydro(thio)pyranyl(furanyl) groups (eg tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl); silyl groups (eg, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyl-di-t-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl); alkoxymethyl groups (eg methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2trichloroethoxymethyl and bis(2-chloroethoxy)methyl); and aralkyl groups (e.g., benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl). Any deprotection methods commonly used in the art can be used.

An inert solvent used in the context of this document includes, for example, water; ether solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2 dimethoxyethane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether; halogenated hydrocarbon solvents such as methylene chloride, chloroform, 1,2-dichloroethane and carbon tetrachloride; aromatic hydrocarbon solvents such as benzene, toluene and xylene; lower alcohol solvents such as methanol, ethanol, and isopropanol; and polar solvents such as DMF, DMSO, hexamethylphosphoric triamide and acetonitrile. An inert solvent is used alone or in a mixture of two or more solvents.

Reaction Scheme 2 is carried out according to the conventional process such as hydrolysis and reduction.

Such a hydrolysis process is preferably carried out in the presence of a base or an acid, including Lewis acids. Such a base includes, for example, inorganic bases such as alkali metal hydroxides (for example, sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxides (for example, magnesium hydroxide and calcium hydroxide), alkali metal carbonates (for example, sodium carbonate and potassium carbonate ), alkaline earth metal carbonates (eg magnesium carbonate and calcium carbonate) and alkali metal bicarbonates (eg sodium bicarbonate and potassium bicarbonate); and organic bases such as trialkylamines (eg trimethylamine and triethylamine), picoline, DBN, DABCO and DBU. Such acid includes organic acids (eg, formic acid, acetic acid, propionic acid, trichloroacetic acid, and trifluoroacetic acid) and inorganic acids (eg, hydrochloric acid, hydrobromic acid, and sulfuric acid). Deprotection using trihaloacetic acids (eg trichloroacetic acid and trifluoroacetic acid) can be carried out in the presence of cation traps (eg anisole and phenol). Bases and acids in the form of a liquid can also act as a solvent.

The reaction temperature in the hydrolysis process is not limited, and in general, the reaction proceeds under any conditions such as cooling, room temperature, and heating.

The reduction process includes, for example, chemical reduction and catalytic

- 11 040222 restoration.

The reducing agent used in chemical reduction includes, for example, metals (for example, tin, zinc, and iron) and a combination of metal-containing compounds (for example, chromium chloride and chromium acetate) and organic or inorganic acids (for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid and hydrobromic acid).

The catalyst used in catalytic reduction includes, for example, conventional catalysts such as platinum catalysts (for example, platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, and platinum wire), palladium catalysts (for example, palladium sponges, palladium black, palladium oxide, palladium carbon, colloidal palladium, palladium barium sulfate and palladium barium carbonate), nickel catalysts (e.g. reduced nickel, oxidized nickel and Raney nickel), cobalt catalysts (e.g. reduced cobalt and Raney cobalt), iron catalysts (eg reduced iron and Raney iron) and copper catalysts (eg reduced copper, Raney copper and Ullmann copper).

The reduction reaction is carried out in a conventional solvent which does not adversely affect the reaction, such as water; alcohols such as methanol, ethanol, trifluoroethanol and ethylene glycol; ethers such as acetone, diethyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, methylene chloride and ethylene chloride; esters such as methyl acetate and ethyl acetate; aprotic polar solvents such as acetonitrile and N,Ndimethylformamide; basic solvents such as pyridine; and other organic solvents; and their mixtures. The reduction reaction is usually carried out at room temperature to 200°C, preferably room temperature to 150°C, for about 1-30 hours.

Reaction Scheme 3

pN (5) (3)

In the scheme, the values of R ¹ are the same as defined above, and P ^N is an amino protecting group.

Compound (3) can be obtained by removing the amino protecting group in compound (5). The process for removing the amino protecting group may be carried out according to a conventional method such as hydrolysis in Reaction Scheme 2 and hydrogenolysis.

The amino protecting group includes, for example, alkoxycarbonyl, alkanoyl, and aryl-substituted alkyl.

The alkoxycarbonyl group includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

The alkanoyl group includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, t-butylcarbonyl, and hexanoyl.

An aryl-substituted alkyl _group includes, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, diphenylmethyl, trityl, and C _{1_6} alkyl substituted with phenyl, optionally substituted with the same or different 1-3 substituents. Substituents on the phenyl group include, for example, halogen, C ₁ _ ₆ alkyl, halogen-C ₁ _ ₆ alkyl, C ₁ _ ₆ alkyl-O-, halogen-C ₁ _ ₆ alkyl-O-, hydroxy-C ₁ _ ₆ alkyl, hydroxyhalo-C ₁ _ ₆ alkyl, hydroxy-C ₁ _ ₆ alkyl-O-, hydroxyhalo-C ₁ _ ₆ alkyl-O- and C ₃ _ ₆ cycloalkyl. When the phenyl group is substituted with two or more groups, these groups may be independent and the same or different from each other.

The compound of the present invention, starting materials and intermediates as used herein include chemically acceptable geometric isomers, stereoisomers, optical isomers and tautomers. Each isomer can be separated by conventional optical resolution or obtained from appropriate optically active starting materials.

The compound of the present invention, starting materials and intermediates within the meaning of this document may be in the form of a salt, and each target compound obtained in each reaction step may also form a salt. When the compound obtained in a certain reaction step is in free base form, such compound can be converted to its desired salt by known methods. Where the compound is in the form of a salt, such compound may be converted to its free base form or to its other desired salt. Said salts include the salts illustrated later in the document.

As used herein, salts include pharmaceutically acceptable acid addition salts and base addition salts. Acids in acid addition salts include,

- 12 040222 for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid; organic acids such as formic acid, propionic acid, oxalic acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, para-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, malonic acid, succinic acid, maleic acid, fumaric acid acid, malic acid and lactic acid; and amino acids such as lysine, arginine, aspartic acid and glutamic acid. Bases in base addition salts include, for example, metals such as alkali metal (eg sodium and potassium) and alkaline earth metal (eg calcium and magnesium); inorganic bases such as alkali metal carbonate (for example, lithium carbonate, potassium carbonate, sodium carbonate and cesium carbonate), alkali metal hydrogen carbonate (for example, lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate) and alkali metal hydroxide (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and cesium hydroxide); organic bases such as methylamine, diethylamine, trimethylamine, triethylamine, N-ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, quinoline, piperidine, imidazole, dimethylaminopyridine, dimethylaniline, picoline, choline, N-methylmorpholine, DBN, DBU and DABCO; and ammonium salts.

The compound of the present invention also includes various hydrates, solvates and crystalline polymorphs of the compounds of formula (1) and their salts.

The compound of the present invention includes compounds of formula (1) in which any one or more atoms are replaced by one or more isotopes, as well as compounds of formula (1) in which R ¹ is deuterium. Such isotopes include deuterium ( ² H), tritium ( ³ H), ¹³ C, ¹⁴ N, and ¹⁸ O.

The compound of the present invention also includes pharmaceutically acceptable co-crystals or co-crystal salts. Such co-crystals or co-crystal salts refer to a crystalline substance formed at room temperature from two or more molecules, each of which has different physical properties (eg, structures, melting points, and heats of fusion). Such co-crystals or co-crystal salts can be obtained according to known co-crystallization methods.

The compound of the present invention also includes pharmaceutically acceptable prodrugs. Such prodrugs include compounds of formula (1) in which one of the substituents is modified with reactive functional groups such as OH, COOH and amino.

Basically, it is thought that the vasopressin V _1a receptor occurs in the blood vessels and myocardium and can cause vasoconstriction, while the vasopressin V 2 receptor occurs in the renal tubules and endothelium and can cause water retention. In view of such vasopressin receptor action, a vasopressin antagonist compound of the present invention acting as an antagonist of both vasopressin V _1a and vasopressin V ₂ can provide, for example, vasodilation effects, antihypertensive effects, hepatic glucose release inhibition effects, inhibition of mesangial cell proliferation, aquaretic effects, platelet aggregation inhibition effects, antiemetic effects, urinary excretion promoting effects, factor VIII suppression, cardiac hyperfunction, inhibition of mesangial cell contraction, inhibition of hepatic gluconeogenesis, inhibition of aldosterone secretion, inhibition of endothelin production, regulation of renin secretion, regulation of memory, thermoregulation, or regulation of prostaglandin production.

The present compound may also be useful as an active ingredient of drugs such as vasodilators, antihypertensive agents, aquatic agents, platelet aggregation inhibitors, urinary excretion agents, heart failure drugs, or kidney failure drugs, and it may be useful for diagnosis, prevention and / or treatment of various diseases associated with vasopressin receptors, such as Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease (PKD), inappropriate vasopressin secretion syndrome (SIADH), liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, kinesia, water metabolism disorder and various ischemic disorders, preferably heart failure, renal failure and PKD, more preferably PKD.

The compound of the present invention also has better metabolic stability than drugs such as tolvaptan, which are known to be primarily metabolized by the hepatic metabolizing enzyme CYP3A4 and may have an extended duration of pharmacological effects. The compound of the present invention also has reduced side effects and high tolerability and safety.

Illustrated are medicinal formulations (hereinafter referred to as pharmaceutical compositions) containing a compound of the present invention in ca.

- 13 040222 as an active ingredient.

Such medical formulations are prepared by formulating a mixture of a compound of the present invention with pharmaceutically acceptable carriers into conventional medical formulation forms. Such carriers include conventional diluents and bases such as fillings, bulking agents, binders, humectants, disintegrants, surfactants, and lubricants.

Such medical compositions may be in any form selected depending on the therapeutic purposes from various forms such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injectable forms (such as solutions and suspensions).

Carriers used to formulate tablet forms may be any known carriers commonly used in the art and include, for example, bases such as lactose; binders such as polyvinylpyrrolidone; leavening agents such as starch; absorption enhancers such as sodium lauryl sulfate; humectants such as glycerin and starch; absorbents such as colloidal silicic acid; and lubricants such as polyethylene glycol.

Any tablets with conventional coatings can be formulated as dragees, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, bilayer tablets and multilayer tablets, if desired.

The carriers used to prepare the composition in the form of pills may be any of the known carriers commonly used in the art and include, for example, bases such as glucose; binders such as acacia powder; and leavening agents such as laminaran.

The carriers used to prepare the composition in the form of suppositories may be any known carriers commonly used in the art and include, for example, cocoa butter.

Liquids, emulsions and suspensions prepared for injection are preferably sterilized and isotonic with blood. The diluents used to prepare the composition in the form of a liquid, emulsion or suspension may be any known diluents commonly used in the art and include, for example, water. When preparing isotonic solutions, medical formulations may contain sufficient amounts of salts for preparation. Medical formulations may also contain conventional solubilizers, buffering agents, soothing agents, and, if necessary, colorants, preservatives, flavors, flavors, sweeteners, and other drugs.

The amount of the compound of the present invention included in the medical formulation is not limited, and may optionally be selected from a wide range of amounts. The compound according to the present invention is preferably contained in the medical composition in the range from 0.1 to 70 wt.%.

Any non-limiting route of administration may be used for such a medical formulation, and such routes of administration may be determined depending on various formulation forms, age, sex, disease states of patients, and other conditions. For example, tablets, pills, liquids, suspensions, emulsions, granules and capsules can be administered orally. The injectable forms may be administered intravenously alone or in combination with a conventional replacement fluid such as glucose and amino acid, and may also be administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally if desired. Suppositories may be administered intrarectally.

Dosage sizes of such a medical composition may optionally be selected depending on the dosage regimen, age, sex, disease severity of the patients and other conditions, and the compound of the present invention may generally be administered in the range of 0.01 to 100 mg, preferably in the range of 0 ,1 to 50 mg per day per 1 kg of body weight at a time or in several separate doses. Dosage rates vary depending on various conditions, and smaller than the above ranges, dosage sizes may be sufficient, or larger than the above ranges, amounts may be acceptable.

Examples

The present invention is described in detail in the following Reference Examples, Examples and Test Examples, but is not limited to them. These examples can be modified without departing from the scope of the present invention.

The following abbreviations may be used in this document.

REX: Reference Example No.

EX: Example No.

STR: Structural formula (in formulas, structures marked Chiral refer to absolute configurations).

RProp: Production method (the product is obtained using the corresponding starting material in accordance with the method described in Reference Example No.).

- 14 040222

Prop: Production method (the product is obtained using the appropriate starting material in accordance with the method described in Example No.).

Data: physical data (NMR1: δ (ppm) in ¹ H-NMR (dimethylsulfoxide-66); NMR2: δ (ppm) in 1 H NMR (CDCl3); NMR3: δ (ppm) in ¹ H-NMR (CD3OD), NMR4: δ (ppm) in ¹ H-NMR (in a mixture of CDCl ₃ and dimethylsulfoxide-0 ₆ ))

AcOEt: ethyl acetate

AcOH: acetic acid

AcOMe: methyl acetate

AcONa: sodium acetate

9-BBN: 9-borabicyclo[3.3.1]nonane

VVg ₃ : boron tribromide

Boc ₂ O: di-ot/?ot-butylde and carbonate n-BuLi: n-butyllithium

CDI: 1, G-carbonyldiimidazole

Cs ₂ CO ₃ : cesium carbonate

DCE: 1,2-dichloroethane

DCM: dichloromethane

DEAD: diethyl azodicarboxylate

DHP: 3,4-dihydro-2H-pyran

DIBAL: diisobutyl aluminum hydride

DIPEA: diisopropylethylamine

DMA: N,N-dimethylacetamide

DMAP: 4-(dimethylamino)pyridine

DME: dimethoxyethane

DMEDA: N, N'-dimethyl-!,2-ethylenediamine

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

DPPA: diphenylphosphoryl azide

DPPP: 1,3-diphenylphosphinopropane

Et ₂ O: diethyl ether

EtOH: ethanol

HATU: O-(7-azabenzotriazol-1-yl)-X N, N', N' -tetramethyluronium hexafluorophosphate

HC1: hydrochloric acid

HCO ₂ Na: sodium formate hexane: //-hexane

HOBt: 1-hydroxybenzotriazole

IBX: 2-iodoxybenzoic acid

1w: imidazole

IPA: 2-propanol

IPE: diisopropyl ether

K ₂ CO ₃ : potassium carbonate

KHCO ₃ : potassium bicarbonate

KOtBu: potassium m/tem-butoxide

KOH: potassium hydroxide

K ₃ RO ₄ : potassium orthophosphate

LAH: lithium aluminum hydride

LDA: lithium diisopropylamide

- 15 040222

LHMDS: lithium hexamethyldisilazide

LiOH: lithium hydroxide

MCPBA: l/eota-chloroperoxybenzoic acid

MeCN: acetonitrile

MEK: 2-butanone

MeOH: methanol

NaBH ₄ : sodium boron hydride

NaH: sodium hydride

NaHCO ₃ : sodium bicarbonate

NaOH: sodium hydroxide

NaOtBu: sodium otreot-butoxide

Na ₂ SO ₄ : sodium sulfate

NCS: N-chlorosuccinimide

NH ₄ C1: ammonium chloride

NM0: N-methylmorpholine

NMP: N-methylpyrrolidone

Pd/C: palladium charcoal

Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium (0)

Ph: phenyl

PPTS: Pyridinium / Jura toluenesulfonate

Rug: pyridine

TV AF: tetra-n-butylammonium fluoride

TBDMSC1: tert-butyldimethylsilyl chloride

TEA: triethylamine

TFA: Trifluoroacetic acid

THF: tetrahydrofuran

TMPDA: N, Ν, Ν', Ν'-tetramethyl-1,3-propanediamine

TMSC1: chlorotrimethylsilane

TsCl: para-toluenesulfonyl chloride

WSC: 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

ZC1: benzyl chloroformate

In the context of this document, room temperature usually refers to a temperature from about 10°C to about 35°C. Unless otherwise indicated, the ratios in mixed solvents refer to the ratio by volume (v/v). Unless otherwise stated, % refers to % by weight (wt%).

¹ H-NMR (Proton Nuclear Magnetic Resonance) spectra were measured on a Fourier NMR spectrometer (any one of Bruker AVANCE 300 (300 MHz), Bruker AVANCE 500 (500 MHz), Bruker AVANCE III 400 (400 MHz) and Bruker AVANCE III 500 (500 MHz). MHz)) at room temperature.

Silica gel modified with aminopropylsilane was used to carry out column chromatography on alkaline silica gel.

The absolute configuration of the compound was determined by X-ray crystallography (e.g., Shigeru Ooba and Shigenobu Yano, Kagakusha no tame no Kisokoza 12 X-ray crystallography (1 ed., 1999)) or established according to Shi asymmetric epoxidation rules of thumb (Waldemar Adam, Rainer T. Fell , Chantu R. Saha-Moller and Cong-Gui Zhao: Tetrahedron: Asymmetry 1998, 9, 397-401 Yuanming Zhu, Yong Tu, Hongwu Yu, Yian Shi: Tetrahedron Lett. 1988, 29, 2437-2440).

Reference examples

Reference example 1.

To a suspension of Pd/C (NX type; 500 mg) in THF (80 ml) was added methyl 6-(benzylamino)-2-chloro-5fluoropyridine-3-carboxylate (5 g) and 10% HCl-MeOH (80 ml) , and the mixture was stirred for 3 hours. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated to give methyl 6-amino-2-chloro-5-fluoropyridine-3-carboxylate (3.83 g).

Reference example 2.

To a suspension of TEA (3.87 ml) and Pd(OH) ₂ (280 mg) in THF (50 ml) was added methyl-6-amino-2-chloro-5

- 16 040222 fluoropyridine-3-carboxylate (2.837 g), and the mixture was stirred at room temperature in a hydrogen atmosphere at a pressure of 1 atm for 5 hours. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated, and a saturated aqueous NaHCO ₃ solution and AcOEt were added to the resulting residue. The AcOEt layer was separated and dried over anhydrous Na ₂ SO ₄ . The mixture was filtered and then the filtrate was concentrated to give methyl 6-amino-5-fluoropyridine-3-carboxylate (2.03 g).

Reference example 3.

To a solution of 2-chloro-5-fluorobenzoic acid (1.026 g) in DCM at 0°C was added (COCl) ₂ (1.543 ml) and DMF (14 μl) and the mixture was stirred for 1 h and concentrated. The resulting residue was dissolved in DCM (2.0 ml) and the dissolved residue was added to a solution of methyl 6-amino-5-fluoropyridine-3-carboxylate (1 g) and pyridine (15 ml) in DCM (10 ml). The mixture was stirred at room temperature overnight and then water was added. The precipitated crystal was filtered and washed with water to give methyl 6-(2-chloro-5-fluorobenzamido)-5-fluoropyridine-3-carboxylate (1.25 g).

Reference example 4.

To a solution of methyl 6-(2-chloro-5-fluorobenzamido)-5-fluoropyridine-3-carboxylate (1.25 g) in MeOH (10 ml) was added 5 N NaOH aqueous solution (1.148 ml), and the mixture was stirred at room temperature. temperature during the night. The reaction solution was acidified by adding HCl, the precipitated solid was filtered and washed with water and Et ₂ O to give 6-(2-chloro-5-fluorobenzamido)-5-fluoropyridine-3-carboxylic acid (678.3 mg).

Reference example 5.

A suspension of 5-bromo-1-indanoxime (108 g) in DCM (600 ml) was cooled on ice and TEA (80 ml) and para-TsCl (109 g) were added. The mixture was stirred at room temperature overnight. Approximately half of the solvent was removed under reduced pressure, and then water was added to the reaction mixture. The mixture was stirred, the precipitate was filtered and washed with hexane/AcOEt=1/1 to give a white solid. The aqueous layer was re-extracted with DCM. The combined organic layer was washed with water and brine and dried over anhydrous Na ₂ SO ₄ . The mixture was filtered, then the filtrate was concentrated, the precipitate was filtered and washed with a mixture of hexane:AcOEt=1:1. The resulting solids were combined to give [(1E)-5-bromo-2,3-dihydro-Shinden-1-ylidene]amino-4-methylbenzene-1-sulfonate (166.37 g).

Reference example 6.

A suspension of [(1E)-5-bromo-2,3-dihydro-1H-inden-1-ylidene]amino-4-methylbenzene-1-sulfonate (4.77 g) in TFA (24 ml) was stirred at 60°C within 2 hours, TFA was removed under reduced pressure, and then the resulting substance was neutralized by adding a saturated aqueous solution of NaHCO ₃ and was extracted with DCM. The DCM layer was washed with water and brine and dried over anhydrous MgSO ₄ . The mixture was filtered and then the filtrate was concentrated under reduced pressure. The resulting black oil was purified by medium pressure column chromatography (hexane/AcOEt). The fractions were concentrated, the solids were filtered and washed with hexane/AcOEt=1:1 to give 6-bromo-1,2,3,4-tetrahydroisoquinolin-1-one (1.14 g).

Reference Example 7

Toluene (20 ml), (COCl) ₂ (2.268 ml) and a drop of DMF were added to 2-(difluoromethyl)benzoic acid (2.238 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the acid chloride. Methyl 6-aminonicotinate (2.374 g) was suspended in pyridine (20 ml) and a solution of the acid chloride in MeCN (10 ml) was added under ice-cooling conditions. The mixture was stirred at room temperature for 1 hour, then water was added and the precipitated crystal was filtered. The crystalline material was washed with water and air dried to give methyl 6-[2-(difluoromethyl)benzamido]pyridine-3-carboxylate (3.60 g).

Reference example 8.

To methyl 6-[2-(difluoromethyl)benzamido]pyridine-3-carboxylate (3.60 g) was added THF (18 ml) and 2N LiOH aqueous solution (17.63 ml). The mixture was stirred at room temperature for 2 hours and then the THF was removed under reduced pressure. Water (30 ml) and concentrated HCl (5 ml) were added to the mixture. The precipitated crystalline substance was filtered and washed with water. The crystalline material was dried in warm air to give 6-[2-(difluoromethyl)benzamido]pyridine-3-carboxylic acid (3.19 g).

Reference example 9.

Suspension of methyl 5-chloropyrazine-2-carboxylate (0.703 g), 2-chlorobenzamide (0.962 g), Cs ₂ CO ₃ (1.67 g), xantphos (0.225 g) and Pd ₂ (dba) ₃ (0.12 d) in dioxane (20 ml) was stirred in an argon atmosphere at 80°C for 9 hours. The suspension was cooled, then AcOEt and water were added to the suspension, and the mixture was stirred. Insoluble matter was removed through Celite. The filtrate was separated, the organic layer was washed with water and brine, dried over anhydrous MgSO4 and filtered. The solvent was removed and the resulting residue was purified by column chromatography (hexane/AcOEt) to give methyl 5-(2-chlorobenzamido)pyrazine-2-carboxylate (1.05 g).

Reference example 10.

To methyl 5-(2-chlorobenzamido)pyrazine-2-carboxylate (469 mg) was added MeOH (4.7 ml) followed by

- 17 040222 under ice-cooling was added 5N aqueous NaOH solution (1.3 ml). The mixture was stirred at room temperature for 2 hours and then adjusted to pH=7 with 1N HCl (6.5 ml) under ice-cooling. The precipitate was filtered and dried at 60° C. to give 5-(2-chlorobenzamido)-pyrazine-2-carboxylic acid (89 mg). The filtrate was further concentrated and the aqueous layer was adjusted to pH=4 with 1N HCl. The precipitated crystal was filtered and dried at 60° C. to give 5-(2-chlorobenzamido)pyrazine-2-carboxylic acid (330 mg).

Reference example 11.

To a solution of 2-chloro-6-methylbenzoic acid (1.08 g) in DCM (25 ml) were added DMF (50 μl) and (COCl) ₂ (1.7 ml) under ice-cooling conditions. The mixture was stirred at room temperature for 1.5 h, then the solvent was removed and the resulting substance was dissolved in DCM (10 ml). The resulting solution was added to a solution of methyl 6-aminonicotinate (0.965 g) and DIPEA (5.5 ml) in DCM (10 ml). The mixture was stirred at room temperature for 37 hours. The solvent was removed, and then AcOEt and water were added to the resulting solution. The mixture was separated, the organic layer was washed with water and brine, dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the resulting residue was purified by column chromatography (hexane/AcOEt) to give an ethyl ester. EtOH (12 ml) was added to the ester, and then 5N NaOH aqueous solution (3.8 ml) was added under ice-cooling conditions. The mixture was stirred at reflux for 7 hours and then 5N HCl (3.8 ml) was added under ice-cooling conditions. The resulting precipitate was filtered and dried at 60° C. to give 6-(2-chloro-6-methylbenzamido)pyridine-3-carboxylic acid (0.686 g).

Reference example 12.

Methyl 5-chloropyrazine-2-carboxylate (879 mg), 2-trifluoromethylbenzamide (1.05 g), Cs ₂ CO ₃ (2.31 g), xantphos (0.268 g) and Pd ₂ (dba) ₃ (0.141 g ) was stirred in dioxane (25.5 ml) under argon at 80° C. for 6 hours. The mixture was cooled and then AcOEt and water were added and the mixture was stirred. The insolubles were then filtered through Celite. The filtrate was separated, the organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and filtered. The solvent was removed and then the resulting residue was purified by column chromatography (hexane/AcOEt). The resulting substance was confirmed as methyl 5-[(2-(trifluoromethyl)benzamido]pyrazine-2-carboxylate (1.69 g) by ¹ H-NMR (CDCl ₃ ), MeOH (16.5 ml) was added thereto, and 5N NaOH aqueous solution (4.1 ml) was then added under ice-cooling conditions The mixture was stirred at room temperature for 4 hours The mixture was adjusted to pH=4 by adding 5N HCl (4.1 ml), the resulting precipitate was filtered and dried 60° C. to give 5-[2-(trifluoromethyl)-benzamido]-pyrazine-2-carboxylic acid (1.56 g).

Reference example 13.

2-Methylfuran-3-carboxylic acid (2.87 g) was dissolved in DMA (30 ml), the mixture was cooled on ice, and then SOCl ₂ (1.963 ml) was added. The mixture was stirred for 30 minutes and methyl 4-amino3-methoxybenzoate (3.75 g) was added. The mixture was then stirred at room temperature for 1 hour and then water was added. The precipitated crystalline substance was filtered. The resulting solid was dissolved in THF (30 ml) and then 2N LiOH aqueous solution (31.0 ml) was added. The mixture was stirred at 60° C. for 1 hour. 1N HCl (90 ml) was added to the mixture, and the mixture was stirred for 30 minutes under ice-cooling conditions. The precipitated crystal was filtered, washed with water, and then dried in warm air to give 3-methoxy-4-(2-methylfuran-3-amido)benzoic acid (4.81 g).

Reference example 14.

To a solution of methyl 4-amino-3-methoxybenzoate (2.0 g) in pyridine (27 ml) under nitrogen atmosphere was added 2-(trifluoromethyl)benzoyl chloride (1.7 ml), and the mixture was stirred at room temperature for 2 h Water was added to the reaction solution, the precipitate was filtered and washed with water. MeOH (30 ml) and 5N NaOH aqueous solution (4.4 ml) were added to the resulting solid, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized by adding 5N hydrochloric acid and water. The precipitate was filtered, washed with water and dried to give 3-methoxy-4-(2(trifluoromethyl)benzamido)benzoic acid (3.2 g).

Reference example 15.

To a solution of methyl 3-fluoro-4-[2-(trifluoromethyl)benzamido]benzoate (5.03 g) in MeOH (50 ml) was added 1 N aqueous NaOH solution (22.11 ml) at room temperature, and the mixture was stirred in during the night. 1N HCl was added to acidify the mixture, and then the mixture was stirred for 2 hours. The precipitated crystalline substance was filtered, washed with water and dried in air at 60°C to obtain 3-fluoro-4-[2-(trifluoromethyl)benzamido]benzoic acids (4.70 g).

Reference example 16.

To a solution of methyl 4-amino-3-(methoxymethoxy)benzoate (10.6 g) in pyridine (100 ml) was added 2-chlorobenzoyl chloride (6.99 ml) and the mixture was stirred at room temperature overnight. After the disappearance of the starting materials was confirmed, the mixture was poured into water, the resulting powder was filtered, washed with water and dried to obtain methyl 4-(2-chlorobenzamido)-3-(methoxymethoxy)benzoate

- 18 040222 (quantitative output).

Reference example 17.

To a suspension of methyl 4-(2-chlorobenzamido)-3-(methoxymethoxy)benzoate (17.5 g) in MeOH (200 ml) was added 5 N aqueous NaOH (20 ml) and the mixture was stirred at 60°C for 4, 5 h. After concentrating the mixture, 5N HCl (20 ml) was added to the mixture. The resulting powder was filtered, washed with water, and then dried to give 4-(2-chlorobenzamido)-3-(methoxymethoxy)benzoic acid (15.2 g).

Reference example 18.

To a solution of methyl 4-amino-3-(methoxymethoxy)benzoate (10 g) in pyridine (50 ml) was added 2(trifluoromethyl)benzoyl chloride (7.67 ml), and the mixture was stirred at room temperature overnight. After confirming the ester production by LCMS, water was added to the reaction solution, and the AcOEt mixture was extracted. The organic layer was concentrated. MeOH was added to the residue, which caused the residue to dissolve. A 5N NaOH aqueous solution (20 ml) was added to the solution, and the mixture was stirred at 60°C. After stirring for 8 hours, the mixture was cooled and then concentrated. 5N HCl (20 ml) was added to the concentrate to give a powder, the powder was filtered, washed with water and dried to give 3-(methoxymethoxy)-4-[2-(trifluoromethyl)benzamido]benzoic acid (16.5g).

Reference example 19.

To a solution of 2-chloro-4-fluorobenzoyl chloride (1.0 ml) in DMA (10 ml) was added 4-amino-3-methoxybenzoic acid (1.253 g) and the mixture was stirred at room temperature for 1 hour. Water was then added and the mixture was stirred. The precipitated powder was filtered, washed with water and then dried to give 4-(2-chloro-4-fluorobenzamido)-3-methoxybenzoic acid (2.4 g).

Reference example 21.

2-Chloro-5-fluorobenzoic acid (5.63 g) was dissolved in DMA (50 ml) and SOCl ₂ (2.82 ml) was added. The mixture was stirred at room temperature for 1.5 h and then 4-amino-3-fluorobenzoic acid (5 g) was added. The mixture was stirred at room temperature for 1 hour and then water was added. The precipitated solid was filtered, washed with water and then dried at 60° C. to give 4-(2-chloro-5-fluorobenzamido)-3-fluorobenzoic acid (9.59 g).

Reference example 22.

To a solution of 4'-fluoro-[1,1'-biphenyl]-2-carboxylic acid (2.5 g) in anhydrous DCM (40 ml) at room temperature was added SOCl ₂ (0.844 ml) and DMF (45 μl) and the mixture was stirred at 40° C. for 3 hours. The reaction solution was concentrated, and a solution of the resulting acid chloride in anhydrous DCM (20 ml) at 0° C. was added dropwise to a solution of methyl 6-aminonicotinate (1.759 g) and pyridine (1.870 ml) in anhydrous DCM (50 ml). The mixture was stirred overnight and then 1N HCl was added and the mixture was extracted twice with AcOEt/hexane (10/1). The combined organic layer was washed with aqueous NaHCO ₃ , dried over anhydrous MgSO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) and then crystallized from acetone-Et ₂ O. The filtrate was further concentrated and then purified by silica gel column chromatography (hexane/AcOEt). The material obtained was crystallized from an Et2O/n-hexane mixture and filtered. The products were combined to give methyl 6-{4'-fluoro-[1,1'-biphenyl]-2-amido}pyridine-3-carboxylate (3.36 g).

Reference example 23.

To a solution of methyl 6-{4'-fluoro-[1,1'-biphenyl]-2-amido}pyridine-3-carboxylate (3.85 g) in MeOH-THF (50 ml-40 ml) at room temperature 1N NaOH aqueous solution (16.48 ml) was added and the mixture was stirred overnight. The mixture was acidified with 1N HCl and extracted with AcOEt. The aqueous layer was further extracted with AcOEt, and then the combined organic layer was washed with brine. The organic layer was dried over anhydrous MgSO4 and then filtered and the filtrate was concentrated under reduced pressure. The resulting white powder was filtered, washed with hexane, and air dried to give 6-{4'-fluoro-[1,1'-biphenyl]-2-amido}pyridine-3-carboxylic acid (3.26 g).

Reference example 25.

DMF (50 ml), MeOH (10 ml) and TEA (10 ml) were added to 2-bromo-1-(difluoromethyl)-4-fluorobenzene (4.95 g). Pd(OAc) ₂ (0.494 g) and DPPP (0.907 g) were added and the mixture was stirred under a carbon monoxide atmosphere at 1 atm pressure at 70° C. for 24 hours. Water and AcOEt were then added to the mixture, and the insolubles were filtered. Water was added to the filtrate and the AcOEt mixture was extracted. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and then filtered and the filtrate was concentrated under reduced pressure to give methyl 2-(difluoromethyl)-5fluorobenzoate (2.08 g).

Reference example 26.

To methyl 2-(difluoromethyl)-5-fluorobenzoate (2.07 g) were added MeOH (15 ml) and 5 N NaOH aqueous solution (4.06 ml), and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture. and 1N HCl and extracted with a mixture of AcOEt. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and then filtered and the filtrate was concentrated under reduced pressure.

- 19 040222 to obtain 2-(difluoromethyl)-5-fluorobenzoic acid (1.83 g).

Reference example 27.

To a solution of 4-amino-3-methoxybenzoic acid (1.0 g) in DMA (8.0 ml) was added dropwise ortho-toluolyl chloride (0.74 ml) under ice-cooling under nitrogen atmosphere, and the mixture was stirred at room temperature within 1 day. Water was added to the mixture, the precipitate was filtered and washed with water to give 3-methoxy-4-(2-methylbenzamido)benzoic acid (1.6 g).

Reference example 30.

SOCl ₂ (0.36 ml) was added dropwise to a solution of 2-chloro-5-methylbenzoic acid (0.83 g) in DMA (6.0 ml) at room temperature under nitrogen, and the mixture was stirred for 2 hours. 4-Amino-3-methoxybenzoic acid (1.0 g) was added to the reaction solution, and the mixture was stirred at room temperature for 1 day. Water was added to the mixture, the precipitate was filtered and washed with water to give 3-methoxy-4-(2-chloro-5-methylbenzamido)benzoic acid (1.4 g).

Reference example 31.

To a solution of 2-chloro-5-methylbenzoic acid (0.83 g) in DCM (3 ml) under nitrogen atmosphere were added (COCl) ₂ (0.51 ml) and DMF (19 μl), and the mixture was stirred at room temperature in over 1 hour. The mixture was concentrated, the resulting residue was added dropwise to a solution of methyl 6-aminonicotinate (0.74 g) in pyridine (4.0 ml) under ice-cooling conditions, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction solution, the precipitate was filtered and washed with water. MeOH (12 ml) and 5N NaOH aqueous solution (4.9 ml) were added to the resulting solid, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was neutralized by adding 5N HCl (4.9 ml) and water under ice-cooling conditions, the precipitate was filtered and washed with water to obtain 6-(2-chloro-5-methylbenzamido)pyridine-3-carboxylic acid (1.03 g) .

Reference example 32.

Methyl 5-chloropyrazine-2-carboxylate (4.44 g), 2-chloro-5-fluorobenzamide (6.70 g), Cs ₂ CO ₃ (10.9 g), Pd ₂ dba ₃ (0.754 g) and xantphos (1.4 g) was suspended in dioxane (150 ml) and the mixture was stirred under argon at 80° C. for 5 hours. The mixture was distilled with AcOEt and then water was added. Insoluble matters were filtered off. The filtrate was extracted with AcOEt, washed with brine, and then dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt/hexane). The resulting material was concentrated and then dried under vacuum to give methyl 5-(2-chloro-5-fluorobenzamido)pyrazine-2-carboxylate (9.6 g).

Reference example 33.

Methyl 5-(2-chloro-5-fluorobenzamido)pyrazine-2-carboxylate (9.6 g) was dissolved in MeOH (100 ml). A 5N NaOH aqueous solution (18.60 ml) was added to the solution, and the mixture was stirred at room temperature for 4 hours. The mixture was adjusted to pH<4 with 5N HCl and diluted with water. The resulting solid was then filtered, washed with water and AcOEt, and dried at 60° C. to give 5-(2chloro-5-fluorobenzamido)pyrazine-2-carboxylic acid (6.2 g).

Reference example 35.

Mixture of 1,2,3,4-tetrahydroisoquinolin-1-one (1.0 g), 1,4-dioxane (10.0 ml), methyl 6-chloronicotinate (1.39 g), Pd ₂ (dba) ₃ (0.124 g), xantphos (0.197 g) and Cs ₂ CO ₃ (2.88 g) were stirred for 1 day at reflux under nitrogen. After cooling to room temperature, water was added to the reaction solution, and a mixture of AcOEt was extracted. The organic layer was dried over anhydrous Na ₂ SO ₄ and then filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give methyl 6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)pyridine-3-carboxylate (1.76 g).

Reference example 37.

MeOH (10.0 ml) and 5 N NaOH aqueous solution (6 , 23 ml), and the mixture was stirred at room temperature for 3 hours. The reaction solution was acidified by adding 5N HCl under ice-cooling conditions, the precipitate was filtered and washed with water to obtain 6-(1-oxo-1,2,3,4- tetrahydroisoquinolin-2yl)pyridine-3-carboxylic acid (1.63 g).

Reference example 39.

Mixture of 1,2,3,4-tetrahydroisoquinolin-1-one (0.509 g), methyl 4-iodo-3-methoxybenzoate (1.01 g), CuI (66.0 mg), DMEDA (74.0 µl) , K ₃ PO ₄ (1.47 g) and toluene (5.0 ml) were stirred at 90° C. under nitrogen for 1 day. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give methyl 3-methoxy-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)benzoate (1.08 g).

Reference example 41.

To a solution of 4-fluoro-2-methylbenzoic acid (2.77 g) in DMA (50 ml) under nitrogen atmosphere was added SOCl ₂ (1.379 ml) and the mixture was stirred at room temperature for 1 h. acid (3 g). The mixture was stirred at room temperature for 3

- 20 040222 h, and then water was added. The precipitated crystal was filtered and washed with water to give 4-(4-fluoro-2-methylbenzamido)-3-methoxybenzoic acid (5.20 g).

Reference example 44.

To a solution of 2-(difluoromethyl)pyridine-3-carboxylic acid (1.0 g) in DCM (3 ml) under nitrogen atmosphere were added (COCl) ₂ (0.556 ml) and DMF (1 drop), and the mixture was stirred at room temperature in for 2 h, and then at 50°C for 30 min. The residue was added dropwise to a solution of methyl-6-aminonicotinate (1.06 g) in pyridine (8.0 ml) under ice-cooling, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction solution, and the AcOEt mixture was extracted. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) and by recrystallization (hexane/AcOEt) to give methyl 6-[2-(difluoromethyl)pyridine-3-amido]pyridine-3-carboxylate (732 mg).

Reference example 45.

A mixture of methyl 6-[2-(difluoromethyl)pyridine-3-amido]pyridine-3-carboxylate (732 mg), THF (4.0 ml) and 2N LiOH aqueous solution (3.57 ml) was stirred at room temperature in for 2 hours. The reaction solution was neutralized by adding 5N HCl under ice-cooling, the precipitate was filtered and washed with water to give 6-[2-(difluoromethyl)pyridine-3-amido]pyridine-3-carboxylic acid (603 mg).

Reference example 48.

Methyl 5-chloropyrazine-2-carboxylate (1.0 g), [1,1'-biphenyl]-2-carboxamide (1.257 g), Cs ₂ CO ₃ (2.454 g), Pd ₂ dba ₃ (0.170 g) and xantphos (0.315 g) were suspended in dioxane (30 ml) and the mixture was stirred under argon at 80° C. overnight. The mixture was diluted with AcOEt and then water was added. Insoluble matters were filtered off. The filtrate was extracted with AcOEt, washed with brine and then dried over anhydrous Na2SO4. The filtrate was filtered and concentrated under reduced pressure, and then the residue was purified by column chromatography (hexane/AcOEt). The resulting material was concentrated and then dried under vacuum to give methyl 5-{[1,1'biphenyl]-2-amido}pyrazine-2-carboxylate (1.49 g).

Reference example 49.

Methyl 5-{[1,1'-biphenyl]-2-amido}pyrazine-2-carboxylate (1.49 g) was dissolved in MeOH (30 ml), 5N NaOH aqueous solution (1.788 ml) was added, and the mixture was stirred at room temperature for 24 hours. The mixture was adjusted to pH=5-6 with 5N HCl and water was added. The precipitated crystal was filtered, washed with water and AcOEt and dried at 60° C. to give 5{[1,1'-biphenyl]-2-amido}pyrazine-2-carboxylic acid (1.3 g).

Reference example 53.

Methyl 5-chloropyrazine-2-carboxylate (692 mg), 4-fluoro-[1,1'-biphenyl]-2-carboxamide (948.7 mg), Cs ₂ CO ₃ (1697 mg), Pd ₂ dba ₃ (183 mg) and xantphos (348 mg) were suspended in dioxane (25 ml) and the mixture was stirred under argon at 80° C. for 2 days. The mixture was diluted with AcOEt and then water was added. The mixture was extracted with AcOEt. The organic layer was washed with brine and then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/AcOEt). The resulting material was concentrated and then the resulting solid was dispersed, washed with AcOEt/hexane, filtered and dried at 60° C. to give methyl 5-{4-fluoro-[1,1'-biphenyl]-2-amido}pyrazine- 2 carboxylate (1.1 g).

Reference example 54.

Methyl 5-{4-fluoro-[1,1'-biphenyl]-2-amido}pyrazine-2-carboxylate (1.1 g) was suspended in MeOH (18 ml) and 5 N NaOH aqueous solution (1.879 ml) was added . The mixture was stirred at room temperature for 4 days. The mixture was adjusted to pH=5-6 by adding 5N HCl. Water was added to the mixture, and the mixture was stirred under ice-cooling conditions. The precipitated crystal was filtered and dried at 60° C. to give 5-{4-fluoro-[1,1'-biphenyl]-2-amido}pyrazine-2-carboxylic acid (620.8 mg).

Reference example 55.

4-Fluoro-[1,1'-biphenyl]-2-carboxylic acid (1.0 g) was suspended in toluene (10 ml) and then (COCl) ₂ (0.442 ml) and DMF (16 μl) were added under conditions cooling on ice. The mixture was then warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and a solution of the resulting acid chloride in MeCN (10 ml) was added dropwise to a suspension of methyl 6-aminonicotinate (0.640 g) in pyridine (20 ml). The mixture was stirred for 1 hour. Water was added to the mixture and the precipitated solid was filtered. The solid was suspended in MeOH (20 ml) and 5N NaOH (2.102 ml) was added. The mixture was stirred at room temperature overnight. The mixture was adjusted to pH=5 by adding 5N HCl. Water was added to the mixture, the precipitated solid was filtered and dried at 60°C to give 6-{4fluoro-[1,1'-biphenyl]-2-amido}pyridine-3-carboxylic acid (1.00 g).

- 21 040222

Reference example 58.

2-Phenyl-3-pyridinecarboxylic acid (1.00 g) was suspended in toluene (10 ml), (COCl) ₂ (0.479 ml) and DMF (35 μl) were added under ice-cooling conditions, the mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure and the resulting acid chloride was suspended in MeCN (5 ml). Methyl 6-aminonicotinate (0.694 g) and pyridine (20 ml) were then added under ice-cooling conditions, and the mixture was stirred for 1 hour. Water was then added to the mixture, and the resulting solid was filtered. The solid was suspended in MeOH (20 ml) and 5N NaOH aqueous solution (1.825 ml) was added. The mixture was stirred at room temperature overnight. The mixture was adjusted to pH=5 by adding 5N HCl. Water was added to the mixture, the resulting solid was filtered and dried at 60°C to obtain 6-(2-phenylpyridine-3amido)pyridine-3-carboxylic acid (849.3 mg).

Reference example 59.

Methyl 5-chloropyrazine-2-carboxylate (459 mg), 2-phenylpyridine-3-carboxamide (580.3 mg), Cs ₂ CO ₃ (1127 mg), Pd ₂ dba ₃ (122 mg) and xantphos (231 mg ) was suspended in dioxane (15 ml) and the mixture was stirred in an argon atmosphere at 80° C. for 60 h. The mixture was diluted with AcOEt, then water was added and the AcOEt mixture was extracted. The organic layer was washed with brine and then dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure, and then the resulting residue was purified by column chromatography (hexane/AcOEt). The resulting material was concentrated and dried in vacuo to give methyl 5-(2-phenylpyridine-3amido)pyrazine-2-carboxylate (417.2 mg).

Reference example 61.

To a suspension of 5-fluoro-2-methylbenzoic acid (3.99 g) in DCM (50 ml) at 0°C was added (COCl) ₂ (5.14 ml) and DMF (91 μl) and the mixture was stirred at room temperature in for 1 hour. The reaction solution was concentrated and then azeotropically distilled twice with DCM. A solution of the residue in DCM was added to a solution of methyl 6-amino-5-fluoropyridine-3-carboxylate (2 g) in DCM (30 ml) and pyridine (9.51 ml) and the mixture was stirred overnight. A saturated NaHCO ₃ aqueous solution was added to the mixture, and the AcOEt mixture was extracted. The organic layer was washed with 1N HCl and brine, and then dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and added to the resulting residue MeOH (50 ml) and 5N NaOH aqueous solution (5.17 ml). The mixture was stirred at room temperature overnight. The mixture was neutralized with HCl, the precipitated solid was filtered and dried to give 5-fluoro-6-(5-fluoro-2-methylbenzamido)pyridine-3-carboxylic acid (2.54 g).

Reference example 62.

To a suspension of 6-bromo-1,2,3,4-tetrahydroisoquinolin-1-one (1.0 g), 1-chloro-4-fluoro-2-iodobenzene (1.134 g), DMEDA (0.094 ml) and K3PO4 ( 1.878 g) in toluene (10 ml) CuI (0.084 g) was added under a stream of nitrogen and the mixture was stirred at 90° C. under nitrogen atmosphere overnight. Then, 1-chloro-4-fluoro-2-iodobenzene (0.3 g) was added at room temperature, and the mixture was stirred at 90° C. under nitrogen atmosphere overnight. The mixture was cooled and then concentrated. The resulting crude product was purified by medium pressure column chromatography (hexane/AcOEt) to give 6-bromo-2-(2-chloro-5fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-one (0.75 g).

Reference example 69.

tert-Butyl acrylate ( 0.929 ml), LiCl (0.090 g) and TEA (1.474 ml), and then PdCl ₂ (PPh ₃ ) ₂ (0.074 g) was added to the mixture under a stream of nitrogen. The mixture was stirred at 150° C. under nitrogen for 5 hours. Water was then added at room temperature and the AcOEt mixture was extracted. The organic layer was concentrated, and then the resulting crude product was purified by medium pressure column chromatography (hexane/AcOEt) to give t-butyl-(2E)-3-[2-(2-chloro-5-fluorophenyl)-1oxo-1,2 ,3,4-tetrahydroisoquinolin-6-yl]prop-2-enoate (0.85 g).

Reference example 70.

To a solution of tert-butyl-(2E)-3-[2-(2-chloro-5-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6yl]prop-2-enoate (0.85 d) NaIO ₄ (2.262 g) and OsO ₄ (immobilized cat.; 0.230 g) were added to THF:H ₂ O (3:2, 10 ml) and the mixture was stirred at 50° C. for 2.5 hours. The mixture was cooled and then filtered through Celite. Water was added to the filtrate and the AcOEt mixture was extracted. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated to give 2-(2-chloro-5-fluorophenyl)-1-oxo1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde (0.7 g, crude). To a solution of 2-(2-chloro-5-fluorophenyl)-1oxo-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde (0.7 g) in DCM/t-BuOH/H ₂ O (1/1/ 1; 6 ml) 2methyl-2-butene (1.221 ml), NaClO2 (1.042 g) and NaH2PO4 (1.383 g) were added and the mixture was stirred at room temperature overnight. Water was added to the mixture, the mixture was extracted with AcOEt and washed with brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 2-(2-chloro-5-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (0.67 g).

- 22 040222

Reference example 79.

To a solution of 5-fluoro-2-(trifluoromethyl)benzoic acid (2.54 g) in DMA (20 ml) was added SOCl ₂ (0.933 ml) and the mixture was stirred at room temperature for 2.5 hours. the remaining starting materials were added to the mixture with additional SOCl ₂ (0.170 ml). The mixture was then stirred for 1 hour. 4-Amino-meta-toluic acid (1.757 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The mixture was then homogenized by adding 5N NaOH aqueous solution (20 ml) and water, and then washing the aqueous layer with AcOEt. The aqueous layer was acidified with 5N HCl and then iPr ₂ O was added. The mixture was stirred for a while, the precipitated solid was filtered and dried at 60° C. to give 4-[5-fluoro-2(trifluoromethyl)benzamido]-3-methylbenzoic acids (2.874 g).

Reference example 81.

4,4'-Difluoro-[1,1'-biphenyl]-2-carboxylic acid (1.75 g) was dissolved in DMA (10 ml), SOCl ₂ (0.709 ml) was added and the mixture was stirred at room temperature for 2 h. 4-Aminobenzoic acid (1.025 g) was added to the reaction solution, and the mixture was stirred at room temperature for 15 h. The disappearance of starting materials was detected by LC-MS. Water was added to the reaction solution, the precipitated solid was filtered, washed with water, air dried at 60°C, and then dried under reduced pressure at 60°C to obtain 4-{4,4'difluoro-[1,1 '-biphenyl]-2-amido}benzoic acid (2.58 g).

Reference example 95.

To a solution of 4,2'-difluoro-1,1'-biphenyl-2-carboxylic acid (2.00 g) in DCM (50 ml) under nitrogen atmosphere were added (COCl) ₂ (1.495 ml) and DMF (50 μl) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and then the residue was dissolved in DCM (50 ml). Then, methyl 6-aminonicotinate (1.364 g) and pyridine (2.072 ml) were added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and then the concentrate was dissolved in THF (15 ml) and MeOH (15 ml) . Under ice-cooling, 5N NaOH aqueous solution (5.12 ml) was added to it, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized by adding 5N hydrochloric acid and water under ice-cooling, the resulting precipitate was filtered and washed with water with obtaining 6-{2',4-difluoro-[1,1'-biphenyl]-2-amido}pyridine-3-carboxylic acid (2.60 g).

Reference example 97.

4-Fluoro-2'-methoxy-[1,1'-biphenyl]-2-carboxylic acid (2.5 g) was dissolved in DMA (100 ml), DMF (10 µl) and SOCl2 (0.963 ml) were added and stirred mixture at room temperature for 2 hours. 4-Aminobenzoic acid (1.420 g) was added to the mixture, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, the precipitated solid was filtered and dried in air at 60° C to give 4-{4-fluoro-2'-methoxy-[1,1'-biphenyl]-2amido}benzoic acid (3.8 g).

Reference example 98.

4-Fluoro-2'-methoxy-[1,1'-biphenyl]-2-carboxylic acid (2.5 g) was dissolved in DMA (20 ml), SOCl ₂ (0.963 ml) was added and the mixture was stirred at room temperature in over 2 hours. 4-Amino-3-fluorobenzoic acid (1.606 g) was added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the AcOEt mixture was extracted. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was crystallized from DCM. The resulting solid was dispersed and washed with AcOEt/hexane=1/3, filtered and air dried to give 3-fluoro-4-{4-fluoro-2'methoxy-[1,1'-biphenyl]-2-amido} benzoic acid (3.32 g).

Reference Example 99.

4-Fluoro-2'-methoxy-[1,1'-biphenyl]-2-carboxylic acid (2.5 g) was dissolved in DCM/DMA=2/1 (120 ml), (COCl)2 ( 10.15 ml) and pyridine (1.642 ml) and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated and DCM (50 ml) and DMA (30 ml) were added. Then, methyl 6-aminonicotinate (1.576 g) and pyridine (1.642 ml) were added successively and the mixture was stirred at room temperature for 15 hours. Disappearance of the starting materials was detected by LC-MS, but the diacyl yield was approximately 10%. The reaction solution was concentrated. The residue was dissolved in MeOH/THF=1/1 (60 ml), 1N NaOH (30 ml) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated and washed with a small amount of AcOEt, and the aqueous layer was separated. To the resulting aqueous layer was added 5N HCl (7 ml) and the mixture was adjusted to pH 3-4 by further addition of 1N HCl. The precipitated solid was filtered and air dried at 60°C to give 6-{4-fluoro-2'methoxy-[1,1'-biphenyl]-2-amido}pyridine-3-carboxylic acid (2.26 G).

Reference example 109.

To a solution of 4,3'-difluoro-1,1'-biphenyl-2-carboxylic acid (2.0 g) in DCM (30 ml) under nitrogen atmosphere were added (COCl) ₂ (1.495 ml) and DMF (51 μl) and the mixture was stirred at room temperature for 1.5 hours. The residue under ice-cooling conditions was added dropwise to a solution of methyl-6

- 23 040222 aminonicotinate (1.364 g) in pyridine (15 ml) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, the precipitate was filtered and washed with water. MeOH (20 ml), THF (20 ml) and 5N NaOH aqueous solution (5.12 ml) were added to the resulting solid, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized by adding 5N hydrochloric acid and water under cooling conditions. on ice, the precipitate was filtered and washed with IPE to give 6-{3',4-difluoro-[1,1'-biphenyl]-2-amido}pyridine-3-carboxylic acid (2.38 g).

Reference example 116.

7-Methyl-1,2,3,4-tetrahydroisoquinolin-1-one (3 g), methyl 4-iodobenzoate (4.88 g), CuI (0.354 g), DMEDA (0.396 ml) and K ₃ PO ₄ (7.90 g) was mixed in 1,4-dioxane (50 ml) and the mixture was stirred at 90° C. overnight. The mixture was filtered through Celite and then the filtrate was washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent was removed. The obtained crude crystalline substance was washed with Et ₂ O and dried in air at 60°C to obtain methyl 4-(7-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)benzoate (4.42 G).

Reference example 121.

A solution of methyl 4-(7-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)benzoate (4.42 g) in EtOH (90 ml) was cooled on ice and then 5 N aqueous NaOH solution (14.97 ml) and water. The mixture was stirred at room temperature for 3 hours. The solvent was removed and then the residue was adjusted to pH=1 with 5N HCl.

The resulting crystal was filtered and air-dried at 60° C. to obtain 4(7-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)benzoic acid (2.45 g).

Reference example 137.

To a solution of 2-chlorobenzoyl chloride (0.227 ml) in DMA (8 ml) was added 4-amino-3-methoxybenzoic acid (300 mg) and the mixture was stirred at room temperature overnight. Water was added to the mixture and the mixture was stirred for 30 minutes. The precipitate was then filtered, washed with water and Et ₂ O and air dried at 60° C. to give 4-(2-chlorobenzamido)-3-methoxybenzoic acid (470 mg).

Reference example 138.

To a suspension of 2-(trifluoromethyl)pyridine-3-carboxylic acid (9.76 g) in DCM (200 ml) at 0°C was added (COCl) ₂ (13.41 ml) and DMF (0.119 ml) and the mixture was stirred at 0° C. for 1 hour and then stirred at 30-40° C. for 2 hours. The reaction solution was concentrated, and then the DCM concentrate was diluted. The resulting solution was added to a suspension of methyl 6-aminonicotinate (7.77 g) in pyridine (20.65 ml) and DCM (200 ml). The mixture was stirred at room temperature for 2 hours and then the DCM was removed under reduced pressure. Water was added to the residue and the AcOEt mixture was extracted. The organic layer was dried over anhydrous Na ₂ SO ₄ and then filtered and concentrated. The resulting residue was dissolved in MeOH-THF (4:1; 200 ml), and then a 5N NaOH aqueous solution (20.43 ml) was added and the mixture was stirred at 60° C. for 2 hours. The reaction solution was concentrated and the MeOH was removed. The residue was then diluted with water and adjusted to pH (4-5) by adding aq. HCl. The precipitated solid was filtered and washed with water to give 6-[2-(trifluoromethyl)pyridine3-amido]pyridine-3-carboxylic acid (11.21 g).

Reference example 139.

N-[(52) -7-chloro-1-(4methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-ylidene]butan-1-amine (197 g) and the mixture was stirred at room temperature for 3 days . To the mixture were added concentrated HCl (203 ml) and ice water, and the mixture was stirred. The precipitate was filtered and washed with water to give 7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (187 g).

Reference example 140.

7-Chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (240 g) was added to concentrated sulfuric acid under ice-cooling conditions. acid (265 ml) and the mixture was stirred at room temperature for 4 hours. The reaction solution was added to 50% NaOH aqueous solution (796 g) and ice (3 L), the precipitate was filtered and washed with heated water to obtain 7-chloro-4, 4difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (138 g).

Reference example 141.

To a solution of 7-chloro-4,4-difluoro-5-(hydroxymethyl)-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro1H-1-benzazepin-5-ol (286 mg) in MeOH ( 10 ml) at room temperature was added Mg (250 mg) and I ₂ (34.7 mg) and the mixture was stirred under nitrogen atmosphere. The mixture was heated at reflux for 4 h, and then was added a saturated aqueous solution of NaHCO ₃ . The mixture was filtered through Celite and washed with AcOEt. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and then the resulting residue was purified by column chromatography (hexane/AcOEt) to give 7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1 H-1-benzazepine5 -ola (90 mg).

- 24 040222

Reference example 142.

To a solution of 7-chloro-4,4-difluoro-5-(hydroxymethyl)-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro1H-1-benzazepin-5-ol (250 mg) in THF ( 2 ml) under nitrogen atmosphere at room temperature was added Im (122 mg), and then at 0°C was added TBDMSCl (135 mg). The mixture was stirred at the same temperature for 1 hour and then diluted with water and extracted with AcOEt. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated, and the resulting residue was purified by column chromatography (hexane/AcOEt) to give 5-{[(tert-butyldimethylsilyl)oxy]methyl}-7-chloro-4,4-difluoro1 -(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (278 mg).

Reference example 143.

5-{[(tert-Butyldimethylsilyl)oxy]methyl}-7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5tetrahydro-1H-1-benzazepin-5-ol ( 278 mg), MeOH (5 ml) and Mg (63.5 mg) were stirred under nitrogen at room temperature. The mixture was heated under reflux for 5 h, and then was added a saturated aqueous solution of NaHCO ₃ . The mixture was filtered through Celite and washed with AcOEt. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography (hexane/AcOEt) to give 5-{[(tert-butyldimethylsilyl)oxy]methyl}-7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine -5-ol (102 mg).

Reference example 144.

A mixture of 7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (113 g), THF (400 ml), Boc ₂ O (114 ml) and DMAP (1.79 g) was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from IPA/hexane. The filtrate was further concentrated under reduced pressure, recrystallized from IPA/hexane and washed with hexane to give tert-butyl-7-chloro-4,4-difluoro-5oxo-2,3,4,5-tetrahydro-1H-1-benzazepine -1-carboxylate (117 g).

Reference example 145.

To a solution of 7-chloro-4,4-difluoro-5-methyl-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1benzazepin-5-ol (0.769 g) in MeOH (20 ml ) under nitrogen atmosphere at room temperature was added Mg (0.465 g) and heated the mixture under reflux for 5 hours Then was added a saturated aqueous solution of NaHCO ₃ , the mixture was filtered through Celite and washed with AcOEt. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue was then purified by column chromatography (hexane/AcOEt) to obtain 7-chloro-4,4-difluoro-5-methyl-2,3,4,5tetrahydro-1H-1-benzazepin-5-ol (0.414 g).

Reference example 146.

To a solution of trimethylsulfoxonium iodide (0.982 g) in DMSO (12 ml) was added KOtBu (0.375 g) and the mixture was stirred under nitrogen at room temperature for 30 minutes. Then, tert-butyl-7-chloro-4,4-difluoro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (0.74 g) was added at room temperature. The mixture was stirred at room temperature for 2 hours and then water was added. The mixture was extracted with AcOEt. The combined organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. DMF/H ₂ O=4:1 (12 ml) and AcONa (1.464 g) were then added to the obtained residue at room temperature, and the mixture was stirred at 80° C. for 24 hours. The reaction mixture was extracted with AcOEt, washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue was then recrystallized from DCM-hexane to give tert-butyl-7-chloro-4,4-difluoro-5-hydroxy-5(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1 -carboxylate (0.491 g).

Reference example 147.

A mixture of 7-chloro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (20.0 g), nbutylamine (8.48 ml), cyclohexane (150 ml) and TFA (0.661 ml) were stirred at reflux for 12 h with removal of water in a Dean-Stark trap. The reaction solution was concentrated under reduced pressure, and the residue was washed with AcOEt/hexane to give N-[(5Z)-7-chloro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1- benzazepine-5-ylidene]butan-1-amine (21.4 g).

Reference example 150.

tert-Butyl-(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-({[(2R)-2-(4-methylbenzenesulfonamido)-3phenylpropanoyl]oxy}methyl)-2,3 mixture ,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (0.20 g), EtOH (1.0 ml) and 5 N NaOH aqueous solution (0.18 ml) were stirred at room temperature for 3 h. Water was added to the reaction solution, and a mixture of AcOEt was extracted. The organic layer was dried over Na2SO4 and then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give tert-butyl(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro -1H-1-benzazepine-1-carboxylate (99 mg).

Reference example 151.

A mixture of [(5R)-7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl-(2S)-2(naphthalene- 1-sulfonamido)-3-phenylpropanoate (1.10 g), potassium trimethylsilanolate (1.05 g) and THF (9.0

- 25 040222 ml) was stirred at room temperature for 1 h, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt), dispersed and washed with DCM/hexane to give (5R)-7-chloro-4,4-difluoro-5(hydroxymethyl)-2,3,4,5-tetrahydro -1H-1-benzazepin-5-ol (350 mg).

Reference example 152.

tert-Butyl-(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1benzazepine-1-carboxylate (500 mg) was dissolved in EtOH (10 ml), 12N HCl (0.115 ml) was added and the mixture heated to reflux. After 1 hour the reaction was not complete, additional 12 N HCl (0.5 eq.) was added to the mixture and the mixture was heated at reflux for 1 hour. The mixture was concentrated, dissolved in AcOEt, and re-concentrated to obtain a crystalline substance. The crystalline material was dried under vacuum to give (5R)-7-chloro-4,4-difluoro-5(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol hydrochloride (412, 51 mg).

Reference example 153.

tert-Butyl-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine1-carboxylate (200 mg), TEA (Ο, 23θ ml), THF (2 ml), 4-bromobenzoyl chloride (145 mg) and DMAP (6.72 mg) were added at room temperature and the mixture was stirred for 30 minutes. The reaction solution was concentrated, and the resulting residue was purified by column chromatography (hexane/AcOEt) to obtain tert-butyl-5-[(4-bromobenzoyloxy)-methyl]-7-chloro-4,4-difluoro-5-hydroxy-2,3 ,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (317 mg).

Reference example 154.

tert-Butyl-(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (21, 86 g) was dissolved in THF (200 ml), then TEA (25.1 ml) and 4-bromobenzoyl chloride (13.19 g) were added and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture and the AcOEt mixture was diluted. The mixture was washed with 1N HCl, 1N NaOH and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. AcOEt (20 ml) and DCM (30 ml) were added to the obtained residue, which led to the formation of a crystalline substance. The crystalline substance was dispersed and washed with AcOEt:DCM:hexane=2:3:2, and then filtered and dried at 60°C to obtain tert-butyl-(5R)-5-[(4bromobenzoyloxy)methyl]-7-chloro- 4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine-1 carboxylate (24.7 g; Lot 1). The filtrate was concentrated under reduced pressure, purified by column chromatography (AcOEt/hexane) and concentrated. Then, the concentrate was crystallized from a mixture of DCM/AcOEt/hexane, filtered and dried at 60°C to obtain tert-butyl-(5R)-5[(4-bromobenzoyloxy)methyl]-7-chloro-4,4-difluoro-5 -hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (6.1 g; Lot 2). The filtrate was further concentrated and then crystallized from DCM/hexane. The resulting material was filtered and dried at 60°C to give tert-butyl-(5R)-5-[(4bromobenzoyloxy)methyl]-7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5- tetrahydro-1H-1-benzazepine-1-carboxylate (2.2 g; Lot 3). The structures of the substances in Lot 1, Lot 2 and Lot 3 were confirmed by ¹ H-NMR. The optical purity in each batch was 100% ee, 99.9% ee. and 100% ee, respectively. The batches were combined to give tert-butyl-(5R)-5-[(4-bromobenzoyloxy)methyl]-7-chloro-4,4difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine- 1-carboxylate (33.0 g) (It is believed to be present in the form of a co-crystal with DCM (1:1) or a solvate with DCM).

Reference Example 155 tert-Butyl-(5R)-5-[(4-bromobenzoyloxy)methyl]-7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro1H-1-benzazepine- 1-carboxylate (33.0 g) was dissolved in DCM (100 ml), then TFA (46.5 ml) was added and the mixture was stirred at room temperature. The mixture was stirred for 3 hours and neutralized by adding saturated aqueous sodium bicarbonate under ice-cooling. The mixture was extracted with AcOEt, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting solid was filtered and dried at 60° C. to give [(5R)-7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin5-yl]methyl -4-bromobenzoate (23.35 g).

Reference Example 156 tert-Butyl 7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine 1-carboxylate (50 mg) was dissolved in THF (2 ml), then TEA (0.057 ml) and 4-bromobenzoyl chloride (30.2 mg) were added and the mixture was stirred at room temperature. The reaction mixture was quenched by the addition of water, and the mixture was diluted with AcOEt. The mixture was washed with 1N HCl, 1N NaOH and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (AcOEt/hexane) and dried under vacuum. The resulting tert-butyl 5-[(4-bromobenzoyloxy)methyl]-7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5tetrahydro-1H-1-benzazepine-1-carboxylate was dissolved in DCM (2 ml), TFA (0.318 ml) was added and the mixture was stirred at room temperature for 2 hours. The mixture was cooled on ice, neutralized with saturated aqueous sodium bicarbonate and extracted with AcOEt. The extract was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Received

- 26 040222 the residue was purified by column chromatography (hexane/AcOEt), concentrated and then dried in vacuo to give (7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H -1-benzazepin-5yl)methyl-4-bromobenzoate (38.3 mg).

Reference examples 157 and 158.

tert-Butyl-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine 1-carboxylate (1 g), TEA (1.149 ml ), THF (10 ml), (S)-2-(4-methylphenylsulfonamido)-3-phenylpropanoyl chloride (0.929 g) and DMAP (0.034 g) were added at room temperature, and the mixture was stirred for 20 h. The reaction solution was concentrated under reduced pressure, and purified the resulting residue by column chromatography (hexane/AcOEt), and then recrystallized from a mixture of DCM/n-hexane to obtain tert-butyl-(5S)-7-chloro-4,4-difluoro-5-hydroxy-5( {[(2S)-2-(4-methylbenzenesulfonamido)-3-phenylpropanoyl]oxy}methyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (430 mg; Reference Example 157) and tert-butyl-(5R)-7-chloro-4,4-difluoro-5hydroxy-5-({[(2S)-2-(4-methylbenzenesulfonamido)-3-phenylpropanoyl]oxy}methyl)-2,3 ,4,5-Tetrahydro 1H-1-benzazepine-1-carboxylate (740 mg; Reference Example 158).

Reference example 159.

To a solution of 7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5one (1.50 g) in anhydrous THF (20 ml) at 0° C., lithium aluminum deuteride (0.163 g) was added and the mixture was stirred overnight. Water (0.16 ml), 15% NaOH aqueous solution (0.16 ml) and water (0.48 ml) were added to the reaction solution, the mixture was stirred and then filtered through Celite and washed with AcOEt. Water was added to the filtrate and the filtrate was extracted with AcOEt. The combined organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give 7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro( ^5-2H )1H-1 -benzazepin-5-ol (1.04 g).

Reference example 160.

To a solution of 7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro( ^5-2H )-1H-1-benzazepin-5-ol (1.04 g ) in anhydrous MeOH (20 ml) magnesium (0.390 g) was added and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with AcOEt (20 ml) and then 5N HCl (10.16 ml) was added at 0°C. Water was then added to the mixture and stirred. The mixture was stirred at room temperature and extracted with AcOEt. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 7-chloro-4,4-difluoro-2,3,4,5-tetrahydro( ^5-2 H)-1H-1benzazepin-5-ol (473 mg).

Reference example 161.

tert-Butyl-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine 1-carboxylate (133 g), THF (1200 ml ), TEA (153 ml), DMAP (4.47 g) and (R)-2-(4methylphenylsulfonamido)-3-phenylpropanoyl chloride (148 g) were mixed under ice-cooling conditions, and the mixture was stirred at room temperature for 3 hours. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized (ether/hexane). The filtrate was purified by silica gel column chromatography (hexane/AcOEt) and recrystallized (ether/hexane) to give tert-butyl-(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-({[ (2R)-2-(4methylbenzenesulfonamido)-3-phenylpropanoyl]oxy}methyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (92.4 g).

Reference example 162.

From the filtrate tert-butyl-(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-({[(2R)-2-(4-methylbenzenesulfonamido)-3-phenylpropanoyl]oxy}-methyl) -2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate was obtained tert-butyl-(5S)-7-chloro-4,4-difluoro-5-hydroxy-5-({[(2R) -2-(4-methylbenzenesulfonamido)-3-phenylpropanoyl]oxy}methyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (128 g).

Reference example 163.

5-Fluoro-2-(pyridin-2-yl)benzoic acid (688 mg) was dissolved in DMA (20 ml), SOCl ₂ (0.301 ml) was added, and the mixture was stirred at room temperature for 2 hours. Methyl -4-amino-3-fluorobenzoate hydrochloride (651 mg), and the mixture was stirred at room temperature for 15 hours. An aqueous solution of NaHCO ₃ was added to the reaction solution, and a mixture of AcOEt was extracted. The organic layer was washed with aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The precipitated solid was dispersed and washed with AcOEt/hexane=1/2, the resulting solid was filtered and air dried to give methyl 3-fluoro-4-[5-fluoro-2-(pyridin-2-yl)benzamido ]benzoate (970 mg).

Reference example 164.

Methyl 3-fluoro-4-[5-fluoro-2-(pyridin-2-yl)benzamido]benzoate (970 mg) was dissolved in MeOH/THF=3/1, 5N NaOH aqueous solution (2.63 ml) was added ) and the mixture was stirred at 60° C. for 6 hours. The reaction solution was concentrated, acidified by adding 5N HCl (3.68 ml), concentrated and dried under reduced pressure. The residue was dissolved in ethanol and filtered off insoluble

- 27 040222 washing substances. The filtrate was concentrated, THF was added to the residue, the mixture was again concentrated and dried at 50°C under reduced pressure to obtain 3-fluoro-4-[5-fluoro-2(pyridin-2-yl)benzamido]benzoic acid hydrochloride (1, 02 d).

Reference example 165.

To a solution of tert-butyl-(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-({[(2R)-2-(4-methylbenzenesulfonamido)-3-phenylpropanoyl]oxy}methyl)- 2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (2 g) in DCM (4 ml) TFA (2.317 ml) was added at room temperature and the mixture was stirred for 1 h. The mixture was neutralized by adding saturated aqueous solution of NaHCO ₃ and then diluted with AcOEt. The precipitated solid was filtered and washed with water and AcOEt to give [(5R)-7chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl] methyl-(2R)-2-(4-methylbenzenesulfonamido)-3-phenylpropanoate (1.35 g).

Reference example 166.

Trimethylsulfoxonium iodide (228 mg), DMSO (4 ml) and KOtBu (87 mg) were stirred under nitrogen at room temperature for 30 minutes. 7-Chloro-4,4difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (200 mg) was added at room temperature and the mixture was stirred for 2 h The mixture was diluted with water and extracted with AcOEt. The organic layer was washed with water and brine, and then dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and the resulting residue was purified by column chromatography (hexane/AcOEt) to give 7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydrospiro[1 benzazepine-5,2 '-oxirane] (200 mg; including ~0.2 eq AcOEt).

Reference example 167.

To a solution of methyltriphenylphosphonium bromide (956 mg) and 7-chloro-4,4-difluoro-1-(4methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (860 mg) in anhydrous THF (10 ml) under nitrogen at 0° C. KOtBu (300 mg) was added. The mixture was stirred at room temperature for 2 hours, then water was added and the AcOEt mixture was extracted. The organic layer was dried over anhydrous Na2SO4 and then filtered and concentrated. The resulting residue was purified by column chromatography (hexane/AcOEt) to give 7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-5methylidene-2,3,4,5-tetrahydro-1H-1-benzazepine (270 mg).

Reference example 168.

To a solution of 7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-5-methylidene-2,3,4,5-tetrahydro-1H-1benzazepine (270 mg) in THF/H ₂ O/acetone (1/1/2; 8 ml) NMO (165 mg) and 4% aq. OsO ₄ (447 mg). The mixture was stirred at room temperature for 1 week, then a saturated aqueous Na ₂ SO ₃ solution was added and the AcOEt mixture was extracted. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography (hexane/AcOEt) to give 7-chloro-4,4-difluoro-5(hydroxymethyl)-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1- benzazepin-5-ol (210 mg).

Reference example 169.

To a solution of 7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5one (1 g) in THF (10 ml) under nitrogen atmosphere at 0° C., 1.0 M methylmagnesium bromide (3.37 ml) was added dropwise. The mixture was stirred at 0°C for 2 h, then a saturated aqueous solution of NH4C1 was added and the mixture was extracted with AcOEt. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue was recrystallized from DCM/AcOEt/hexane to give 7chloro-4,4-difluoro-5-methyl-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5- ol (769 mg).

Reference example 170.

To a solution of trimethylsulfoxonium iodide (80 g) in DMSO (500 ml) under nitrogen atmosphere was added KOtBu (30.4 g) and the mixture was stirred at room temperature for 1 hour. Then tert-butyl-7-chloro-4 was added at room temperature ,4-difluoro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1carboxylate (60 g), the mixture was stirred for 2.5 h, and then ice water (2 l). The mixture was filtered and washed with water. AcOEt and water were added to the resulting residue, and the AcOEt mixture was extracted. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. DMF/H ₂ O=2:1 (600 ml) and AcONa (119 g) were added to the resulting residue at room temperature, and the mixture was stirred at 80°C for 24 hours. The reaction solution was poured into ice water (2 L), the mixture was filtered and washed with water. AcOEt and water were added to the resulting residue, and the AcOEt mixture was extracted. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was triturated with the addition of DCM (2 ml/g) and hexane (2 ml/g). The insoluble matter was filtered to give tert-butyl-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro1H-1-benzazepine-1-carboxylate (29.4 g ). The filtrate was concentrated and the residue was purified by column chromatography (hexane/AcOEt) to give tert-butyl-7-chloro-4,4-difluoro-5-hydroxy-5(hydroxymethyl)-2,3,4,5-tetrahydro-1H- 1-benzazepine-1-carboxylate (4.82 g) and tert-butyl-7-chloro-4,4difluoro-1,2,3,4-tetrahydrospiro[1-benzazepine-5,2'-oxetane]-1- carboxylate (18.38 g).

- 28 040222

Reference examples 171 and 172.

tert-Butyl-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate mixture (2.0 g) , THF (20 ml), TEA (2.3 ml), DMAP (0.067 g) and N-(1-naphthalenesulfonyl)-L-phenylalanyl chloride (2.47 g) were stirred at room temperature for 2 hours. The reaction solution was concentrated under conditions reduced pressure and purified the resulting residue by silica gel column chromatography (hexane/AcOEt) to obtain tert-butyl-(5S)-7-chloro-4,4-difluoro-5hydroxy-5-({[(2S)-2-(naphthalene -1-sulfonamido)-3-phenylpropanoyl]oxy}methyl)-2,3,4,5-tetrahydro-1H1-benzazepine-1-carboxylate (1.56 g; Reference Example 171) as a highly polar product and tert -butyl-(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-({[(2S)-2-(naphthalene-1-sulfonamido)-3-phenylpropanoyl]oxy}methyl)-2 ,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (1.51 g; Reference Example 172) as a low polarity product.

Reference example 174.

To a solution of tert-butyl-(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-({ [(2S)-2-(naphthalene-1-sulfonamido)3-phenylpropanoyl]oxy}methyl) -2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (1.3 g) in DCM (8.0 ml) TFA (2.143 ml) was added under nitrogen atmosphere. The resulting solution was stirred at room temperature for 1.5 hours. A saturated NaHCO ₃ aqueous solution was added to the solution, and a mixture of AcOEt was extracted. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give [(5R)-7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5tetrahydro-1 H-1 -benzazepin-5-yl]methyl-(2S)-2-(naphthalene-1-sulfonamido)-3-phenylpropanoate (1.18 g, contains ~0.9 eq AcOEt).

Reference example 175.

A mixture of [(5S)-7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl-(2S)-2(naphthalene- 1-sulfonamido)-3-phenylpropanoate (827 mg), potassium trimethylsilanolate (784 mg) and THF (7.0 ml) were stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) and then dispersed and washed with DCM/hexane to give (5S)-7-chloro-4,4-difluoro-5(hydroxymethyl)-2,3,4,5 -tetrahydro-1H-1-benzazepin-5-ol (257 mg).

Reference example 176.

A mixture of tert-butyl-(5S)-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1benzazepine-1-carboxylate (0.97 d), EtOH (10 ml) and concentrated HCl (0.667 ml) were stirred at 70° C. for 1 hour. The reaction solution was concentrated under reduced pressure. AcOEt was added to the residue and the mixture was further concentrated under reduced pressure to give (5S)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1- benzazepin-5-ol hydrochloride (820 mg).

Reference example 177.

To a mixture of toluene/H ₂ O=1:1 (1 ml) at room temperature was added tert-butyl-7-chloro-4,4difluoro-1,2,3,4-tetrahydrospiro[1-benzazepine-5,2'-oxetane ]-1-carboxylate (200 mg) and tetrabutylammonium sulfate (377 mg), and then the mixture was stirred at 100° C. for 1.5 days. The reaction mixture was purified by alkaline silica gel column chromatography (hexane/AcOEt) to give 7chloro-4,4-difluoro-5-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5- ol (122 mg).

Reference example 178.

To a solution of 7-chloro-4,4-difluoro-5-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (1.728 g) and Im (1.271 g) in DCM (30 ml) at 0°C was added TBDMSCl (1.125 g). The mixture was stirred at room temperature for 10 minutes and then diluted with water and extracted with AcOEt. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography (hexane/AcOEt) to give 5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1 -benzazepin-5-ol (2.016 g).

Reference example 179.

To a solution of 7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydrospiro[1-benzazepine5,2'-oxirane] (8 g) in DMF:H ₂ O =4:1 (50 ml) in a nitrogen atmosphere at room temperature was added NaN ₃ (6.50 g). The mixture was stirred at 70° C. for 4 hours and then water was added. The precipitated crystalline substance was filtered and washed with water. The resulting material was washed with IPA to give 5-(azidomethyl)-7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H1-benzazepin-5-ol (quantitative yield ).

Reference example 180.

To a solution of 5-(azidomethyl)-7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H1-benzazepin-5-ol (9.8 g) in EtOH (80 ml) at room temperature under nitrogen was added zinc powder (5.79 g) and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated. The resulting crude product was dried under vacuum. Boc ₂ O (6.10 ml) was added to a THF (80 ml) solution of the resulting material, and the mixture was stirred under nitrogen at room temperature for 30 minutes. The reaction solution was concentrated, and the resulting residue was purified by column chromatography (hexane/AcOEt) to obtain

- 29 040222 I eat tert-butyl-M-{[7-chloro-4,4-difluoro-5-hydroxy-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-III-1benzazepine-5- yl]methyl}carbamate (6.92 g).

Reference example 181.

To a solution of tert-butyl-M-{[7-chloro-4,4-difluoro-5-hydroxy-1-(4-methylbenzenesulfonyl)-2,3,4,5tetrahydro-1H-1-benzazepin-5-yl] methyl}carbamate (6.92 g) in MeOH (80 ml) under nitrogen atmosphere were added iodine (3.40 mg) and magnesium (3.7 g) and heated the mixture under reflux for 3 hours. To the reaction solution was added 1 n HCl (294 ml) and the reaction solution was extracted with AcOEt. The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography (hexane/AcOEt) to give tert-butyl-N-[(7-chloro4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine-5 -yl)methyl]carbamate (4.05 g).

Reference example 182.

SOCl2 (0.316 ml) was added to a solution of 4-(2-chloro-5-fluorobenzamido)-3-methoxybenzoic acid (1.338 g) in DMA (15 ml) under nitrogen at room temperature, and the mixture was stirred for 2 h. temperature was added tert-butyl-N-[(7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5tetrahydro-1H-1-benzazepin-5-yl)methyl]carbamate (1 g), and the mixture was stirred for 1 day. Saturated aqueous NaHCO ₃ was added to the mixture, the precipitated solid was filtered and washed with water. The resulting crude crystalline material was purified by column chromatography (hexane/AcOEt) to give tert-butyl-N-({7-chloro-1-[4-(2-chloro-5-fluorobenzamido)-3methoxybenzoyl]-4,4-difluoro- 5-Hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl}methyl)carbamate (1.73 g; contains ~0.7 eq AcOEt).

Reference example 183.

To a solution of tert-butyl-(5S)-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro1H-1-benzazepine-1-carboxylate (515 mg ) in anhydrous THF (5.0 ml) under nitrogen atmosphere under ice-cooling conditions was added 55% NaH (154 mg). TsCl (283 mg) was added to the reaction solution at the same temperature, and the mixture was stirred at room temperature for 2 hours. A 1N NaOH aqueous solution was added to the reaction solution, and the AcOEt mixture was extracted. The organic layer was dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/AcOEt) to give tert-butyl-(5S)-7-chloro-4,4-difluoro-1,2,3,4-tetrahydrospiro [1-benzazepine-5,2'-oxirane]-1-carboxylate (371 mg).

Reference example 185.

tert-Butyl-(5S)-7-chloro-4,4-difluoro-1,2,3,4-tetrahydrospiro[1-benzazepine-5,2'-oxirane]-1 carboxylate mixture (371 mg), EtOH (5.5 ml) and NaBH ₄ (81 mg) were stirred at 50° C. for 6 hours. Water was added to the reaction solution, and the AcOEt mixture was extracted. The organic layer was dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/AcOEt) to give tert-butyl-(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-methyl-2,3,4 ,5-tetrahydro-1H-1-benzazepine-1-carboxylate (334 mg).

Reference example 187.

tert-Butyl-(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-methyl-2,3,4,5-tetrahydro-1H-1-benzazepine 1-carboxylate mixture (334 mg), DCM (4.0 ml) and TFA (0.740 ml) were stirred for 1 hour. The reaction solution was neutralized by adding saturated sodium bicarbonate aqueous solution and extracted with AcOEt. The organic layer was dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/AcOEt) to give (5R)-7-chloro-4,4-difluoro-5-methyl-2,3,4,5-tetrahydro- 1H-1benzazepin-5-ol (183 mg).

Reference example 189.

To a solution of 2-chloro-N-{5-[7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1benzazepine-1-carbonyl] pyridin-2-yl}-5-fluorobenzamide (820 mg) in DCM (5 ml) TMPDA (0.736 ml) and TsCl (337 mg) were added at 0°C. The mixture was stirred at 0° C. for 6 h and then aqueous sodium bicarbonate was added, the mixture was extracted with AcOEt, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give N-[5-({7-chloro-4,4- difluoro-1,2,3,4-tetrahydrospiro[1-benzazepin-5,2'oxirane]-1-yl}carbonyl)pyridin-2-yl]-2-(trifluoromethyl)benzamide (882 mg).

Reference example 190.

A suspension of pentamethylcyclopentadienylridium (III) chloride dimer (0.829 g) and N-((1R,2R)-2amino-1,2-diphenylethyl)-2,3,4,5,6-pentafluorobenzenesulfonamide (1.48 g) in water ( 800 ml) was stirred under nitrogen atmosphere at 50°C for 4 hours. The suspension was cooled, then HCO ₂ Na (198 g) was added and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0°C, DCM ( 500 ml) and 7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (225 g) and the mixture was stirred at 0° C. overnight. The DCM layer was separated and concentrated to give (5R)-7chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (228 g ).

- 30 040222

Reference example 191.

To a solution of (5R)-7-chloro-4,4-difluoro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (284 g) in MeOH ( 1 L) magnesium (17.80 g) was added at room temperature and the mixture was stirred while heating at 70°C. AcOEt (1 L) was added to the reaction solution, and the mixture was stirred. The reaction solution was slowly poured into a mixture of 5N HCl (1.465 L), water (500 ml) and AcOEt (1 L), and the mixture was stirred. After the solids had dissolved, the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated. Hexane (1 L) and Et ₂ O (300 ml) were added to the concentrate, the mixture was heated under reflux, dispersed and washed. The resulting substance was immediately filtered by hot filtration to obtain a powder, and the powder was dried to obtain (5R)-7chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (119 g ).

Reference example 192.

To a solution of 6-[2-(trifluoromethyl)benzamido]pyridine-3-carboxylic acid (2.280 g) in DMA (40 ml) was added SOCl ₂ (1.0 ml) and the mixture was stirred at room temperature overnight. Then, a solution of (5R)-7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (1.145 g) in DMA (20 ml) was added and stirred mixture at room temperature overnight. AcOEt and water were added to the mixture, the mixture was extracted with AcOEt, washed with saturated aqueous sodium bicarbonate and brine, filtered and concentrated. The residue was then purified by medium pressure column chromatography (hexane/AcOEt). The resulting crude crystalline material was recrystallized from AcOEt/hexane to give (5R)-N-{5-[(5R)-7-chloro-4,4-difluoro-5hydroxy-2,3,4,5-tetrahydro-1H- 1-benzazepine-1-carbonyl]pyridin-2-yl}-2-(trifluoromethyl)benzamide (1.2 g).

Reference example 195.

SOCl ₂ (0.104 ml) was added dropwise to a solution of 6-{[1,1'-biphenyl]-2-amido}pyridine-3-carboxylic acid (440 mg) in DMA (20 ml) in a water bath. The mixture was stirred at the same temperature for 40 min, and then a solution of (5R)-7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5ol (323 mg) was added in DMA (3 ml). The mixture was stirred for 2 h, then an aqueous solution of NaHCO ₃ was added and extracted with a mixture of AcOEt/hexane (10/1). The combined organic layer was washed with water and dried over anhydrous MgSO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography (hexane/AcOEt), crystallized from acetone/hexane, the crystal was filtered and washed with Et ₂ O/hexane (1/20) to give N-{5-[(5R)-7-chloro -4,4difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-[1,1'-biphenyl]-2carboxamide (390 mg) .

Reference example 196.

SOCl ₂ (75 µl) was added to a solution of 4-(2-chloro-5-fluorobenzamido)benzoic acid (264 mg) in DMA (3.0 ml) and the mixture was stirred at room temperature for 30 minutes. Then (5R)-7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (200 mg) was added at 0°C and the mixture was stirred for 4 h Then a saturated aqueous solution of NaHCO ₃ was added and the AcOEt mixture was extracted. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography (hexane/AcOEt) and crystallized from AcOEt/hexane to give 2-chloro-N-{4-[(5R)-7-chloro-4,4-difluoro-5-hydroxy-2, 3,4,5-tetrahydro-1 H-1 benzazepine-1-carbonyl]phenyl}-5-fluorobenzamide (374.4 mg).

Reference example 199.

SOCl was added to a solution of 6-{4-fluoro-[1,1'-biphenyl]-2-amido}pyridine-3-carboxylic acid (360 mg) in DMA (4.0 ml) under nitrogen atmosphere under ice-cooling conditions. ₂ (86.0 µl) and the mixture was stirred at the same temperature for 2 hours. Then (5R)-7-chloro-4,4-difluoro2,3,4,5-tetrahydro-1H-1 was added at the same temperature -benzazepin-5-ol (250 mg) and the mixture was stirred at room temperature for 3 days. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and a mixture of AcOEt was extracted. The organic layer was washed with 1N NaOH aqueous solution and brine, and then dried over Na ₂ SO ₄ . Na ₂ SO ₄ was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/AcOEt) to give N-{5-[(5R)-7-chloro-4,4-difluoro-5- hydroxy-2,3,4,5-tetrahydro1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-4-fluoro-[1,1'-biphenyl]-2-carboxamide (429 mg).

Reference example 201.

4-{4-Fluoro-[1,1'-biphenyl]-2-amido}benzoic acid (746 mg) was dissolved in DMA (10 ml), SOCl2 (0.187 ml) was added and the mixture was stirred at room temperature for 2 h (5R)-7-Chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (400 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. A 1N NaOH aqueous solution was added to the reaction solution, and a mixture of AcOEt was extracted. The organic layer was washed with 1N aqueous NaOH and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (hexane/AcOEt) to give N-{4-[(5R)-7-chloro-4,4-difluoro-5-hydroxy2,3,4,5-tetrahydro-1H-1-benzazepine- 1-carbonyl]phenyl}-4-fluoro-[1,1'-biphenyl]-2-carboxamide (940 mg).

- 31 040222

Examples

Example 1

SOCl ₂ (30.0 μl) was added to a solution of 6-(2-chlorobenzamido)pyridine-3-carboxylic acid (113 mg) in DMA (1.0 ml) under nitrogen atmosphere under ice-cooling conditions, and the mixture was stirred at the same temperature for 2 hours. At the same temperature, 7-chloro-4,4-difluoro-5-(hydroxymethyl)2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (90.0 mg ) and stirred the mixture at room temperature for 3 days. Saturated aqueous NaHCO ₃ and water were added to the reaction solution, the precipitate was filtered and purified by alkaline silica gel column chromatography (hexane/AcOEt) to obtain 2-chloro-N-{5-[7-chloro-4,4-difluoro-5 -hydroxy-5-(hydroxymethyl)-2,3,4,5tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}benzamide (50.0 mg).

Example 2

To a solution of 6-[2-(trifluoromethyl)benzamido]pyridine-3-carboxylic acid (164 mg) in DMA (2 ml) was added SOCl ₂ (38 μl) and the mixture was stirred at 0°C for 2 h under nitrogen atmosphere, and then 5-{[(tert-butyldimethylsilyl)oxy]methyl}-7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1benzazepin-5-ol (100 mg). The mixture was stirred at room temperature for 3 days, and then a saturated aqueous solution of NaHCO ₃ was added. The precipitated solid was filtered and washed with water. The solids were dissolved in THF (2 ml), a 1M solution of TBAF in THF (0.529 ml) was added and the mixture was stirred for 2 h under nitrogen atmosphere. Water was added to the mixture and the AcOEt mixture was extracted. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography (hexane/AcOEt) and recrystallized from EtOH to give N-{5-[7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5 -tetrahydro1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-2-(trifluoromethyl)benzamide (86 mg).

Example 3

SOCl ₂ (0.161 ml) was added to a solution of 6-(2-chloro-5-fluorobenzamido)pyridine-3-carboxylic acid (654 mg) in DMA (7 ml) and the mixture was stirred at 0° C. for 2 h under atmosphere nitrogen. At 0°C, 7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (450 mg) was added and the mixture was stirred at room temperature over 18 hours. Saturated aqueous NaHCO ₃ was added to the mixture, the precipitated solid was washed with water and purified by column chromatography (hexane/AcOEt) to give 2-chloro-N-{5-[7-chloro-4,4 -difluoro-5-hydroxy-5(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-5-fluorobenzamide (740 mg).

Example 8

SOCl2 (152 µl) was added to a solution of 6-[2-(trifluoromethyl)benzamido]pyridine-3-carboxylic acid (651 mg) in DMA (7.0 ml) under nitrogen atmosphere under ice-cooling conditions, and the mixture was stirred at the same temperature. temperature for 2 hours. At the same temperature, 7-chloro-4,4-difluoro-5-methyl-2,3,4,5tetrahydro-1H-1-benzazepin-5-ol (400 mg) was added and the mixture was stirred at room temperature for 2.5 days. A saturated NaHCO ₃ aqueous solution and water were added to the reaction solution. The precipitate was filtered and washed with water, and then purified by alkaline silica gel column chromatography (hexane/AcOEt) and recrystallized (hexane/AcOEt) to give Ν-[5-(7-χλορ4,4-difluoro-5-hydroxy-5- methyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl)pyridin-2-yl]-2-(trifluoromethyl)benzamide (836 mg).

Example 13

SOCl2 (0.128 ml) was added to a solution of 6-(2-trifluorobenzamido)nicotinic acid (549 mg) in DMA (6 ml) under nitrogen atmosphere under ice-cooling conditions, and the mixture was stirred at room temperature for 2 hours. Then at room temperature (5R)-7-chloro-4,4-difluoro-5(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (500 mg) was added and the mixture was stirred for 3 days. A saturated NaHCO ₃ aqueous solution and water were added to the reaction solution, and the precipitate was filtered. The resulting solid was mixed with ethanol (10 ml) and 5N NaOH aqueous solution (0.885 ml) and the mixture was stirred at room temperature for 30 minutes.

The reaction solution was neutralized by adding ice water and 5N HCl, the precipitate was filtered and washed with water. The resulting solid was purified by alkaline silica gel column chromatography (hexane/AcOEt) to give N-{5-[(5R)-7-chloro-4,4-difluoro-5-hydroxy-5(hydroxymethyl)-2.3, 4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-2-(trifluoromethyl)benzamide (400 mg).

Example 14

SOCl ₂ (39 μl) was added to a solution of 6-(2-chloro-5-fluorobenzamido)pyridine-3-carboxylic acid (160 mg) in DMA (2.0 ml) under nitrogen atmosphere under ice-cooling conditions, and the mixture was stirred at at the same temperature for 2 hours. Then (5S)-7-chloro-4,4-difluoro-5(hydroxymethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine was added at the same temperature -5-ol (110 mg), and the mixture was stirred at room temperature for 3 hours. Saturated aqueous NaHCO3 and water were added to the reaction solution, the precipitate was filtered and purified by alkaline silica gel column chromatography (hexane/AcOEt/MeOH) to give 2 -chloro-N-{5-[(5S)-7-chloro-4,4-difluoro-5-hydroxy-5

- 32 040222 (hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-5-fluorobenzamide (156 mg).

Example 15

SOCl ₂ (50 μl) was added to a solution of 6-(2-chloro-5-fluorobenzamido)pyridine-3-carboxylic acid (203 mg) in DMA (2.5 ml) at 0°C under nitrogen atmosphere and the mixture was stirred for 2 hours. Then (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (140 mg) and the mixture was stirred at room temperature for 3 hours. Saturated aqueous NaHCO ₃ was added to the mixture. The precipitated crystal was filtered, washed with water, purified by alkaline silica gel column chromatography (hexane/AcOEt/MeOH) and recrystallized (hexane/AcOEt) to give 2-chloro-N-{5-[(5R)-7- chloro-4,4-difluoro-5-hydroxy-5(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-5-fluorobenzamide (202 mg ).

Example 16

SOC12 (136 μl) was added to a solution of 6-[2-(trifluoromethyl)benzamido]pyridine-3-carboxylic acid (581 mg) in DMA (5.0 ml) under nitrogen atmosphere under ice-cooling conditions, and the mixture was stirred at the same temperature for 2 hours. Then 7-chloro-4,4-difluoro-5(hydroxyethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (400 mg) was added at the same temperature and the mixture was stirred at room temperature for 3 hours. Saturated aqueous NaHCO ₃ and water were added to the reaction solution, the precipitate was filtered and then purified by alkaline silica gel column chromatography (hexane/AcOEt) to obtain N-{5-[7- chloro-4,4-difluoro-5-hydroxy-5-(2-hydroxyethyl)-2,3,4,5tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-2-(trifluoromethyl) benzamide (53 mg).

Example 17.

SOCl2 (65.0 μl) was added to a solution of 6-(2-chlorobenzamido)pyridine-3-carboxylic acid (248 mg) in DMA (1.5 ml) under nitrogen atmosphere under ice-cooling conditions, and the mixture was stirred at the same temperature for 2 hours. Then, at the same temperature, [(5R)-7-chloro-4,4-difluoro-5-hydroxy2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl -4-bromobenzoate (400 mg) and the mixture was stirred at room temperature for 1 day. A saturated NaHCO ₃ aqueous solution and water were added to the reaction solution, and the precipitate was filtered. Ethanol (2.0 ml) and 5N NaOH aqueous solution (0.448 ml) were added to the resulting solid, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was neutralized by adding ice water and 5N HCl, the precipitate was filtered and washed with water. The resulting solid was purified by silica gel column chromatography (hexane/AcOEt) and recrystallized (hexane/AcOEt) to give 2-chloro-N-{5[(5R)-7-chloro-4,4-difluoro-5-hydroxy -5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}benzamide (200 mg).

Example 19.

6-(2,3-Dichlorobenzamido)pyridine-3-carboxylic acid (153 mg) was dissolved in DMA (1 ml) and then SOC12 (42 μl) was added under ice-cooling conditions. The mixture was stirred for 30 minutes. Then (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (100 mg) was added and the mixture was stirred at room temperature. temperature during the night. A saturated NaHCO ₃ aqueous solution was added to the mixture, and the AcOEt mixture was extracted. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated. The residue was purified by column chromatography (hexane/AcOEt), crystallized from hexane/AcOEt, and filtered to give 2,3-dichloro-N-{5-[(5R)-7-chloro-4,4-difluoro-5- hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1benzazepine-1-carbonyl]pyridin-2-yl}benzamide (135 mg).

Example 21.

4-[2-(Trifluoromethyl)benzamido]benzoic acid (152 mg) was dissolved in DMA (2 ml) and then SOCl2 (42 μl) was added. The mixture was stirred at room temperature for 2.5 hours. Then (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine- 5-ol (100 mg) and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with AcOEt and water was added. The mixture was extracted with AcOEt/hexane. The organic layer was washed with 1N HCl, 1N NaOH and brine and dried over anhydrous Na ₂ SO ₄ . Filtered with Na ₂ SO ₄ and concentrated the filtrate under reduced pressure. The resulting residue was then purified by column chromatography (AcOEt/hexane, then AcOEt/MeOH) and concentrated to give a crystal. The crystalline material was dispersed, washed with AcOEt/hexane and filtered. The resulting substance was dried under vacuum at 60°C to obtain N-{4-[(5R)-7-chloro-4,4difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro- 1H-1-benzazepine-1-carbonyl]phenyl}-2(trifluoromethyl)benzamide (135.8 mg).

Example 23.

4-(2-Chloro-5-fluorobenzamido)benzoic acid (145 mg) was dissolved in DMA (2 ml) and then SOCl2 (42 μl) was added. The mixture was stirred at room temperature for 2.5 hours. Then (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine- 5-ol (100 mg) and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with AcOEt and water was added.

- 33 040222

The mixture was extracted with AcOEt/hexane. The organic layer was washed with 1N HCl, 1N NaOH and brine, dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt/hexane, then AcOEt/MeOH) and concentrated to give a crystal. The crystalline material was dispersed and washed with AcOEt/hexane and filtered. The resulting substance was dried under vacuum at 60°C to obtain 2-chloro-N-{4-[(5R)-7-chloro-4,4-difluoro-5hydroxy-5-(hydroxymethyl)-2,3,4, 5-tetrahydro-1H-1-benzazepine-1-carbonyl]phenyl}-5-fluorobenzamide (124.7 mg).

Example 24.

4-(2-Chloro-5-fluorobenzamido)-3-fluorobenzoic acid (154 mg) was dissolved in DMA (2 ml) and then SOCl ₂ (42 μl) was added. The mixture was stirred at room temperature for 2.5 hours. Then (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine- 5-ol (100 mg) and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with AcOEt and water was added. The mixture was extracted with AcOEt/hexane and washed with 1N HCl, 1N NaOH and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt/hexane, then AcOEt/MeOH) and concentrated to give a crystal. The crystalline material was dispersed, washed with AcOEt/hexane and filtered. The resulting substance was dried under vacuum at 60°C to obtain 2-chloro-N-{4-[(5R)-7-chloro-4,4-difluoro-5hydroxy-5-(hydroxymethyl)-2,3,4, 5-tetrahydro-1H-1-benzazepine-1-carbonyl]-2-fluorophenyl}-5-fluorobenzamide (114.9 mg).

Example 25.

4-(2,5-Dichlorobenzamido)benzoic acid (153 mg) was dissolved in DMA (2 ml) and then SOCl2 (42 μl) was added. The mixture was stirred at room temperature for 2.5 hours. Then (5R)7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5 was added -ol (100 mg) and the mixture was stirred at room temperature for 3 hours. The mixture was extracted with AcOEt and water was added. The mixture was extracted with AcOEt/hexane. The organic layer was washed with 1N HCl, 1N NaOH and brine, dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt/hexane, then AcOEt/MeOH). After concentration, the concentrate was dried under vacuum, and the resulting amorphous substance was dried under vacuum at 60°C to obtain 2,5-dichloro-N-{4-[(5R)-7-chloro-4,4difluoro-5-hydroxy -5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]phenyl}benzamide (95.8 mg).

Example 26.

4-(2,5-Dichlorobenzamido)-3-fluorobenzoic acid (162 mg) was dissolved in DMA (2 ml) and SOCl2 (42 μl) was added. The mixture was stirred at room temperature for 2.5 hours. Then (5R)7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5 was added -ol (100 mg) and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with AcOEt and water was added. The mixture was extracted with AcOEt/hexane. The organic layer was washed with 1N HCl, 1N NaOH and brine, dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt/hexane, then AcOEt/MeOH). After concentration, the concentrate was dried under vacuum, and the resulting amorphous substance was dried under vacuum at 60°C to obtain 2,5-dichloro-N-{4-[(5R)-7-chloro-4,4difluoro-5-hydroxy -5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]-2-fluorophenyl}benzamide (154 mg).

Example 33.

6-(2,3-Dichlorobenzamido)pyridine-3-carboxylic acid (124 mg) was dissolved in DMA (1 ml) and the solution was cooled on ice. Then SOCl ₂ (34 μl) was added and the mixture was stirred for 30 minutes. Then (5S)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin5-ol hydrochloride (100 mg) was added and the mixture was stirred at room temperature within 2 hours To the mixture was added a saturated aqueous solution of NaHCO ₃ and was extracted with a mixture of AcOEt. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated. The residue was purified by column chromatography (hexane/AcOEt), crystallized from hexane/AcOEt and filtered to give 2,3-dichloro-N-{5-[(5S)-7-chloro-4,4-difluoro-5-hydroxy -5-(hydroxymethyl)2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}benzamide (120 mg).

Example 34.

SOCl2 (120 µl) was added to a solution of 4-(2-chloro-5-fluorobenzamido)-3-methoxybenzoic acid (459 mg) in DMA (6.0 ml) under nitrogen atmosphere under ice-cooling conditions, and the mixture was stirred at the same temperature. temperature for 2 hours. Then 5-(2-(tert-butyldimethylsilyloxy)ethyl)-7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine was added at the same temperature -5-ol (500 mg) and the mixture was stirred at room temperature for 1 day. In another reaction vessel to a solution of 4-(2-chloro-5-fluorobenzamido)-3-methoxybenzoic acid (459 mg) in DMA (6.0 ml) under atmosphere

SOC12 (120 μl) was added under ice-cooling conditions, and the mixture was stirred at the same temperature for 2 hours. The mixture was added at room temperature to the reaction solution, and the mixture was stirred for 1 day. A saturated NaHCO ₃ aqueous solution and water were added to the reaction solution, and the precipitate was filtered. To a solution of the resulting solid in THF (4.0 ml) was added a 1M solution of TBAF in THF (2.55 ml), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the AcOEt mixture was extracted. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane/AcOEt/MeOH) and recrystallized (hexane/AcOEt) to give 2-χλορ-Ν{4-[7-chloro-4,4-difluoro-5-hydroxy-5-(2- hydroxyethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]2-methoxyphenyl}-5-fluorobenzamide (205 mg).

Example 37.

SOCl ₂ (43.0 μl) was added to a solution of 4-(5-fluoro-2-methylbenzamido)benzoic acid (162 mg) in DMA (2.5 ml) under nitrogen atmosphere under ice-cooling conditions, and the mixture was stirred at the same temperature for 2 hours. Then (5R)-7-chloro-4,4-difluoro-5(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol was added at the same temperature (120 mg) and stirred the mixture at room temperature for 1 day. Saturated aqueous NaHCO ₃ and water were added to the reaction solution, the precipitate was filtered and purified by alkaline silica gel column chromatography (hexane/AcOEt/MeOH) to obtain N-{4-[(5R)-7-chloro-4,4-difluoro -5-hydroxy-5-(hydroxymethyl)2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]phenyl}-5-fluoro-2-methylbenzamide (159 mg).

Example 51.

6-(2,4-Dichlorobenzamido)pyridine-3-carboxylic acid (165 mg) was dissolved in DMA (2 ml) and then SOCl2 (44 µl) was added. The mixture was stirred at room temperature. After stirring the mixture for 2 hours, (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1benzazepin-5-ol (100 mg) was added and the mixture was stirred overnight. The mixture was diluted with AcOEt and then water was added. The mixture was extracted with AcOEt/hexane, washed with 1N HCl, 1N NaOH and brine, dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt/hexane, then AcOEt/MeOH). After concentration, the concentrate was dried under vacuum and the resulting amorphous substance was dried under vacuum at 60°C to obtain 2,4-dichloro-N-{5-[(5R)-7-chloro-4,4difluoro-5-hydroxy-5 -(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2yl}benzamide (80.5 mg).

Example 52.

6-(2,4-Dichloro-5-fluorobenzamido)pyridine-3-carboxylic acid (175 mg) was dissolved in DMA (2 ml) and then SOCl ₂ (44 μl) was added. The mixture was stirred at room temperature. After 2 h, (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (100 mg) was added and the mixture was stirred during the night. The mixture was diluted with AcOEt and then water was added. The mixture was extracted with AcOEt/hexane. The organic layer was washed with 1N HCl, 1N NaOH and brine, dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt/hexane, then AcOEt/MeOH). After concentration, the concentrate was dried under vacuum and the resulting amorphous substance was dried under vacuum at 60°C to obtain 2,4-dichloro-N-{5-[(5R)-7-chloro-4,4difluoro-5-hydroxy-5 -(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-5fluorobenzamide (61.8 mg).

Example 57.

3-Methoxy-4-(2-methylfuran-3-amido)benzoic acid (161 mg) was dissolved in DMA (2 ml) and then SOCl2 (48 µl) was added. The mixture was stirred at room temperature for 2 hours. Then (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5- ol (110 mg) and stirred the mixture for 3 days. The mixture was diluted with AcOEt and water was added. The mixture was extracted with AcOEt/hexane. The organic layer was washed with 1N HCl, 1N NaOH and brine, dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt/hexane, then AcOEt/MeOH), concentrated and then dried in vacuo. The resulting solid was filtered and dried under vacuum at 60° C. to give N-{4-[(5R)-7-chloro-4,4-difluoro-5-hydroxy-5(hydroxymethyl)-2,3,4, 5-tetrahydro-1H-1-benzazepine-1-carbonyl]-2-methoxyphenyl}-2-methylfuran-3 carboxamide (132.7 mg).

Example 58.

4-(2-Chloro-4-fluorobenzamido)-3-methoxybenzoic acid (189 mg) was dissolved in DMA (2 ml) and then SOCl2 (48 μl) was added. The mixture was stirred at room temperature for 2 hours. Then (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5- ol (110 mg) and stirred the mixture for 3 days. The mixture was diluted with AcOEt and water was added. The mixture was extracted with AcOEt/hexane. The organic layer was washed with 1N HCl, 1N NaOH and brine.

- 35 040222 solution, dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt/hexane, then AcOEt/MeOH). After concentration, the concentrate was dried under vacuum and the resulting amorphous substance was dried under vacuum at 60° C. to obtain 2-chloro-N-{4-[(5R)-7-chloro-4,4-difluoro-5hydroxy-5- (hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]-2-methoxyphenyl}-4-fluorobenzamide (141.3 mg).

Example 63.

SOCl ₂ (30.0 μl ) and stirred the mixture for 2 h. Then (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5 ol (80 mg) and the mixture was stirred for 7 hours. Saturated aqueous NaHCO ₃ and water were added to the reaction solution, the precipitate was filtered and purified by alkaline silica gel column chromatography (hexane/AcOEt/MeOH) to give N-{5-[ (5R)-7-chloro4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridine-2yl}-[1, 1'-biphenyl]-2-carboxamide (104 mg).

Example 65.

tert-Butyl-N-({7-chloro-1-[4-(2-chloro-5-fluorobenzamido)-3-methoxybenzoyl]-4,4-difluoro-5-hydroxy2,3,4,5-tetrahydro- 1H-1-benzazepin-5-yl}methyl)carbamate (1.2 g), EtOH (10 ml) and concentrated HCl (0.449 ml) were mixed at room temperature under nitrogen and the mixture was heated under reflux for 3 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by alkaline silica gel column chromatography (hexane/AcOEt/MeOH) and acid silica gel column chromatography (hexane/AcOEt/MeOH) to give N-{4[5-(aminomethyl) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]-2-methoxyphenyl}-2-chloro-5-fluorobenzamide (715 mg).

Example 66.

SOCl ₂ (30 μl) was added to a solution of 6-[2-(trifluoromethyl)pyridine-3-amido]pyridine-3-carboxylic acid (123 mg) and DMA (1.5 ml) at room temperature under nitrogen atmosphere and the mixture was stirred for 2 hours. Then (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (80 mg) and stirred the mixture for 1 day. A saturated NaHCO ₃ aqueous solution and water were added to the reaction solution. The precipitate was filtered, washed with water and purified by alkaline silica gel column chromatography (hexane/AcOEt/MeOH) to give N-{5-[(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl )-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-2-(trifluoromethyl)pyridine-3-carboxamide (83 mg).

Example 71.

To a solution of 4-(2-chloro-4-fluorobenzamido)-3-methylbenzoic acid (194 mg) in DMA (2.5 ml) at room temperature under nitrogen was added SOC12 (43.0 μl) and the mixture was stirred for 2 h. Then (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5tetrahydro-III-1-benzazepin-5-ol hydrochloride (120 mg) was added at room temperature and the mixture was stirred for 1 day. Saturated aqueous NaHCO ₃ and water were added to the reaction solution, the precipitate was filtered and purified by alkaline silica gel column chromatography (hexane/AcOEt/MeOH) to obtain 2-chloro-N-{4-[(5R)-7-chloro-4 ,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]-2-methylphenyl}-4-fluorobenzamide (174 mg).

Example 91.

To a solution of 6-{4'-fluoro-[1,1'-biphenyl]-2-amido}pyridine-3-carboxylic acid (753 mg) in DMA (6.0 ml) under ice-cooling under nitrogen atmosphere was added SOCl2 (162 µl) and the mixture was stirred at the same temperature for 2 h. 1H-1-benzazepin-5-yl]methyl-4-bromobenzoate (500 mg) and the mixture was stirred at room temperature for 1 day. A saturated NaHCO ₃ aqueous solution and water were added to the reaction solution, and the precipitate was filtered. The resulting solid was mixed with EtOH (10 ml) and 5N NaOH aqueous solution (1.11 ml) and the mixture was stirred at room temperature for 10 minutes. The reaction solution was neutralized by adding ice water and 5N HCl, the precipitate was filtered and washed with water. The resulting solid was purified by alkaline silica gel column chromatography (hexane/AcOEt/MeOH) to give N-{5-[(5R)-7-chloro-4,4-difluoro-5hydroxy-5-(hydroxymethyl)-2,3 ,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-4'-fluoro[1,1'-biphenyl]-2-carboxamide (620 mg).

Example 96.

6-{4-Fluoro-[1,1'-biphenyl]-2-amido}pyridine-3-carboxylic acid (542 mg) was dissolved in DMA (5 ml) and then SOCl2 (0.133 ml) was added. The mixture was stirred at room temperature for 2 hours. Then, [(5R)-7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine-5- yl]methyl-4-bromobenzoate (480 mg) and the mixture was stirred at room temperature for 4 days. Water was added to the mixture and the resulting solid was filtered. The solid was suspended in EtOH (20 ml) and 5N NaOH aqueous solution (1.075 ml) was added. The mixture was stirred for 1 hour and then

- 36 040222 was adjusted to pH=8 by adding 1N HCl. The mixture was extracted with AcOEt. The organic layer was washed with 1N HCl, 1N NaOH and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Biotage alkaline silica (NH-Si) column: AcOEt/hexane then AcOEt/MeOH) and (Biotage acidic silica (Kp-Si) column: AcOEt/hexane). After concentration, the concentrate was dried under vacuum, and the resulting amorphous substance was dried under vacuum at 60° C. to give N-{5-[(5R)-7-chloro-4,4-difluoro-5hydroxy-5-(hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-4-fluoro[1,1'-biphenyl]-2-carboxamide (511.5 mg).

Example 97.

6-(2-Phenylpyridine-3-amido)pyridine-3-carboxylic acid (160 mg) was dissolved in DMA (2 ml) and then SOCl ₂ (45 μl) was added. The mixture was stirred at room temperature for 2 hours. Then (5R)-7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5- ol (110 mg) and stirred the mixture for 2 days. The mixture was diluted with AcOEt and water was added. The mixture was extracted with AcOEt/hexane. The organic layer was washed with 1N HCl, 1N NaOH and brine, dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt/hexane, then AcOEt/MeOH). After concentration, the concentrate was dried under vacuum, and the resulting amorphous substance was dried under vacuum at 60° C. to give N-{5-[(5R)-7-chloro-4,4-difluoro-5hydroxy-5-(hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-2-phenylpyridine-3-carboxamide (115.9 mg).

Example 99.

SOCl2 (162 µl) was added to a solution of 4-(2-chlorobenzamido)-3-methoxybenzoic acid (684 mg) in DMA (6.0 ml) under ice-cooling under nitrogen atmosphere, and the mixture was stirred at the same temperature for 2 h. Then, at the same temperature, [(5R)-7-chloro-4,4-difluoro-5-hydroxy2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl-4-bromobenzoate was added (500 mg) and stirred the mixture at room temperature for 1 day. A saturated NaHCO ₃ aqueous solution and water were added to the reaction solution, and the precipitate was filtered. EtOH (10 ml) and 5N NaOH aqueous solution (1.11 ml) were added to the resulting solid, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was neutralized by adding ice water and 5N HCl, the precipitate was filtered and washed with water. The resulting solid was dissolved in AcOEt and washed with 1N NaOH aqueous solution and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give 2-chloro-N-{4-[(5R)-7-chloro-4,4difluoro-5-hydroxy-5-(hydroxymethyl)-2,3, 4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]-2-methoxyphenyl}benzamide (620 mg).

Example 100.

SOCl ₂ (43 μl) was added to a solution of 4-(2-chloro-5-fluorobenzamido)-3-methoxybenzoic acid (189 mg) in DMA (4 ml) at 0°C and the mixture was stirred for 2 h. 7-chloro-4,4difluoro-2,3,4,5-tetrahydro( ^5-2H )-1H-1-benzazepin-5-ol (114 mg) in DMA (2 ml) and the mixture was stirred at room temperature in during the night. Water was added to the reaction solution, and a mixture of AcOEt was extracted. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by medium pressure column chromatography (hexane/AcOEt) and recrystallized from hexane to give 2-chloro-N-{4-[7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5- tetrahydro( ^5-2H )-1H-1-benzazepine-1-carbonyl]2-methoxyphenyl}-5-fluorobenzamide (155 mg).

Example 101.

SOCl ₂ (48 µl) was added to a solution of 4-(2-chloro-5-fluorobenzamido)-3-methoxybenzoic acid (224 mg) in DMA (4 ml) at 0°C and the mixture was stirred for 2 h. 7-chloro-4,4difluoro-2,3,4,5-tetrahydro( ^5-2H )-1H-1-benzazepin-5-ol (129 mg) in DMA (2 ml) and the mixture was stirred at room temperature in during the night. Water was added to the reaction solution, the mixture was extracted with AcOEt, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The concentrate was purified by medium pressure column chromatography (hexane/AcOEt) and recrystallized from MeCN to give N-{4-[7chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro( ^5-2H )-1H-1-benzazepine-1-carbonyl]-2-methoxyphenyl}-2(trifluoromethyl)benzamide (183 mg).

Example 102.

SOCl2 (23 μl) was added to a solution of 4-(5-fluoro-2-methylbenzamido)-3-fluorobenzoic acid (92 mg) in DMA (1.0 ml) under ice-cooling under nitrogen atmosphere, and the mixture was stirred at the same temperature for 2 hours. Then (5R)-7-chloro-4,4-difluoro-5-methyl2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (60 mg ) and stirred the mixture at room temperature for 1 day. A saturated NaHCO ₃ aqueous solution and water were added to the reaction solution, and

- 37 040222 filtered the precipitate. The resulting solid was dissolved in AcOEt and washed with 1N NaOH aqueous solution and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give N-{4-[(5R)-7-chloro-4,4difluoro-5-hydroxy-5-methyl-2,3,4,5-tetrahydro- 1H-1-benzazepine-1-carbonyl]-2-fluorophenyl}-5-fluoro-2-methylbenzamide (100 mg).

Example 125.

To a solution of N-[5-({7-chloro-4,4-difluoro-1,2,3,4-tetrahydrospiro[1-benzazepine-5,2'-oxiran]-1yl}carbonyl)-pyridine-2- yl]-2-(trifluoromethyl)benzamide (100 mg) in MeOH (1 ml) was added ethanolamine (0.112 ml), and the mixture was stirred at 70°C for 4 hours. Saturated aqueous NaHCO ₃ was added to the mixture, the mixture was extracted with AcOEt and dried over anhydrous Na ₂ SO ₄ . Filtered with Na ₂ SO ₄ , the filtrate was concentrated under reduced pressure and dried under vacuum to give N-[5-(7-chloro-4,4-difluoro-5-hydroxy-5-{[(2-hydroxyethyl)amino] -methyl}-2,3,4,5-tetrahydro-1H-1benzazepine-1-carbonyl)pyridin-2-yl]-2-(trifluoromethyl)benzamide (107.2 mg).

Example 127

To a solution of 4-[5-fluoro-2-(trifluoromethyl)benzamido]benzoic acid (769 mg) in DMA (7 ml) was added SOC12 (0.172 ml) dropwise. The mixture was stirred for 1 hour and then [(5R)-7-chloro-4,4difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl-4 -bromobenzoate (700 mg). The mixture was stirred for 5 days. Saturated aqueous NaHCO ₃ was added to the mixture, and the resulting solid was filtered. The resulting material was suspended in EtOH (15 ml) and 5N aqueous NaOH solution (1.567 ml) was added dropwise. The mixture was stirred at room temperature for 30 minutes. Then 5N HCl was added. The resulting solid was filtered, washed with water and then dissolved in THF. The solution was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated, and then the crude product was purified by medium pressure column chromatography (hexane/AcOEt/MeOH) and dried at 60° C. under reduced pressure to give N-{4-[(5R )-7chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]phenyl}5-fluoro-2-(trifluoromethyl )benzamide (772 mg).

Example 132.

SOCl ₂ (0.172 ml) was added dropwise to a solution of 3-fluoro-4-[5-fluoro-2-(trifluoromethyl)benzamido]benzoic acid (812 mg, 2.351 mmol) in DMA (7 ml). The mixture was stirred for 1 h and then [(5R)-7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl was added -4-bromobenzoate (700 mg) and the mixture was stirred for 2 days. Saturated aqueous NaHCO3 was added to the mixture and the resulting solid was filtered. The resulting material was suspended in EtOH (15 ml) and 5 N NaOH aqueous solution (1.567 ml) was added dropwise. The mixture was stirred for 30 minutes. 5N HCl was added to the mixture, the resulting solid was filtered, washed with water and then dissolved in THF. The solution was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and then the crude product was purified by column chromatography (hexane/AcOEt/MeOH) and dried under reduced pressure at 60°C to obtain N-{4-[(5R)- 7-chloro-4,4-difluoro-5-hydroxy-5(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]-2-fluorophenyl}-5-fluoro-2 -(trifluoromethyl)benzamide (840 mg).

Example 153.

To a solution of 4-{4-fluoro-[1,1'-biphenyl]-2-amido}benzoic acid (901 mg) in DMA (7 ml) was added SOC12 (0.196 ml) dropwise. The mixture was stirred for 1 h and then [(5R)-7-chloro-4,4difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl-4 was added -bromobenzoate (600 mg). The mixture was stirred for 2 days. Saturated aqueous NaHCO3 was added to the mixture and the resulting solid was filtered. The resulting material was suspended in EtOH (15 ml) and 5 N NaOH aqueous solution (1.343 ml) was added dropwise. The mixture was stirred at room temperature for 30 minutes. 5N HCl was added, the resulting solid was filtered, washed with water and then dissolved in THF. The solution was dried over anhydrous Na ₂ SO _4; filtered, concentrated, and then the crude product was purified by column chromatography (hexane/AcOEt/MeOH) and dried under reduced pressure at 60° C. to give N-{4-[(5R)-7-chloro-4,4-difluoro -5-hydroxy-5(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]phenyl}-4-fluoro-[1,1'-biphenyl]-2-carboxamide ( 722 mg).

Example 157.

SOCl2 (0.147 ml) was added dropwise to a solution of 4-[2-(difluoromethyl)-5-fluorobenzamido]-3-fluorobenzoic acid (659 mg) in DMA (7 ml). The mixture was stirred for 1 h and then [(5R)-7chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl-4 was added -bromobenzoate (600 mg). The mixture was stirred for 2 days. Saturated aqueous NaHCO3 was added to the mixture and the resulting solid was filtered. The resulting material was suspended in EtOH (15 ml) and 5N NaOH (1.343 ml) was added dropwise. The mixture was stirred for 30 minutes. 5N HCl was added, the resulting solid was filtered, washed with water and then dissolved in THF. The solution was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and then the crude product was purified by the method

- 38 040222 column chromatography (hexane/AcOEt/MeOH) and dried under reduced pressure at 60° C. to give N-{4-[(5R)-7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl)-2,3,4,5-tetrahydro-1H-1benzazepine-1-carbonyl]-2-fluorophenyl}-2-(difluoromethyl)-5-fluorobenzamide (603 mg).

Example 160.

SOCl ₂ (0.049 ml) was added to a solution of 4-{[1,1'-biphenyl]-2-amido}benzoic acid (167 mg) in DMA (2 ml) at room temperature under nitrogen atmosphere and the mixture was stirred for 2 h Then (5S)-7-chloro-4,4-difluoro-5-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol (100 mg) was added and the mixture was stirred at room temperature during the night. Saturated aqueous NaHCO ₃ (4 ml) and water were added to the mixture, and extracted with AcOEt (4 ml) three times. The combined organic layer was washed with 1N aqueous NaOH and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and then the solvent was removed. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give N-{4-[(5S)-7-chloro-4,4-difluoro-5-hydroxy-5-methyl2,3,4,5-tetrahydro- 1H-1-benzazepine-1-carbonyl]phenyl}-[1,1'-biphenyl]-2-carboxamide (163 mg).

Example 165.

SOCl ₂ (0.196 ml) was added dropwise to a solution of 6-{2',4-difluoro-[1,1'-biphenyl]-2-amido}pyridine-3-carboxylic acid (952 mg) in DMA (7 ml) . The mixture was stirred for 2 hours. Then, [(5R)7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl- 4-bromobenzoate (600 mg) and the mixture was stirred overnight. Saturated aqueous NaHCO ₃ was added to the mixture, and the resulting solid was filtered. The resulting material was suspended in EtOH (15 ml) and 5 N NaOH (1.343 ml) was added dropwise. The mixture was stirred for 30 minutes. 5N HCl was added, the resulting solid was filtered and washed with water. The solid was then dissolved in AcOEt. 1N NaOH was added, the AcOEt layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting crude product was purified by column chromatography (hexane/AcOEt) and dried under reduced pressure at 60° C. to give N-{5-[(5R)-7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1carbonyl]pyridin-2-yl}-2',4-difluoro-[1,1'-biphenyl]-2-carboxamide (642 mg).

Example 168.

To a solution of 4-{2',4-difluoro-[1,1'-biphenyl]-2-amido}-3-fluorobenzoic acid (748 mg) in DMA (7 ml) was added SOCl ₂ (0.147 ml) dropwise. The mixture was stirred for 2 hours. Then, [(5R)-7chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl-4 -bromobenzoate (600 mg), and the mixture was stirred for 2 days. Saturated aqueous NaHCO ₃ was added to the mixture, and the resulting solid was filtered. The resulting material was suspended in EtOH (15 ml). 5N NaOH (1.343 ml) was added dropwise and the mixture was stirred for 30 minutes. 5N HCl was added, the resulting solid was filtered, washed with water and then dissolved in THF. The THF solution was dried over anhydrous Na2SO4, filtered, concentrated, and then the crude product was purified by column chromatography (hexane/AcOEt/MeOH) and dried under reduced pressure at 60°C to give N-{4-[(5R)-7 -chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro1H-1 -benzazepine-1-carbonyl]-2-fluorophenyl} -2',4-difluoro- [1,1'-biphenyl]-2-carboxamide (706 mg).

Example 169.

SOCl ₂ (0.147 ml) was added dropwise to a solution of 4-{2',4-difluoro-[1,1'-biphenyl]-2-amido}benzoic acid (712 mg) in DMA (7 ml). The mixture was stirred for 2 hours. [(5R)-7-chloro-4,4difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl-4- bromobenzoate (600 mg) and the mixture was stirred for 2 days. Saturated aqueous NaHCO3 was added to the mixture and the resulting solid was filtered. The resulting material was suspended in EtOH (15 ml) and 5N NaOH (1.343 ml) was added dropwise. The mixture was stirred for 30 minutes. 5N HCl was added, the resulting solid was filtered, washed with water and then dissolved in THF. The THF solution was dried over anhydrous Na2SO4, filtered and concentrated, and then the crude product was purified by column chromatography (hexane/AcOEt/MeOH) and dried under reduced pressure at 60°C to give N-{4-[(5R)-7 -chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1benzazepine-1-carbonyl]phenyl} -2',4-difluoro-[ 1, 1'-biphenyl]-2-carboxamide (664 mg).

Example 187.

SOCl ₂ (49 μl) was added dropwise to a solution of 4-(7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)benzoic acid (192 mg) in DMA (3 ml). The mixture was stirred for 2 hours. Then [(5R)-7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]methyl- 4-bromobenzoate (150 mg) and the mixture was stirred for 3 days. Saturated aqueous NaHCO3 was added to the mixture and the resulting solid was filtered. The resulting material was suspended in EtOH (10 ml) and 5N aqueous NaOH solution (0.336 ml) was added dropwise. The mixture was stirred for 30 minutes. 5N HCl was added, the resulting solid was filtered, washed with water and then dissolved in AcOEt. 1N NaOH was added, the organic layer was washed with water and brine and dried over anhydrous Na2SO4. The material obtained was filtered and concentrated. The resulting crude product was purified by column chromatography (hexane/AcOEt) and dried under reduced pressure at 60° C. to give 2-{4-[(5R)-7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl)

- 39 040222

2,3,4,5-tetrahydro-1H-1-benzazepin-1-carbonyl]phenyl}-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-one (126 mg).

Example 219.

To a solution of 2-chloro-N-{4-[(5R)-7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine-1carbonyl]-2 -fluorophenyl}-4,5-difluorobenzamide (0.60 g) in DMSO (5 ml) was added IBX (0.616 g) and the mixture was stirred at room temperature overnight. Water was added to the mixture, the mixture was extracted with AcOEt, washed with brine, filtered and concentrated. The concentrate was purified by medium pressure column chromatography (hexane/AcOEt), and the crude product was recrystallized from Et ₂ O to give 2-chloro-X-[4-(7-chloro-4,4-difluoro-5,5-dihydroxy2,3 ,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl)-2-fluorophenyl]-4,5-difluorobenzamide (460 mg).

Example 220.

To a solution of 2-chloro-N-{5-[7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1benzazepine-1-carbonyl] pyridin-2-yl}-5-fluorobenzamide (100 mg) in AcOEt (1 ml) was added a solution of MsOH in AcOEt (0.046 ml) and the mixture was stirred at room temperature for 2 days. IPE (1.0 ml) was added, the precipitated solid was filtered and dried under reduced pressure at 80° C. for 2 days to give 2-chloro-N-{5-[7-chloro-4,4-difluoro -5-hydroxy-5(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-5-fluorobenzamide methanesulfonate (112.1 mg).

Example 223.

To a solution of 2,4-dichloro-N-{5-[(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroksimethyl)-2,3,4,5-tetrahydro-1H- 1-benzazepine-1-carbonyl]pyridin-2-yl}-5-fluorobenzamide (100 mg) in AcOEt (1 ml) was added a solution of HCl in AcOEt (0.043 ml) and the mixture was stirred at room temperature overnight. IPE (1.0 ml) was added to the mixture, the precipitated solid was filtered and dried under reduced pressure at 80°C for 2 days to obtain 2,4-dichloro-N-{5-[(5R)-7 -chloro-4,4difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-5fluorobenzamide hydrochloride (48.3 mg).

The following tables present the structures, preparation methods, and physical characteristics of the Reference Example compounds and Example compounds.

Table 1

- 40 040222

- 41 040222

- 42 040222

- 43 040222

- 44 040222

- 45 040222

- 46 040222

- 47 040222

149 Vg _h O 150 HO HO, /F Τι T > O 151 BUT BUT, /F Ha/n 152 HO HO, / F GivUvF uC J H HCl 153 154 Be o BUT, U F CI^^XAf XX / oL _o and 155 Vg v# NO,L F mJ Η 156 o /=/ sh “ΟΐΑ' 157 Up /=h o A r\J NK H y=o nLg civUv XX J oUU 158 An well=o 0^ ^but </ f A/ °A>A 159 %( X *° ιθ O 160 Q 4# § ΧΖ ^Ζ K. V x ^D 161 ^w N'\ h /=o ΗθΔ F ci^AA-f XX J MX 162 and O V/ g ° ΛΆ ° Qj 163 &?' F 164 F

- 48 040222

165 n y=o H.Q. F XX J γΉ n 166 A" o 167 /I'm about 168 HOL NO / F °7% 169 o ΎΧ° Qp ⁰ qDD π 170 ° y5 ° O 171 XT} /=\ σ^χ^/ n\=o HoA F w °^o+ 172 /^0 nA=o HQ/F ΟΙγ^γ^ρ °+o+ 173 n y=o nA; 1e) N- ⁷ Η 174 n \=o NoL F cix^z4~ _F Xd J N-N 175 BUT NOD F CK^zH-F C ) Η 176 n°L n HCI 177 He HOL/F 1 Ύ ) Η 178 oLT H.Q. / F GIx^sT^V-F T I ) H 179 χ θ <gC~ o 180 X ° Y \u003d: O HN but _h / F Ta j N ^ P

- 49 040222

181 V HN 182 HN BUT. /f HO/F Ί1 I > o / Η +A J Cl.-. N^ V F°\ 183 f La / 184 Orf F ^Ci +z+/4-r Ta / 185 ^Ci \/V4"F Ta / θ^οΛ 186 HO, F Fck.^A'VF Ta / V+r 187 hqv f Ta) H 188 HO,/ F CIxXVAf Ta / H 189 oj f Ck^/VV-F ++ 190 HO _F XX j N ^ ^O= +° 191 HO _F Xd J ' l+ H 192 HO _F ^Ci VV\ ^F /+X 193 HO _F Cly^AVF it / 194 HO _F ^C! x^Wf TT ) F C! _n ^ N ⁷ +++ F ^F 195 /d++/'+P? Ta) 196 HQ _F ^C! x^xAA ^f La ) 0 (Vn->V ⁰ H ^N +++ F 197 HO _F -A ⁴ 198 _HQFc ^| \^A4-f Ta / Cl „ ^ΆΑ w F 199 but _F ci-A'+f ++ F 200 HQ _F f ^f Ta / ++ 201 A ^F P° SX 202 ^H YA CK^W AT XX ) ^F /^ o ~~ ++νΑ ^Λ ° h F

In the table, REX154 is considered to be present in the form of a co-crystal with DCM (1:1) or a solvate with DCM.

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table 2

REX RProp Data 1 NMR1 (400MHz) I 7.81 (1H, d, J=11.0Hz), 6.50-5. 45(2H, br), 3. 77(3H, s). 2 NMR2 (400MHz) ; 7.60-7. 50(1H.m), 7.77(1H.dd, J=11.0Hz, 1.8Hz), 5.24-4. 95 (2H, br), 3.89 (3H, s). 3 NMR2 (400MHz) ; 8.79(1H, d, J=1.7Hz), 8.12(1H, dd, J=9.1Hz, 1.8Hz), 7.37-7. 32 (2H, m), 7. 32-7. 27(2H, m), 3.96(3H, s). 4 NMR1 (400MHz) : 13.65(1H, brs), 11.30(1H, s), 8.78-8. 71(1H, m), 8.18(1H, dd, J=10.2Hz, 1.8Hz), 7.63(1H, dd, J=8.9Hz, 4.8Hz), 7.54(1H, d, J =8.4Hz, 3.0Hz), 7.42(1H, dt, J=8.4Hz, 3.0Hz). 5 NMR2 (400MHz) ; 7.96-7. 87 (2H, m), 7. 56-7. 46 (2H, m), 7. 42-7. 31 (3H, m), 4. 87-4. 61(2H, br), 3.08-2. 96(2H, ra), 2. 44(3H, s). 6 NMR2(400MHz); 7.92 (1H, d, J=8.3Hz), 7.49 (1H, dd, J=8.3Hz, 1.9Hz), 7.43-7. 37(1H, m), 6.65-6.37(1H, br), 3.57(2H, td, J=6.6Hz, 2.9Hz), 2.99(2H, t, J=6.6Hz) . 7 NMR2(400MHz); 8.87-8.75(2H, m), 8.46-8. 33 (2H, m), 7.84(1H, d, J=7.5Hz), 7.71 (1H, d, J=7.7Hz), 7.66 (1H, t, J=7.6Hz), 7.59(1H, t, J=7.7Hz), 7.30(1H, t, J=55.6Hz), 3.95(3H, s). 8 NMR1 (400MHz) ; 13.22(1H, brs), 11.47(1H, s), 8.90-8. 86 (1H, m), 8. 36-8. 26 (2H, m), 7. 83-7. 61(4H, m), 7.32(1H, t, J=55.3Hz). 9 NMR2 (400MHz) ; 9.79 (1H, brs), 9.01 (1H, brs), 8.91 (1H, brs), 7.88-7. 82 (1H, m), 7.55-7. 40 (3H, m), 4.04 (3H, s). 10 NMR1 (400MHz) : 11.56(1H, brs), 9.42(1H, brs), 8.9K1H, brs), 7.64(1H, dd, J=8.0Hz, 1.5Hz), 7.57(1H, dd, J=8.0Hz, 1.5Hz), 7.53(1H, ddd, J=8.0Hz, 7.2Hz, 1.8Hz), 7.46(1H, ddd, J=7.5Hz, 7.3Hz, 1.5Hz). eleven NMR1 (400MHz) ; 13.20(1H, brs), 11.47(1H, brs), 8.88-8. 83 (1H, m), 8. 37-8. 30 (2H, m), 7. 39-7. 33 (2H, m), 7. 32-7. 23(1H, m), 2. 30(3H, s). 12 NMR1 (400MHz) ; 11.64(1H, brs), 9.39(1H, brs), 8.9K1H, brs), 7.70-7. 88(4H.m).

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13 NMR1 (400MHz) ; 12.90(1H.brs), 9.00(1H, s), 8.04(1H, d, J=8.2Hz), 7.62(1H, d, J=2.1Hz), 7.58(1H, dd, J=8 .2Hz, 1.7Hz), 7.56(1H, d, J=1.7Hz), 7.02(1H, d, J=2.1Hz), 3.92(3H, s), 2.56(3H, s). 14 NMR1(400MHz): 12.92(1H, s), 9.96(1H, s), 8.15(1H, d, J=4.4Hz), 7.83(1H, d, J=8.OHz) , 7. 80-7. 73 (1H, m), 7. 73-7. 64(2H, m), 7.61(1H, dd, J=8.4Hz, 1.2Hz), 7.55(1H, d, J=1.6Hz), 3.87(3H, s). 15 NMR1 (500MHz); 13.42-13. 91 (1H, m), 10.72 (1H, s), 8.08(1H, t, J=8. OHz), 7.91-7. 68(6H, m). 16 NMR2(400MHz) ; 8.84(1H, brs), 8.65(1H, d, J=8.9Hz), 7.85-7. 76 (3H, m), 7.50-7. 38(3H, m), 5.08(2H, brs), 3.91(3H, s), 3.50(3H, s). 17 NMR2 (400MHz) : 8.88(1H, s), 8.70(1H, d, J=8.4Hz), 7.88-7.81(3H, m), 7.51-7. 40(3H, m), 5.32(2H, s), 3.51(3H, s). 18 NMR1 (400MHz): 9.96(1H, s), 8.15(1H, dJ=8.3Hz), 7.84-7. 55 (6H, m), 5.33 (2H, s), 3.51 (3H, s). 19 NMR1 (400MHz) : 12.94(1H, s), 9.90(1H, s), 8.21(1H, d, J=7.8Hz), 7.68-7. 56(4H, m), 7.33(1H, dt, J=8.5Hz, 2.4Hz), 3.88(3H, s). 20 19 NMR3(400MHz) ; 8.36(1H, d, J=8.4Hz), 7.73(1H, dd, J=8.4Hz, 1.8Hz), 7.69(1H, d, J=1.7Hz), 7.53 -7. 48(1H, m), 7.37(1H _T d, J=8.1Hz), 7.24(1H, t, J=8.6Hz), 3.96(3H, s). 21 NMR1 (500 MHz) ; 13.20(1H, brs), 10.73(1H, s), 8. 16(1H, t, J=8. OHz), 7.83(1H, d, J=8.4Hz), 7. 76(1H, dd, J=11.1Hz, 1.6Hz), 7.62(1H, dd, J=8.9Hz, 4.8Hz), 7.58(1H, dd, J-8.4HZ, 3.0Hz), 7.4K1H, dt, J=8.6Hz, 3.0Hz). 22 NMR2(400MHz) ; 8.55(1H, dd, J=2.OHz, 1.OHz), 8.39(1H, s), 8.36-8. 21(2H, m), 7.72(1H, dd, J=9.5Hz, 1.4Hz), 7.56(1H, dt, J-7.5Hz, 1.4Hz), 7.47(1H, dt. J=7.5Hz, 1.3Hz), 7.44-7. 35 (3H, m), 7. 11-7. 03 (2H, m), 3.91 (3H, s). 23 NMR1 (400MHz) ; 13.15(1H, s), 11.11(1H, s), 8.78(1H, d, J=1.8Hz), 8.24(1H, d, J=8.7Hz, 2.3Hz), 8.17- 8. 07(1H, m), 7. 64-7. 54 (2H, m), 7. 52-7. 37 (4H, m), 7.26-7.16 (2H, m).

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24 19 NMR2 (400MHz) ; 8.60UH, d, +8.5Hz), 8.53(1H, s). 7.82(1H, dd, J=8.5Hz, 1.7Hz), 7.63(1H, d, J=1.7Hz), 7.39(1H, d, J=4.9Hz), 6.96(1H, d, J=4.9Hz), 4.01 (3H, s), 2.60 (3H, s). 25 NMR2 (500MHz) ; 7.83(1H, dd, +8.4Hz, 5.4Hz), 7.76-7. 70(1H, m), 7.50(1H, t, J=55.4Hz), 7.38-7. 30 (1H, m), 3.95 (3H, s). 26 NMR2(500MHz) ; 7.92-7. 83(2H, m), 7.54(1H, t, +55.3Hz), 7.44-7. 33 (1H, m). 27 NMR1 (5OOMHz); 9.43(1H, s), 8.15(1H, d, +8.0Hz), 7.61(1H, dd, J=13.0Hz, 1.5Hz), 7.56(1H, d, +2.0Hz) 0Hz), 7.50(1H, d, J=7.5Hz), 7.43-7. 36 (1H, m), 7. 33-7. 26 (2H, m), 3.88 (3H, s), 2.41 (3H, m). 28 27 NMR1 (500MHz) ; 12.91(1H, brs), 9.44(1H, s), 8.14(1H, d, J=8.OHz), 7.6K1H, dd, J=8. 5Hz, 1.5Hz), 7.55(1H, d, J=1.5Hz), 7.47(1H, d, J=7.5Hz), 7.43(1H, ddd, J=7.5Hz, 7.5Hz, 1.5Hz), 7.34(1H, d, J=7.5Hz), 7.30(1H, ddd, +7.5Hz, 7.5Hz, 1.0Hz), 3.88(3H, s), 2.76C2H, q , J=7. 5Hz), 1.19 (3H, t, +7.5Hz). 29 27 NMR1 (500MHz) ; 12.93(1H, brs), 9.64(1H, s), 8.11(1H, d, +8.0Hz), 7.6K1H, dd, J=7. 5Hz, 1.5Hz), 7.56(1H, d, J=1.5Hz), 7.37-7.29(2H, m), 7.43(1H, ddd, J=8.5Hz, 8.5Hz, 3.0Hz), 3. 88 (3H, s), 2.37 (3H, s). thirty NMR1 (500MHz); 12.92(1H, brs), 9.77(1H, s), 8.20(1H, d, J=8.0Hz), 7.6K1H, d, +7.5Hz), 7.55(1H, d, J=1.0Hz), 7.45-7. 37(2H, m), 7.32(1H, dd, +8.OHz, 1.5Hz), 3.88(3H, s), 2.34(3H, s). 31 NMR1 (500MHz); 13. 22(1H, brs), 11.34(1H, s), 8.86-8. 84 (1H, m), 8. 36-8. 27 (2H, m), 7.50-7. 38(2H, m), 7.32(1H, dd, +8.OHz, 2.0Hz), 2.34(3H, s). 32 NMR2(500MHz); 9.77(1H, d, J=1.3Hz), 9.18(1H, s), 8.97(1H, d, J=1.5Hz), 7.59(1H, dd, J=8.3Hz, 3.1Hz ), 7.48 (1H, dd, +8.9Hz, 4.8Hz), 7.26-7. 18(1H, m), 4.04(3H, s). 33 NMR1 (500MHz) : 13.54(1H, brs), 11.83(1H, s), 9.50(1H, s), 9.00(1H, d, J=1.2Hz), 7.68-7. 59(2H, m), 7.43(1H, dt, +8.6Hz, 3.1Hz). 34 thirty NMR3 (400MHz) ; 7.97(1H, s), 7.93(1H, d, +8.3Hz), 7.7K1H, d, J=8.3Hz), 7.58(1H, dd, J=8.9Hz, 4.7Hz), 7.46 (1H, dd, +8.2Hz, 3.0Hz), 7. 32-7. 20(1H, m), 2.43(3H, s).

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35 NMR2 (500MHz) ; 9.05 (1H, dd, J=2.5Hz, 1.0Hz). 8. 29 (1H, dd, J=9. OHz, 2. 5Hz), 8. 23 (1H, dd, J=9. OHz, 1. OHz), 8. 20(1H, dd, J=8. OHz, 1.0Hz), 7.51 (1H, ddd, J=7.5Hz, 7.5Hz, 1.5Hz), 7.43-7.37 (1H, m), 7.31-7. 26 (1H, m), 4. 39 (2H, t, J=6.5Hz), 3.95(3H, s), 3.13 (2H, t, J=6.5Hz), 36 thirty NMR1 (500MHz): 13.54-12.35(18, br), 10.01 (1H, s), 8.22(18, d, J=8.2Hz), 7.87-7. 79 (2H, m), 7.6K1H, d, J=8.3Hz), 7.55 (1H, s), 3.88 (3H, s). 37 NMR1 (500MHz) ; 13.20(1H, brs), 8.96(18, dd, J=2.5Hz, 0.5Hz), 8.29(18, dd, J=9.OHz, 4.0Hz), 8.13(1H, dd, J=8.5 Hz, 0.5Hz), 8.04 (1H, dd, J=7.5Hz, 1.0Hz), 7.58 (1H, ddd, J=7.5Hz, 7.5Hz, 1.5Hz), 7.47-7. 38 (2H, m), 4.29 (2H, t, J=6.5Hz), 3.13 (2H, t, J=6.5Hz). 38 27 NMR1 (500MHz) ; 13.07(1H, brs), 11.05(1H, s), 7.90(1H, dd, J=8.5Hz, 8.5Hz), 7.74 (1H, dd, J=13.5Hz, 2.0 Hz), 7.69-7.60(28, m), 7.52(1H, dd, J=8.5Hz, 2.0Hz), 7.44(18, ddd, J=8.5Hz, 8.5Hz, 3.0Hz). 39 NMR2 (500MHz) ; 8.14(1H, dd, J=7.5Hz, 1.OHz), 7.71(1H, dd, J=7, 5Hz, 1.5Hz), 7.68(1H, J=1.5Hz), 7.47(1H, ddd, J=7.5Hz, 7.5Hz, 1.5Hz), 7.41-7. 34 (2H, m), 7. 26-7. 22(1H, m), 3.94(3H, s), 3.90(38, s), 3.90-3. 77(2H, m), 3.15(28, t, J=1.5Hz). 40 37 NMR1 (500M8z) : 13.10(18, brs), 7.91(1H, dd, J=8. OHz, 1.0Hz), 7.63-7.57(28, m), 7.54(1H, ddd, J=7.5Hz, 1.5Hz), 7.43(1H, J=7.5Hz), 7.41-7. 25(2H, m). 3.85(3H, s), 3.78(2H, t, J=1.5Hz), 3.12(2H, t, J=1.5Hz). 41 NMR2(500MHz) ; 8.65(18, d, J=8.4Hz), 8.29(18, s), 7.84(1H, dd, J=8.5Hz, 1.88z), 7.64(18, d, J=1.8 Hz), 7.55 (1H, dd, J=8.4Hz, 5.8Hz), 7.11-6. 90(2H, m), 4.04-3. 90(3H, m), 2.55(38, s). 42 thirty NMR1 (500MHz) ; 13. 21 (1H, brs), 10. 71 (1H, s), 8. 17(18, dd, J=8.0Hz, 8.0Hz), 7.95-7.85 (28, m), 7.82(1H, d, J=8.5Hz), 7.75(18, dd, J=6.OHz, 1.5Hz). 43 thirty NMR1 (500MHz); 13.21(18, brs), 10.75(1H, s), 8.18(18, dd, J=8.0Hz, 8.0Hz), 7.98(18, d, J=6.5Hz), 7.88-7. 79 (2H, m), 7.76(18, dd, J=6. OHz, 1.5Hz).

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44 NMR2 (500MHz) ; 8.90(1H, dd, J=2.5Hz, 1.0Hz). 8.84(1H, dd, J=5.OHz, 1.5Hz), 8.67(1H, brs), 8.42(1H, dd, J=8.5Hz, 0.5Hz), 8.39(1H, dd, J=8.5Hz, 2.0Hz), 8.08(1H, dd, J=2.5Hz, 1.5Hz), 7.58(1H, dd, J=8.OHz, 5.0Hz), 7.00(1H, t, J=54.5Hz), 3.96(3H, s). 45 NMR1 (500MHz) ; 13. 25(1H, brs), 11.60(1H, s), 8.89-8. 86 (1H, m), 8.8K1H, dd, J=5. OHz, 1.5Hz), 8.35(1H, dd, J=8.5Hz, 2.5Hz), 8.30(1H, d, J=8.5Hz), 8.19(1H, d, J=7.5Hz ), 7.7O(1H, dd, J=8.OHz, 5.0Hz), 7.17(1H, t, J=54.OHz). 46 thirty NMR1 (500MHz) ; 12.79(1H, brs), 10.66(1H, s), 7.94(2H, d, J=9.0Hz), 7.84(2H, d, J=9.OHz), 7.67(1H , dd, J=11.0Hz, 8.5Hz), 7.45HH, dd, J=12. OHz, 8.0Hz), 2.37 (3H, s). 47 thirty NMR1 (500MHz); 13.06(1H, brs), 10.82(1H, s), 7.88(1H, dd, J=8.5Hz, 8.5Hz), 7.76(1H, dd, J=13.5Hz, 2.0Hz) , 7.69(1H, dd, J=11.OHz, 8.5Hz), 7.54(1H, dd, J=8.5Hz, 2.0Hz), 7.46(1H, dd, J=11.5Hz, 8.0Hz ), 2. 37 (3H, s). 48 NMR2 (500MHz); 9.68-9. 58 (1H, m), 8.74 (1H, s), 7.97-7. 78 (2H, m), 7. 67-7. 30 (8H, m), 3.99 (3H, s). 49 NMR1 (500MHz); 13.45(1H, brs), 11.46(1H, s), 9.31(1H, s), 8.90(1H, s), 7.81-7. 15 (9H, m). 50 thirty NMR1 (500MHz) ; 13.19(1H, brs), 10.44(1H, s), 8.03(1H, dd, J=8.OHz, 8.0Hz), 7.8Ц1Н, dd, J=8.5Hz, 1.5Hz), 7. 75 (1H, dd, J=10. OHz, 2.0Hz), 7.65 (1H, dd, J=11.0Hz, 8.0Hz), 7.44(1H, dd, J=12.0Hz, 8.0Hz), 2. 38 (3H, s). 51 thirty NMR1 (500MHz) : 12.86(1H, brs), 9.97(1H, s), 7.84(1H, d, J-1.5Hz), 7.80(1H, dd. J=8.5Hz, 1.5Hz), 7.71 -7.60(2H, m), 7.44(1H, dd, J=12.0Hz, 8.0Hz), 2.41(3H, s), 2.33(3H, s). 52 thirty NMR1 (500MHz) : 12.93(1H, brs), 9.68(1H, s), 7.84(1H, d, J=3.0Hz), 7.65-7. 56 (2H, m), 7.56 (1H, d, J=1.5Hz), 7.4K1H, dd, J=12.0Hz, 8.0Hz), 3.88 (3H, s), 2.37 (3H, s). 53 NMR2 (500MHz) ; 9.61(1H, s), 8.64(1H, s), 8.09(1H, brs), 7.56(1H, dd, J=8.8Hz, 2.7Hz), 7.50-7 . 18(7H, m), 3.99(3H, s). 54 NMR1 (500MHz) : 15.50-12. 50(1H, br), 11.54(1H, s), 9.29(1H, brs), 8.9K1H, s), 7.78-7.05(8H, m).

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55 NMR1 (500MHz) ; 13.16(1H, brs), 11.2K1H, brs), 8.77(1H, s), 8.23(1H, d, J=8.9Hz), 8.10(1H, brs), 7.56-7. 24 (8H, m). 56 thirty NMR1 (400MHz) ; 12.80(1H, s), 10.90(1H, s), 7.98-7. 94(3H, m), 7. 81-7. 41 (3H, m), 7. 61-7. 56 (1H, m). 57 thirty NMR1 (400MHz) ; 12.90(1H, brs), 10.10(1H, s), 8.17(1H, d, J=8.0Hz), 7.93-7. 89 (1H, m), 7. 63-7. 52(4H, m), 3.88(3H, s). 58 NMR1 (500MHz) ; 13.18(1H, s), 11.37(1H, s), 8.90-8. 71(2H, m), 8.28(1H, d, J=7.9Hz), 8.19(1H, brs), 8.02(1H, d, J=7.4Hz), 7.65(2H, d, J =7.1Hz), 7.56-7. 22 (4H, m). 59 NMR1 (500MHz) ; 11.74(1H, s), 9.39(1H, brs), 8.94(1H, s), 8.90-8. 72(1H, m), 8. 18-8. 00 (1H, m), 7.81-7. 12(6H, m), 3.90(3H, s). 60 54 NMR1 (500MHz) : 13.48(1H, m), 11.69(1H, s), 9.38(1H, brs), 8.92(1H, s), 8.85-8. 75(1H, m), 8.07(1H, dd, J=7.7Hz, 1.7Hz), 7.73-7. 61(2H, m), 7.52(1H, dd, J=7.7Hz, 4.8Hz), 7.50-7. 31 (3H, m). 61 NMR1 (500MHz) ; 14.30-12. 84 (1H, br), 11.08(1H, s), 8.77(1H, d, J=1.2Hz), 8.18(1H, dd, J=10.2Hz, 1.8Hz), 7.40-7. 34(2H, m), 7.28(1H, td, J=8.6Hz, 2.8Hz), 2.39(3H, s). 62 NMR2(400MHz) ; 8.10(1H, d, J=8.3Hz), 7.52(1H, dd, J=8.3Hz, 1.9Hz), 7.43(1H, d, J=0.8Hz), 7.34(1H, dd, J= 8.8Hz, 5.6Hz), 7.28-7.25(1H, m), 7.09-7. 04(1H, m), 3.90-3. 78(2H, m), 3.32-3. 25 (1H, m), 3. 11-3. 03 (1H, m). 63 35 NMR2(500MHz) ; 9.04(1H, d, J=1.5Hz), 8. 32-8. 27(1H, m), 8.2K1H, d, J=9.0Hz), 8.13(1H, d, J=7.5Hz), 7.38(1H, d, J=8.5Hz), 7.89(1H, s ), 4.39(2H, t, J=6.5Hz), 3.95(3H, s), 3.1K2H, t, J=6.5Hz). 64 39 NMR2(500MHz) ; 8. 13-8. 05(3H, m), 7.48(2H, d, J=8.5Hz), 7.56(1H, dd, J=8.Hz5, 2.0Hz), 7.28-7. 24(1H, m), 4.04(2H, t, J=6.5Hz), 3.93(3H, s), 3.15(2H, t, J=6.5Hz).

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65 37 NMR1 (500MHz) ; 13, 29(1H, brs), 8.95HH, dd, J=2.5Hz, 0.5Hz), 8.29(1H, dd, J=9.OHz, 2.5Hz), 8.11(1H, dd , J=9.OHz, 0.5Hz), 8.02HH, d, J=8.5Hz), 7.57-7. 54(1H, m), 7.50(1H, dd, J=8.5Hz, 2.0Hz), 4.29(2H, t, J=6.5Hz), 3.14(2H, t, J=6.5Hz ). 66 37 NMR1 (500MHz) ; 12.95(1H, s), 7.98(2H, d, J=8.5Hz), 7.95(1H, d, J=8.5Hz), 7.56(2H, d, J=8.5Hz), 7.53( 1H, d, J=2.OHz), 7.47(1H, dd, J=8.5Hz, 2.0Hz), 4.03(2H, t, J=6.5Hz), 3.16(2H, t, J=6.5Hz ). 67 39 NMR2 (500MHz); 8.08(2H, dd, J=8.5Hz, 1.5Hz), 7.52(2H, dd, J=8.5Hz, 1.5Hz), 7.42(1H, d, J=8.0Hz), 7.35(1H, dt, J=7.5Hz, 1.5Hz), 7.17(1H, d.J=7.5Hz), 3.99(2H, t, J=5.5Hz), 3.95-3. 83(3H, m), 3.14(2H, t, J=5.5Hz). 68 37 NMR1 (500MHz) ; 12.96(1H, s), 7.98(2H, d, J=8.5Hz), 7.58(2H, d, J=8.5Hz), 7.53-7. 42 (2H, m), 7. 37 (1H, d, J=7. OHz), 3.96(2H, t, J=6. OHz), 3.14(2H, t, J=6. ohz). 69 NMR2(400MHz) ; 8.14(1H, d, J=8. OHz), 7.59(1H, d, J=16.0Hz), 7.53-7. 50(1H, m), 7. 38-7. 33 (2H, m), 7. 28-7. 20(1H, m), 7.12-6. 98(1H, m), 6.46(1H, d, J=16. OHz), 3.91-3.80(2H, m), 3.36-3. 13 (1H, m), 3. 14-3. 07(1H, m), 1.52(9H, s). 70 NMR3 (400MHz) ; 8.12(1H, d, J=8.OHz), 8.06-8. 03(2H, m), 7.54HH, dd, J=8.8Hz, 5.6Hz), 7.45(1H, dd, J=8.4Hz, 2.8Hz), 7.26-7. 20(1H, m), 4.00-3. 89 (2H, m), 3. 41-3. 24 (2H, m). 71 thirty NMR1 (500MHz) : 13.51-12. 65(1H, br), 10. 26(1H, brs), 7.90-7.84(1Hm), 7.75-7. 70(1H.m), 7.67-7. 57 (ZN, sh), 7. 52-7. 43 (4H, m), 7. 41-7. 36 (2H, m), 7. 35-7. 30 (1H, m). 72 thirty NMR3(400MHz): 8.24(1H, t, J=8.2Hz), 7.91-7. 87(1H, m), 7.79(1H, dd, J=11.3Hz, 1.8Hz), 7.39-7. 34(1H, m), 7.13(1H, d, J=7.7Hz), 7.04(1H, t, J=8.9Hz), 2.43(3H, s). 73 thirty NMR1 (500MHz) ; 13,O5(1H, s), 11.08(1H, s), 7.89(1H, t, J=8.5Hz), 7.76(1H, dd, J=8.5Hz, 2.0Hz), 7.52(1H, dd , J=8.5Hz, 2.0Hz), 7.47-7. 39 (1H, m), 7. 22-7. 13(2H, m), 2.33(3H, s).

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74 thirty NMR1 (500MHz) J 13. 45-12. 43 (1H, br), 11.SH1H. s). 7.97(1H, dd, J=8.8Hz, 5.1Hz), 7.90(1H, t, J=8.6Hz), 7.78(1H, dd, J=8.6Hz, 2.5Hz), 7.70( 1H, dd, J=13.3Hz, 1.9Hz), 7.6K1H, dt, J=8. 4Hz, 2.3Hz), 7.50(1H, dd, J=8.6Hz, 1.9Hz). 75 thirty NMR1 (500MHz); 13.20(1H, s), 10.79(1H, s), 8.12(1H, t, J=8.0Hz), 7.94(1H, dd, J=9.0Hz, 5.0Hz), 7.83(1H, d, J=8.5Hz), 7.76(1H, dd, J=11.0Hz, 1.5Hz), 7.71(1H, dd, J=8.5Hz, 2.5Hz), 7.58(1H, dt, J =8.5Hz, 2.0Hz). 76 61 NMR1 (500MHz); 13.62(1H, brs), 11.06(1H, s), 8.65(1H, s), 8.05(1H, d, J=10.2Hz), 7.50-7. 42 (3H, m), 7.37-7.31 (5H, m). 77 thirty NMR3(400MHz) ; 8.22(1H, t, J=8.OHz), 7.89(1H, dd, J=8.5Hz, 0.98Hz), 7.8K1H, d, J=1.8Hz), 7.78-7. 73 (1H, m), 7.6K1H, dd, J=9. 1Hz, 2.5Hz), 7.5K1H, dt, J=8.3Hz, 2.5Hz). 78 thirty NMR1 (500MHz) ; 13.02(1H, brs), 10.80(1H, s), 7.83-7. 79(1H, m), 7.57-7. 51 (3H, m), 7. 48-7. 44(1H, m), 7. 40-7. 29 (6H, m). 79 NMR1 (500MHz) ; 13.40-12. 10(1H, br), 10.23(1H, s), 8.03-7. 90(1H, m), 7. 89-7. 60(4H.m), 7.50-7. 59 (1H, m), 2. 32 (3H, s). 80 61 NMR1 (500MHz) : 13.57 (1H, brs), 10.98 (1H, s), 8.67 (1H, s), 8.06 (1H, dd, J=1.7Hz, 10.2Hz), 7 62-7. 57 (2H, m), 7. 51-7. 30(7H.m). 81 NMR1 (400MHz) : 13.10-12. 30(1H, br), 10.66(1H, s), 7.88(2H, d, J=8.6Hz), 7.65(2H, d, J=8.6Hz), 7.57-7. 38 (5H, m), 7. 21 (2H, t, J=8.8Hz). 82 thirty NMR1 (500MHz) ; 12.64(1H, brs), 10.64(1H, s), 7.86(2H, d, J=8.3Hz), 7.63(2H, d, J=8.3Hz), 7.54-7. 49 (2H, m), 7. 46-7. 34(5H, m), 7. 32-7. 28(1H, m). 83 thirty NMR1 (500MHz) ; 13.13(1H, brs), 10.39(1H, s), 7.92-7. 88(1H, m), 7.73(1H, d, J=8.3Hz), 7.66(1H, d, J=11.1Hz), 7.53-7.48(2H, m), 7.46-7.36 (5H, m), 7.35-7.31 (1H, m). 84 thirty NMR1 (500MHz) ; 12.79 (1H, brs), 10.90(1H, s), 7.95 (2H, d, J=8.8Hz), 7.86-7. 81 (3H, m), 7.7K1H, dd, J=8. 8Hz, 2.1Hz), 7.56(1H, dt, J=8.5Hz, 2.6Hz), 7.28(1H, t, J=55.3Hz).

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85 thirty NMR1 (500MHz); 13.22(1H, brs), 10.73(1H, s), 8.02(1H, t, J=8.0Hz), 7.85-7. 80(2H, m), 7.76(1H, dd, J=11.OHz, 1.8Hz), 7.69(1H, d, J=8.8Hz), 7.56(1H, dt, J= 8.5Hz, 2.6Hz), 7.27(1H, t, J=55.3Hz). 86 35 NMR2 (500MHz); 9.05(1H, s), 8.30(1H, dd, J=8.8Hz, 2.4Hz), 8.21(1H, dd, J=9.2Hz, 0.6Hz), 7.87(1H , dd, J=9.2Hz, 2.7Hz), 7.26(1H, t, J=8.2Hz), 7.2K1H, dt, J=8. 3Hz, 2.8Hz), 4.39(2H, t, J=6.3Hz), 3.95(3H, s), 3.10(2H, t, J=6.4Hz). 87 35 NMR2(500MHz) ; 9.04(1H, s), 8.29(1H, dd, J=8.8Hz, 2.3Hz), 8.2K1H, d, J=8. 7Hz), 8.20 (1H, d, J=9.3Hz), 7.08 (1H, dt, J=8.6Hz, 2.6Hz), 6.97 (1H, dd, J=8.7Hz, 2.5Hz), 4.40(2H, t, J=6.3Hz), 3.95(3H, s), 3.12(2H, t, J=6.4Hz). 88 37 NMR2 (500MHz); 9.09 (1H, s), 8.34 (1H, dd, J=8.8Hz, 2.4Hz), 8.23 (1H, dd, J=8.7Hz, 0.5Hz), 7.87 (1H , dd, J=9.1Hz, 2.7Hz), 7.26(1H, t, J=8.2Hz), 7.22(1H, dt, J=8.3Hz, 2.8Hz), 4.40(2H, t, J=6.4Hz), 3.11 (2H, t, J=6.4Hz). 89 37 NMR2(500MHz) ; 9.10(1H, s), 8.34(1H, dd, J=8.8Hz, 2.3Hz), 8.31(1H, d, J-8.8Hz), 8.22(1H, dd, J=8.7Hz, 5.8Hz), 7.08(1H, dt, J=8.6Hz, 2.5Hz), 6.98(1H, dd, J=8.6Hz, 2.4Hz), 4.42( 2H, t, J=6.3Hz), 3.13 (2H, t, J=6.4Hz). 90 39 NMR2(500MHz) : 8.16(1H, d, J=7.8Hz), 8.10(2H, d, J=8.7Hz), 7.59(1H, t, J=7.7Hz), 7.55(1H, d, J=7.7Hz), 7.51 (2H, d, J=8.7Hz), 7.39 (1H, t, J=7.7Hz), 4.07 (2H, s), 3 .93 (3H, s), 2.44(2H, m), 2.18(2H, m), 2.08 (2H, m). 91 thirty NMR1 (400MHz) : 13.21(1H, brs), 10.66(1H, s), 7.99(1H, t, J=7.9Hz), 7.85-7. 65 (6H, m), 7.32 (1H, t, J=55.4Hz). 92 thirty NMR1 (500MHz) ; 13.00(1H, brs), 10.84, (1H, s), 7.83 (1H, t, J=8.6Hz), 7.63 (1H, dd, J=8.9Hz, 2.1Hz), 7.58 (1H, d, J=13.4Hz), 7.55-7. 48 (2H, m), 7.43-7. 35 (3H, m), 7. 26-7. 18 (2H, m). 93 thirty NMR1 (500MHz) : 14.17-11. 90(1H, br), 10. 39(1H, s), 7. 86(1H, t, J=7.5Hz), 7. 74(1H, d, J=8.4Hz), 7. 68(1H, d, J=10.9Hz), 7.59(1H, dd, J=9.OHz, 2.1Hz), 7.53-7. 46 (2H, m), 7. 44-7. 35 (2H, m), 7. 25-7. 18 (2H, m).

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94 thirty NMR1 (500MHz) ; 14.02-11.41 (1H, br), 10.67(1H, s), 7.88(2H, d, J=8.7Hz), 7.67 (2H, d, J=8.7Hz), 7.60(1H, dd, J=8.9Hz, 2.3Hz), 7.53-7. 46 (2H, m), 7. 42-7. 34 (2H, m), 7. 25-7.17 (2H, m). 95 NMR1 (500MHz) ; 13. SH1H, brs), 11.26(1H, s), 8.81(1H, d, J=2.1Hz), 8.24(1H, dd, J=8.7Hz, 2.1Hz), 8.06(1H, d, J=8.7Hz), 7.61-7. 57 (1H, m), 7. 50-7. 46 (2H, m), 7. 42-7. 33 (2H, m), 7. 25-7. 16 (2H, m). 96 95 NMR1 (500MHz) ; 13.12(1H, brs), 11.08(1H, s), 8.78(1H, d, J=1.7Hz), 8.19(1H, dd, J=8.7Hz, 2.3Hz), 7.99( 1H, d, J=8.7Hz), 7.54(1H, dd, J=9.0Hz, 2.7Hz), 7.39(1H, dt, J=8.6Hz, 2.7Hz), 7.3K1H , dd, J=8. 6Hz, 5.6Hz), 7.21-7.10(4H, m), 2.11(3H, s). 97 NMR2(400MHz) ; 7.97 (2H, d, J=8.7Hz), 7.66 (1H, dd, J=9.0Hz, 2.7Hz), 7.5K1H, brs). 7.45-7. 38(1H, m), 7. 37-7. 19(5H, m), 7.13(1H, dt, J=7.5Hz, 0.8Hz), 6.91(1H, d, J=8.0Hz), 3.64(3H, s). 98 NMR2 (400MHz) ; 8.65-8. 50 (1H, m), 7. 91-7. 78 (2H, m), 7. 71-7. 58 (2H, m), 7. 45-7. 20 (4H, m), 7.13-7.02(14, m), 6.92-6.81 (1H, m), 3.67 (3H, s). 99 NMR2 (400MHz) ; 8.83-8. 69 (1H, m), 8. 36-8. 12 (2H, m), 7.58-7. 15(6H, m), 7.14-6. 96(1H, m), 6.95-6. 79(1H, m), 3. 68(3H, s). 100 37 NMR1 (500MHz) ; 12.95(1H, s), 8.00 (2H, d, J=8.7Hz), 7.97(1H, d, J=7.7Hz), 7.71 (1H, t, J=7.0Hz) , 7. 66(1H, t, J=7.3Hz), 7.57(2H, d, J=8.7Hz), 7.43(1H, t, J=7.7Hz), 4.03(2H, s), 2.36(2H, m), 2. 12(2H, m), 1.98(2H, m). 101 39 NMR2(500MHz) ; 8.15(2H, d, J=8.8Hz), 7.97(1H, d, J=7.2Hz), 7.48(2H, d, J=8.8Hz), 7.37(1H, dt, J=8.1Hz, 5. 4Hz), 7.30-7.21 (1H, m), 4.05 (2H, t, J=6.4Hz), 3.93 (3H, s), 3.19 (2H, t, J=6.5Hz). 102 39 NMR2 (500MHz) ; 8.17(1H, dd, J=8.2Hz, 5.8Hz), 8.09(2H, d, J=8.8Hz), 7.7(1H, dt, J=8.6Hz, 2.6Hz), 7.48 (2H, d, J=8.8Hz), 6.95(1H, dd, J=8.7Hz, 2.6Hz), 4.05(2H, t, J=6.4Hz), 3.93 ( 3H, s), 3.16(2H, t, J=6.4Hz).

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103 39 NMR2(500MHz) ; 8. 09 C2H, d, J=8. 8Hz), 7.84(1H, dd, J=9.1Hz, 2.7Hz), 7.48(2H, d, J=8.8Hz), 7.24(1H, dd, J=8.3Hz, 5.2Hz), 7.19 (1H, dt, J=8.3Hz, 2.8Hz), , 4.04(2H, t. J=6.4Hz), 3.93(3H, s), 3.14(2H, t, J=6.5Hz). 104 37 NMR2 (500MHz); 8.09(2H, d, J=8.7Hz), 7.98(1H, d, J=7.7Hz), 7.53(2H, d, J=8.7Hz), 7.38(1H, dt, J= 8.1Hz, 5.5Hz), 7.25(1H, t, J=8.1Hz), 4.07(2H, t, J=6.5Hz), 3.20(2H, t, J=6.5Hz). 105 37 NMR2 (500MHz); 8.18(1H, dd, J=8.7Hz, 5.8Hz), 8.14(2H, d, J=8.8Hz), 7.52(2H, d, J-8.8Hz), 7.07(1H, dt , J=8.6Hz, 2.6Hz), 6.96(1H, dd, J=8.7Hz, 2.4Hz), 4.07(2H, t, J=6.4Hz), 3.17(2H, t, J=6.4Hz). 106 37 NMR2(500MHz) ; 8.16(2H, d, J=8.7Hz), 7.85(1H, dd, J=9.2Hz, 2.7Hz), 7.53(2H, d, J=8.7Hz), 7.25(1H, dd, J=8.4Hz, 5.2Hz), 7.20(1H, dt, J=8.3Hz, 2.7Hz), 4.06(2H, t, J=6.3Hz), 3.15(2H, t, J=6.4Hz). 107 thirty NMR1 (500MHz) : 14.17-11. 94(1H, br), 10.45(1H, s), 7.88(1H, t, J=7.9Hz), 7.75(1H, d, J=8.3Hz), 7.68(1H, d, J=10.9Hz), 7. 58-7. 52 (2H, m), 7. 48-7. 40 (2H, m), 7.26-7. 22 (2H, m), 7. 20-7. 15 (1H, m). 108 thirty NMR1 (500MHz) ; 12.76(1H, brs), 10.69(1H, s), 7.88(2H, d, J=8.7Hz), 7.65(2H, d, J=8.7Hz), 7.58-7. 54(2H, m), 7.46(1H, dt, J=8.5Hz, 2.8Hz), 7.43-7. 38(1H, m), 7.22(2H, d, J=7.5Hz), 7. 17-7. 12 (1H, m). 109 NMR1 (500MHz) ; 13.98-12. O5(1H, br), 11.26(1H, s), 8.79(1H, d, J=1.8Hz), 8.25(1H, dd, J=8.6Hz, 2.3Hz), 8.12-8 . 07(1H, brs), 7.55-7. 50(2H, m), 7.44(1H, dt, J=8.6Hz, 2.7Hz), 7.42-7. 37 (1H, m), 7. 22-7.18 (2H, m), 7.17-7. 11 (1H, m). 110 39 NMR2 (400MHz) : 8.13(1H, d, J=2.2Hz), 8.09 (2H, d, J^8.8Hz), 7.48(2H, d, J=8.7Hz), 7.45(1H, dd, J=8.1Hz, 2.4Hz), 7.2K1H, d, J=8.2Hz), 4.03(2H, t, J=6.2Hz), 3.93(3H, s), 3.13(2H, t, J=6.4Hz). 111 37 NMR1 (400MHz) : 13.22-12. 71(1H, br), 7.99(2H, d, J=8.7Hz), 7.9O(1H, d, J=2.3Hz), 7.62(1H, dd, J=8.1Hz, 2.3Hz) , 7.56 (2H, d, J=8.7Hz), 7.45 (1H, d, J=8.2Hz), 4.03 (2H, t, J=6.2Hz), 3.14 (2H, t, J =6.4Hz).

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112 39 NMR1 (400MHz) : 8.01 (2H, d, J=8.8Hz), 7.97 (1H, dd, J=7.8Hz, 1.1Hz), 7.72(18, dd, J=8.OHz, 1.2Hz ), 7.60 (2H, d, J=8.8Hz), 7.45(1H, t, J=7.9Hz), 4.07 (2H, t, J=6.4Hz), 3.87(38, s ), 3.20 (2H, t, J=6.4Hz). 113 37 NMR1 (400MHz) : 12.96(1H, brs), 8.03-7. 94(3H, m), 7.72(18, dd, J=8. OHz, 1.2Hz), 7.56(2H, d, J=8.7Hz), 7.45(18, t, J=7.9Hz) , 4.06 (2H, t, J=6.4Hz), 3.20 (2H, t, J=6.4Hz). 114 thirty NMR1 (500MHz) ; 12.75(1H, brs), 10.68(1H, s), 7.92(28, br d, J=8.7Hz), 7.87 (2H, br d, J=8.7Hz), 7.42-7. 38(2H, m), 7.27(1H, dt, J=0.9Hz, 7.5Hz), 7.03(18, d, J=7.8Hz), 2.19-2.13(1H, m), 0.93-0.90 (2H, m), 0.71-0. 68 (2H, m). 115 thirty NMR2(500MHz); 8.75(1H, t, J=7.5Hz), 8.29(1H, d, J=3.2Hz), 7.99(18, d, J=9.2Hz), 7.87(18, dd, J=1.7 Hz, 11.4Hz), 7.63(18, dd, J=0.8Hz, 7.6Hz), 7.43(1H, dt, J-1.0Hz, 7.6Hz), 7.30(1H, t, J=7.5Hz), 7. 07(1H, d, J=7.9Hz), 2. 31-2. 26(1H, m), 1.10-1.06(2H, m), 0.85-0.82(2H, m). 116 NMR2 (400MHz) ; 8.07-8. 10(2H, m), 7.97(18, d, J=1.3Hz), 7.47-7. 51(2H, m), 7.30(1H, dd, J=7.7Hz, 1.3Hz), 7.15(1H, d, J=7.7Hz), 4.02(1H, t, J=6.2Hz), 3.93(3H, s), 3.11(1H, t, J=6.2Hz), 2.40(3H, s). 117 37 NMR1 (500MHz) : 13.13-12.65(18, br), 7.97(2H, d, JMO. 7Hz), 7.83(1H, d, J=9.2Hz), 7.55(28, d, J=10.8Hz), 7 .42(1H, d, J=9.5Hz), 7.30(1H, t, J=9.6Hz), 4.02(28, t, J=8.OHz), 3.06(2H, t, J=8 .1Hz), 2.33(3H, s). 118 39 NMR2(500MHz) : 8.09(28, d, J=11. OHz), 8.04(18, d, J=8. 9Hz), 7.50(2H, d, J=11. OHz), 7.36(18, d, J=8.7Hz), 7.30(1H, t, J-9.6Hz), 4.04(2H, t, J=7.9Hz), 3.93(38, s), 3.09(2H, t, J=8.1Hz) , 2.36(38, s). 119 95 NMR1 (400MHz); 13.70-12.20(18, br), 11.20(18, s), 8.85(1H, dd, J=1.0Hz, 2.1Hz), 8.36-8. 30(2H, m), 7.43(18, dd, J=1.3Hz, 7.6Hz), 7.38(1H, dt, J=1.3Hz, 7.6Hz), 7.24(1H, dt, J=1.OHz, 7.6 Hz), 7.02(18, br d, J=7.8Hz), 2.22-2. 15(1H, m), 0.93-0.88(28, m), 0.71-0. 67 (2H, m).

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120 35 NMR2 (400MHz) : 9.04(1H, brs), 8.33-8. 27 (1H, m), 8.24-8. 13(3H, m), 7. 49-7. 44(1H, m), 7.23(1H, d, J=8.1Hz), 4.38(2H, t, J=6.6Hz), 3.95(3H, s), 3.10(2H, t, J =6.4Hz). 121 NMR1 (400MHz); 12.93(1H, brs), 7.99-7. 96(2H, m), 7.77(1H, d, J=1.4Hz), 7.57-7. 53 (2H, m), 7. 36(1H, dd, J=7.7Hz, 1.4Hz), 7.27(1H, d, J=7.7Hz), 3.99(2H, t, J=6.2Hz), 3.09( 2H, t, J=6.2Hz), 2.36 (3H, s). 122 thirty NMR1 (500MHz) ; 13.08(1H, brs), 11.05JH, s), 7.9K1H, t, J=8.6Hz), 7.84(1H, dd, J=8.7Hz, 5.3Hz), 7.79-7. 71 (2H, in), 7. 60-7. 53 (2H, m), 7. 28 (1H, t, J=55.2Hz). 123 35 NMR2 (400MHz) : 9.05 (1H, brd, J=2.2Hz), 8.30 (1H, dd, J=8.8Hz, 2.4Hz), 8.21 (1H, brd, J=8.8Hz) ), 8.14(1H, brd, J=7.8Hz), 7.58(1H, dd, J=7.9Hz, 1.2Hz), 7.36(1H, t, J=7.9Hz), 4.40 ( 2H, t, J=6.3Hz), 3.95(3H, s), 3.22(2H, t, J=6.4Hz). 124 37 NMR1 (400MHz): 13.29(1H, brs), 8.97(1H, brd, J=2.3Hz), 8.30(1H, dd, J=8.7Hz, 2.4Hz), 8.12( 1H, brd, J=8.7Hz), 8.04(1H, brd, J=7.8Hz), 7.75(1H, dd, J=8.OHz, 1.2Hz), 7.48(1H, t, J=7.9Hz ), 4.33 (2H, t, J=6.7Hz), 3.18 (2H, t, J=6.4Hz). 125 39 NMR2 (500MHz); 8.17(1H, dd, J=8.7Hz, 5.8Hz), 7.99(1H, t, J=8.3Hz), 7.27(2H, d, J=7.9Hz), 7.07(1H , dt, J=8.6Hz, 2.6Hz), 6.96HH, dd J=8.7Hz, 2.5Hz), 4.4(2H, q, J=7.2Hz), 4.03 (2H, t, J= 6.4Hz), 3.16(2H, t, J=6.4Hz), 1.40(3H, t, J=7.1Hz). 126 39 NMR2 (500MHz) ; 8.17(1H, dd, J=8.7Hz, 5.8Hz), 7.89(1H, d, J=8.3Hz), 7.85(1H, d, J=10.8Hz), 7.47(1H, t, J=8.0Hz), 7.07(1H, dt, J=8.6Hz, 2.6Hz), 6.96(1H, dd, J=8.8Hz, 2.5Hz), 4.4(2H, q, J= 7.2Hz), 3.96(2H, t, J=6.3Hz), 3.18(2H, t, J=6.4Hz), 1.41(3H, t, J=7.1Hz). 127 35 NMR2: 9.04(1H, brs), 8.33-8.27(1H, m), 8.24-8.13(2H, m), 7.49-7. 44(1H, m), 7.23(1H, d, J=8.1Hz), 4.38(2H, t, J=6.6Hz), 3.95(3H, s), 3.10(2H, t, J =6.4Hz). 128 37 NMR1 (400MHz) : 13.30(1H, brs), 8.96 (1H, d, J=2.3Hz), 8.30 (1H, dd, J=8.7Hz, 2.2Hz), 8.11 (1H , d, J^8.7Hz), 7.96(1H, brs), 7.65(1H, brd, J=8.1Hz), 7.47(1H, d, J=8.1Hz), 4.29(2H, t, J =6.2Hz), 3.12 (2H, t, J=6.3Hz).

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129 37 NMR1 (400MHz) ; 13.71-12. 56(1H. br). 8.0K1H, dd, +8.6Hz, 6.0Hz), 7.88(1H, m), 7.39C2H, m), 7.25 (2H, m), 4.03 (2H, t, +6.2Hz) , 3.16 (2H, t, +6.0Hz). 130 37 NMR1 (400MHz) ; 13.82-12. 83(1H, br), 7.99(1H, dd, +8.6Hz, 6.0Hz), 7.84(1H, d, J=9.0Hz), 7.76(1H, d, +10.4Hz), 7.62(1H, t, +7.8Hz), 7.29(1H, d, +9.7Hz), 7.24(1H, t, +8.8Hz), 3.95(2H, t, +6.2Hz), 3.18 (2H, t, +6.4Hz). 131 39 NMR2 (500MHz) ; 8.09(1H, d, +8.4Hz), 7.98(1H, t, +8.1Hz), 7.37(1H, dd, +8.4Hz, 2.1Hz), 7.26(3H, m), 4.40 (2H, q, +7.2Hz), 4.03 (2H, t, +6.4Hz), 3.15 (2H, t, +6.4Hz), 1.40(3H, t, +7.2Hz ). 132 39 NMR2(500MHz) ; 8.09(1H, d, +8.4Hz), 7.90(1H, dd, +8.3Hz, 1.7Hz), 7.85(1H, dd, +10.8Hz, 1..8Hz), 7.46(1H, t, + 8.OHZ), 7.36(1H, dd, +8.4Hz, 2.1Hz), 7.27(1H, d, +2.OHz), 4.40(2H, q, +7.1Hz), 3.95 (2H, t, +6.3Hz), 3.16 (2H, t, +6.4Hz), 1.4K3H, t, +7. 2Hz). 133 37 NMR1 (400MHz) ; 13.66-12. 67(1H, br), 7.95(1H, d, +8.4Hz), 7.89(1H, t, +8.5Hz), 7.53(1H, d, +2.OHz), 7.47 (1H, dd, +8.4Hz, 2.2Hz), 7.44(1H, m), 7.38 (1H, dd, +8.5Hz, 2.0Hz), 4.03 (2H, t, +6.3Hz), 3.15 (2H, t, +6.3Hz). 134 37 NMR1 (400MHz) ; 13.77-12. 80(1H, br), 7.93(1H, d, +8.3Hz), 7.84(1H, dd, +8.3Hz, 1.6Hz), 7.77dH, dd, +10. 8Hz, 1.6Hz), 7.63(1H, t, +7.9Hz), 7.54(1H, d, +2.OHz), 7.48(1H, dd, +8.4Hz, 2.1Hz), 3.95 (2H, t, +6.6Hz), 3.17(2H, t, +6.4Hz). 135 39 NMR2(500MHz) : 7.90(1H, dd, +6.9Hz, 1.3Hz), 7.86(1H, dd, +10.9Hz, 1.8Hz), 7.84(1H, dd, +10.1Hz , 2.7Hz), 7.47(1H, t, +8.OHz), 7.25(1H, dd, 8.4Hz, 5.2Hz), 7.20(1H, dd, +8.4Hz, 2.8Hz ), 4.40(2H, q, +7.2Hz), 3.95(2H, t, +6.3Hz), 3.16(2H, t, +6.4Hz), 1.41(3H, t, +7.2Hz ). 136 37 NMR1 (400MHz) ; 7.84(1H, d, +8.8Hz), 7.77(1H, d, +8.2Hz), 7.64(2H, m), 7.45(2H, m), 3.95(2H, t, +6.2Hz ), 3.15 (2H, t, +6.6Hz). 137 NMR1 (500MHz) ; 12.92(1H, s), 9.85(1H, s), 8.22(1H, d, J=8.OHz), 7.65-7. 57 (2H, m), 7. 56-7. 53 (2H, m), 7. 52-7. 47(1H, m), 7.45(1H, t, +7.2Hz), 3.88(3H, s).

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138 NMR2(500MHz) ; 13.54-12. 92 (1H, br). 11.64(1 H. s). 8.96-8. 78(2H, m), 8.36(1H, dd, J=10.9Hz, 2.8Hz), 8.33-8. 18(2H, m), 7.84(1H, dd, J=9.8Hz, 6.0Hz). 139 NMR2 (500MHz) ; 7.55-7. 43 (5H, m), 7. 28-7. 23 (2H, m), 4. 12-4. 02(2H, m), 2. 46-2. 31 (5H, m). 140 NMR2 (500MHz); 7.69(1H, d, J=2.5Hz), 7.28-7. 23 (1 H _r m), 6.67(1H, d, J-9. OHz), 4.70(1H, brs), 3.44-3. 34(2H, m), 2.71-2. 55 (2H, m). 141 NMR2 (400MHz) : 7.75(1H.d, J=2.4Hz), 7.14(1H, dd, J=8.3Hz, 2.4Hz), 6.7K1H, d, J=8.3Hz), 4.19-4. 04 (2H, m), 4.01-3.85 (1H, m), 3.75-3. 58 (1H, m), 3.29-3. 04(2H, m), 2. 49-2. 28 (2H, m), 2. 13-2. 00 (1H, m). 142 NMR2 (400MHz) ; 8.00 (1H, s), 7.81 (2H, d, J=8.OHZ), 7.39 (2H, d, J=8.OHZ), 7.18 (1H, dd, J=8.4Hz) , 2.4Hz), 6.86(1H, d, J=8.4Hz), 4.68(1H, d, J=10.OHz), 4.34-3. 94 (2H, m), 3. 86-3. 68 (1H, m), 3. 32-3. 07(1H, m), 2.94-2. 68 (1H, m), 2.48 (3H, m), 2.37-2. 17 (1H, m), 0.91 (9H, s), 0.14 (3H, s), 0.07 (3H, s). 143 NMR2 (400MHz); 7.79(1H, d, J=2.4Hz), 7.09(1H, dd, J=8.4Hz, 2.4Hz), 6.64(1H, d, J=8.4Hz), 4.23(1H, d, J=10. OHz), 3.9K1H, dt, J=10.0Hz, 2.4Hz), 3.88-3. 83 (1H, m), 3. 75-3. 53 (1H, m), 3. 29-3. 26 (1H, m), 3. 16-2. 98(1H, m), 2. 46-2. 16(2H, m), 0. 83(9H, s), -0. 03(1H, s), -0.12(1H, s). 144 NMR2 (500MHz) ; 7.91-7. 81 (1H, m), 7. 62-7. 33(2H, m), 3.94-3. 67(2H, m), 2.73-2.55(2H, m), 1.60-1.31(9H, m). 145 NMR2 (400MHz) : 7.58 (1H, d, J=2.4Hz), 7.13 (1H, dd, J=8.4Hz, 2.4Hz), 6.7K1H, d, J=8. 4Hz), 4.56(1H, brs), 3.69(1H, brs), 3.2K1H, ddd, J=13. 6Hz, 7.6Hz, 4.0Hz), 3.10(1H, ddd, J=13.2Hz, 9.2Hz, 3.2Hz), 2.56(1H, dddd, J=30.8Hz, 14.4Hz, 9.2Hz, 4.0Hz), 2.27(1H, dddd, J=27.OHZ, 14.4Hz, 7.2Hz, 3.6Hz), 1.69-1. 63 (3H, m). 146 NMR2 (400MHz) ; 7.96-7. 84 (1H, m), 7. 39-6. 97 (2H, m), 4.50-4. 10(1H, m), 4.03-3. 59 (2H, m), 3. 56-3. 35 (1H, m), 3. 21-2. 84(1H, m), 2.75-1. 72 (3H, m), 1. 66-1. 16(9H, m).

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147 NMR2 (400MHz) ; 7.56-7. 51(2H, m), 7. 45(1H, d, J=2.4Hz), 7.41-7. 37(1H, m), 7. 37-7. 33 (1Hm), 7.2K2H, d, J=8. OHz), 3.76(2H, t, J=6.2Hz), 2.92(2H, t, J=7.2Hz), 2.40(3H, s), 2.14-2. 02(2H, m), 1.73(2H, tt, J=6. OHz, 6.0Hz), 1.67-1. 53 (2H, m), 1.38 (2H, tq, J=7.2Hz, 7.2Hz), 0.96 (3H, t, J=7.2Hz). 148 150 NMR2 (400MHz); 7.96-7. 84 (1H, m), 7. 39-6. 97(2H, m), 4.50-4.10(1H, m), 4.03-3. 59 (2H, m), 3. 56-3. 35(1H, m), 3.21-2, 84(1H, m), 2.75-1. 72(3H, m), 1.66-1.16(9H, m). 149 154 NMR2 (400MHz); 8.03-7. 93 (1H, m), 7. 90-7. 70 (2H, m), 7. 63-7. 46 (2H, m), 7. 43-7. 29 (1H, m), 7. 25-7. 01 (1H, m), 5. 06-4. 65(1H, m), 4. 60-4. 06 (2H, m), 3.86-3. 44(1H, m), 3. 21 -2. 88 (1H, m), 2.90-2. 43(1H, m), 2.38-1.93 (1H, m), 1.67-1. 18 (9H, m). 150 NMR2 (400MHz) ; 7.96-7. 84 (1H, m), 7. 39-6. 97 (2H, m), 4.50-4.10 (1H, m), 4.03-3. 59(2H, m), 3.56-3. 35(1H, m), 3. 21-2. 84(1H, m), 2.75-1. 72 (3H, m), 1. 66-1.16 (9H, m). 151 NMR2(400MHz) : 7.75(1H, d, J=2.4Hz), 7.14(1H, dd, J=8.3Hz, 2.4Hz), 6.7K1H, d, J=8. 3Hz), 4. 19-4. 04 (2H, m), 4.01-3.85 (1H, m), 3.75-3. 58 (1H, m), 3. 29-3. 04(2H, m), 2. 49-2. 28 (2H, m), 2. 13-2. 00 (1H, m). 152 NMR1 (500MHz) ; 7.64(1H, d, J=2.4Hz), 7.40-5. 60(6H, m), 3.88-3. 71(2H, m), 3.22(1H, d, J=13.5Hz), 2.90-2. 71 (1H, m), 2. 49-2. 27 (1H, m), 2. 26-2. 10 (1H, m). 153 NMR2 (400MHz) : 8. 03-7. 93 (1H, m), 7. 90-7. 70 (2H, m), 7. 63-7. 46 (2H, m), 7. 43-7. 29 (1H, m), 7. 25-7. 01 (1H, m), 5. 06-4. 65 (1H, m), 4. 60-4. 06 (2H, m), 3.86-3. 44(1H, m), 3. 21-2. 91 (1H, m), 2.90-2. 43(1H, m), 2.38-1. 93(1H, m), 1.67-1. 18(9H, m). 154 NMR2 (400MHz) ; 8.03-7. 93(1H, m), 7. 90-7. 70 (2H, m), 7. 63-7. 46 (2H, m), 7. 43-7. 29 (1H, m), 7. 25-7. 01 (1H, m), 5. 06-4. 65(1H, m), 4. 60-4. 06(2H, m), 3. 86-3. 44(1H, m), 3. 21-2. 91 (1H, m), 2.90-2. 43 (1H, m), 2. 38-1. 93 (1H, m), 1.67-1. 18 (9H, m).

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155 NMR2 (500MHz) ; 7.88-7. 80 (3H, m). 7.60-7. 56(2H, m), 7.16(1H, dd, J=8.3Hz, 2.5Hz), 6.72(1H, d, J=8.3Hz), 5.14(1H, d, J=11.9 Hz), 4. 66-4. 58(1H, m), 3.93(1H, brs), 3.73(1H, d, J=5.9Hz), 3.34-3. 24 (1H, m), 3. 16-3. 07(1H, m), 2.60-2. 28 (2H, m). 156 NMR2 (500MHz) I 7.88-7. 80 (3H, m), 7. 60-7. 56(2H, m), 7.16(1H, dd, J=8.3Hz, 2.5Hz), 6.72(1H, d, J=8.3Hz), 5.14(1H, d, J= 11.9Hz), 4.66-4. 58 (1H, m), 3.93(1H, brs), 3.73(1H, d, J=5.9Hz), 3.34-3. 24 (1H, m), 3. 16-3. 07(1H.m), 2.60-2. 28 (2H, m). 157 NMR2 (500MHz) ; 7.95-7. 79 (1H, m), 7. 69-7. 50 (2H, m), 7. 40-7. 14 (6H, m), 7. 10-6. 94(3H, m), 5.05-3. 78(5H, m), 3. 48(1H, s), 3.15-2. 72(3H, m), 2.61-1.90 (5H, m), 1.65-1. 29 (9H, m). 158 NMR2 (500MHz) ; 7.95-7. 81 (1H, m), 7. 66-7. 51 (2H, m), 7.37-6. 93 (9H, m), 5. 10-4. 84 (1H, m), 4.75-3. 70 (4H, m), 3. 61-3. 48 (1 H, m), 3. 15-2. 81 (3H, m), 2.55-1.90 (5H, m), 1.65-1. 20(9H, m). 159 NMR2 (500MHz) ; 7.68(2H, d, J=8.0Hz), 7.59-7. 53(1H, m), 7.33(2H, d, J=8.OHz), 7.20(1H, dd, J=8.5Hz, 2.5Hz), 6.80(1H, s), 3.92-3. 62 (2H, m), 3.44-3. 02(1H, m), 2. 81-2. 52 (1H, m), 2.46 (3H, s), 2.42-2. 26(1 H, m). 160 NMR2 (500MHz); 7.32(1H, d, J=2.5Hz), 7.15(1H, dd, J=8.3Hz, 2.5Hz), 6.72(1H, d, J=8.3Hz), 3.70(1H , brs), 3.60(1H, brs), 3.30-3.22(1H, m), 3.15-3. 08(1H, m), 2.73-2. 59(1H, m), 2. 21-2. 11 (1H, m). 161 NMR2 (500MHz) : 7.95-7. 79 (1H, m), 7. 69-7. 50 (2H, m), 7.40-7. 14 (6H, m), 7. 10-6. 94(3H, m), 5.05-3. 78 (5H, m), 3.48 (1H, s), 3.15-2. 72(3H, m), 2. 61-1.90 (5H, m), 1.65-1.29 (9H, m). 162 NMR2 (500MHz) ; 7.95-7. 81 (1H, m), 7. 66-7. 51 (2H, m), 7.37-6. 93 (9H, m), 5. 10-4. 84(1H, m), 4.75-3. 70(4H, m), 3.61-3. 48(1H, m), 3.15-2. 81 (3H, m), 2.55-1. 90(5H, m), 1.65-1. 20 (9H, m). 163 NMR2(400MHz) ; 9.60-9. 40(1H, brs), 8. 70-8. 60(1H, m), 8.54(1H, t, J=8.1Hz), 7.90-7. 72(2H, m), 7.72(1H, dd, J=11.6Hz, 1.8Hz), 7.61(1H, dd, J=9.OHz, 2.7Hz), 7.58-7. 45 (2H, m), 7. 37-7. 20 (2H, m), 3.90 (3H, s).

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164 NMR2 (400MHz) ; 8.82(1H, d, J=5.6Hz). 8.40 (1H, t, J=7.9Hz), 8.12-7. 39 (9H, m). 165 NMR2 (500MHz) ; 7.74-7. 68(1H, m), 7.61(2H, d, J-8.3Hz), 7.48-7.19(5H, m), 7.13(1H, dd, J=8.3Hz, 2.5Hz) , 6.99 (2H, dd, J=5.9Hz, 2.2Hz), 6.68 (1H, d, J-8.3Hz), 4.98 (1H, d, J=9.2Hz), 4.67(1H, d, J=11.7Hz), 4.29(1H, dd, J=11.7Hz, 1.7Hz), 4.22-4.08(1H, m), 3.66(1H, d, J=6.1Hz) , 3.4K1H, brs), 3.28-3. 15 (1H, m), 3. 12-2. 81 (3H, m), 2.41 (3H, s), 2.32-2. 05 (2H, m). 166 NMR2 (400MHz) ; 7.65(2H, d, J=8.OHz), 7.50(1H, d, J=2.4Hz), 7.31(2H, d, J=8.0Hz), 7.27(1H, dd, J= 8.4Hz, 2.4Hz), 7.13(1H, d, J=8.4Hz), 4.44-4, 27(1H, m), 3.48-3. 32 (1H, m), 2.95-2. 85 (1H, m), 2.70-2. 49 (1H, m), 2.45 (3H, s), 2.38-2. 19 (2H, m). 167 NMR2 (400MHz) ; 7.49-7. 43 (2H, m), 7. 41-7. 36 (1H, m), 7. 35-7. 29 (1H, m), 7. 23-7. 15(3H, m), 5.38(1H, s), 4.87(1H, s), 4.04-3. 82 (2H, m), 2.41 (3H, s), 2.28 (2H, tt, J=13.2Hz, 5.6Hz). 168 NMR2 (400MHz); 8.00(1H, s), 7.80(2H, d, J=8.0Hz), 7.40(2H, d, J=8.0Hz), 7.19(1H, dd, J=8.4Hz, 2.4Hz), 6.88-6. 74(1H, m), 4. 28-4. 13(3H, m), 3. 54(1H, brs), 3.31-3. 13(1H, m), 2.93-2.70(1H, m), 2.49(3H, s), 2.40-2. 24 (1H, m), 2. 20-2. 08 (1H, m). 169 NMR2 (400MHz) : 8. 08-7. 89(1H, m), 7.81(2H, d, J=8.OHz), 7.49(2H, d, J=8.OHz), 7.18(1H, dd, J=8.4Hz, 2 .4Hz), 7.00-6. 74(1H, m), 4. 37-3. 98(1H, m), 3.33-3. 02 (1H, m), 3. 02-2. 73 (1H, m), 2. 73-2. 56(1H, m), 2.49(3H, s), 2.34-2. 12(1H, m), 1.80(3H, s). 170 NMR2(400MHz); 7.85(1H, brs), 7.38-6. 99(2H, m), 4. 81-4. 63(1H, m), 4. 63-4. 45(1H, m), 4. 40-3. 86(1H, m), 3.19-2. 33(4H, m), 2. 33-1.81 (1H, m), 1.57-1. 26 (9H, m). 171 NMR2 (400MHz); 8.54-8. 41 (1H, m), 8.19 (1H, d, J=7.0Hz), 8.07(1H, d, J=7.8Hz), 7.97-7. 89(1H, m), 7.87(1H, d, J=2.4Hz), 7.68-7. 45 (3H, m), 7. 44-7. 24(1H, m), 7. 24-6. 70(6H, m), 5. 40-5. 00(1H, m), 4.75-3. 34 (5H, m), 3.28-1.78 (5H, m), 1.67-1. 17 (9H, m).

- 68 040222

172 NMR2(400MHz); 8.51-8. 41(1H, m), 8.14(1H, dd, J=7.4Hz, 1.0Hz), 8.04(1H, d, J=8.2Hz), 7, 94-7, 85(2H, m), 7. 64-7. 53 (2H, m), 7. 52-7. 44 (1H, m), 7. 36-7. 23 (1H, m), 7.11-6. 93(4H, m), 6.91-6. 77 (2H, m), 5. 35-5. 05(1 H, m), 4. 74-3. 29 (5H, m), 3.18-1.96(5H _T m), 1.66-1. 13(9H, m). 173 165 NMR2 (400MHz); 8.51-8. 43(1H, m), 8.19(1H, dd, J=7.4Hz, 1.2Hz), 8.05(1H, d, J=8.3Hz), 7.95-7. 88 (1H, m), 7.71 (1H, d, J=2.4Hz), 7.64-7. 55(2H, m), 7. 54-7. 47(1H, m), 7.12(1H, dd, J= 8.3Hz, 2.5Hz), 7. 10-6. 98 (3H, m), 6. 85-6. 78 (2H, m), 6. 66 (1H, d, J=8.3Hz), 5.20(1H, d, J=9.0Hz), 4.7O(1H, d, J=11.6Hz), 4.25-4. 06(2H, m), 3.74-3. 56 (1H, m), 3.50-3. 34(1H, m), 3. 28-3. 15(1H, m), 3.08-2. 95(1H, m), 2. 91-2. 75 (2H, m), 2. 26-2. 06 (2H, m). 174 NMR2 (400MHz) ; 8.51-8. 43(1H, m), 8.11(1H, dd, J=7.3Hz, 1.2Hz), 8.03(1H, d, J=8.2Hz), 7.94-7. 86 (1H, m), 7.73 (1H, d, J=2.5Hz), 7.64-7. 55 (2H, m), 7. 51-7. 43(1H, m), 7.12(1H, dd, J= 8.3Hz, 2.5Hz), 7.10-6. 98 (3H, m), 6.91-6. 84(2H, m), 6.66(1H, d, J=8.3Hz), 5.37(1H, d, J=9.0Hz), 4.57(1H, d, J=11.6Hz), 4. 32-4. 23(1 H, m), 4. 17-4. 05(1H, m), 3. 83-3. 24 (2H, m), 3. 24-3. 11(1H, m), 3.09-2. 94(1H, m), 2.93-2. 78 (2H, m), 2. 27-2. 08 (2H, m). 175 NMR2 (400MHz); 7.75(1H, d, J=2.4Hz), 7.14(1H, dd, J=8.3Hz, 2.4Hz), 6.7K1H, d, J=8.3Hz), 4.19-3. 44 (4H, m), 3.29-3. 02 (2H, m), 2.51-1.82 (3H, m). 176 NMR1 (500MHz) ; 7.6K1H, d, J=2.5Hz), 7.11(1H, dd, J=8.3Hz, 2.5Hz), 6.86(1H, d, J=8.3Hz), 5.75-5. 20 (1H, m), 4.06-3. 27(4H, m), 3.19(1H, d, J=14.3Hz), 2.79-2. 68(1H, m), 2. 67-2. 01 (3H, m). 177 NMR2 (500MHz); 7.81(1H, d, J=2.0Hz), 7.12(1H, dd, J=6.8Hz, 2.0Hz), 6.67(1H, d, J=6.8Hz), 4.17(1H, brs), 3.73-3. 54 (2H, m), 3. 54-3. 43 (1H, m), 3.32-3. 17(1H, m), 3.08-2. 98(1H, m), 2.67-2. 57(1H, m), 2.56-2. 36(1 H, m), 2. 32-2. 18(2H, m), 2.15-2.06(1H, m).

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178 NMR2(500MHz) ; 7.92(1H, d, J=2.5Hz), 7.10(1H, dd, J=8.OHz, 2.5Hz), 6.64(1H, d, J=8.0Hz), 5.37(1H, s) , 3. 73-3. 64(1H, m), 3.59 (1H, d, J=6.5Hz), 3.42-3. 28(1H, m), 3. 27-3. 17(1H.m), 3.00(1H, t, J=13.0Hz), 2.58-2. 34 (2H, m), 2. 32-2. 12 (2H, m), 0.91 (9H, m), 0.032 (3H, s), 0.027 (3H, s). 179 NMR2(500MHz) : 8.06-7. 92 (1H, m), 7. 82 (2H, d, J=8. OHz), 7.41(2H, d, J=8.0Hz), 7.23(1H, dd, J=8. 5Hz, 2.0Hz), 6.88(1H, d, J=8.5Hz), 4.23(1H, d, J=8.0Hz), 4.00(2H, s), 3.31-3.24(1H, m), 3.20(1H, t, J=14. OHz), 2.86-2. 65(1H, m), 2. 49(3H, s), 2.43-2. 16 (1H, m). 180 NMR2 (500MHz); 8.03(1H, d, J=2.5Hz), 7.81 (2H, d, J=8.5Hz), 7.42 (2H, d, J=8.0Hz), 7.17(1H, dd, J=8.5Hz, 2.5Hz), 6.70(1H, d, J=8.5Hz), 5.88(1H, s), 5.0K1H, dd, J=6. 5Hz, 6.5Hz), 4.20(1H, d, J=15.OHZ), 4.07(1H, dd, J=10.OHz, 6.0Hz), 3.97(1H, dd, J= 15. OHz, 7.0Hz), 3.2K1H, t, J-9.0Hz), 3.00-2. 71 (1H, m), 2.50 (3H, s), 2.40-2. 24(1H, m), 1.14(9H, m). 181 NMR2(500MHz) ; 7.78(1H, d, J=2.OHz), 7.12(1H, dd, J=8.5Hz, 2.0Hz), 6.67(1H, d, J=8.OHz), 4.63(1H, s), 4. 51-4. 08(1H, m), 4.02(1H, dd, J=14.OHz, 6.5Hz), 3.69(2H, dd, J=14.OHz, 5.5Hz), 3.29-3.16 (1H, m), 3.05(1H, d, J=12.2Hz), 2.56-2. 14 (2H, m). 1.38(9H, s). 182 NMR2(500MHz) ; 9.00-7.00 30 (5H, m). 7.28-6. 43 (5H, m), 5. 30-4. 52 (3H, m), 4. 32-1. 97 (8H, m), 1.52-1.33 (9H, Hi) . 183 NMR2 (500MHz) ; 7.55-7. 41 (1H, m), 7. 39-6. 94 (2H, m), 4. 32-2. 09(6H, m), 1.65-1.20(9H, m). 184 183 NMR2 (500MHz) : 7.55-7. 41 (1H, m), 7. 39-6. 94 (2H, m), 4. 32-2. 09 (6H, m), 1.65-1. 20 (9H, m). 185 NMR2 (500MHz) ; 8.05-6. 95 (3H, m), 4.50-4. 16 (1H, m), 3.17-2. 37(3H, m), 2.30-2. 11(1H, m), 1.85-1.20(12H, m). 186 185 NMR2(500MHz) ; 8.05-6. 95 (3H, m), 4.50-4. 16 (1H, m), 3. 17-2. 37(3H, m), 2. 30-2. 11 (1H, m), 1.85-1. 20 (12H, m).

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187 NMR2(500MHz) ; 7.58(1H.d, J=2.5Hz). 7.13(1H.dd, J=8.5Hz, 2.5Hz), 6.72(1H, d, J=8.5Hz), 4.55(1H, brs), 3.68(1H, brs), 3.21 (1H, ddd, J=13.5Hz, 7.0Hz, 4.0Hz), 3.10 (1H, ddd, J=13.5Hz, 9.0Hz, 3.0Hz), 2.57 (1H, dddd, J=30. 5Hz, 14.5Hz, 9.0Hz, 4.0Hz), 2.27 (1H, dddd, J=27.5Hz, 14.5Hz, 7.5Hz, 3.5Hz), 1.69-1. 63 (3H, m). 188 187 NMR2 (500MHz); 7.58(1H, d, J=2.5Hz), 7.13(1H, dd, J=8.5Hz, 2.5Hz), 6.72(1H, d, J=8.5Hz), 4.55(1H, brs), 3.68(1H, brs), 3.21(1H, ddd, J=13.5Hz, 7.0Hz, 4.0Hz), 3.10(1H, ddd, J=13.5Hz, 9.0Hz, 3.0Hz), 2.57(1H, dddd, J=30.5Hz, 14.5Hz, 9.0Hz, 4.0Hz), 2.27(1H, dddd, J=27.5Hz, 14.5Hz, 7.5Hz, 3.5Hz), 1.69-1. 63(3H, m). 189 NMR2 (500MHz): 8.80-8.60 (1H, m), 8.21-7.90 (2H, m), 7.80-7.52 (5H, m), 7.50-7.35 (1H, m), 7.20-7.13 (1H, m), 6.73-6.60 (1H, m), 5.18-5.02 (1H, m), 3.70-3.60 (0.7H, m), 3.35-3.07 (2H, m), 2.90-2.60 (1H, m), 2.58-2.20 ( 1.3H, m). 190 NMR2 (400 MHz): 7.68-7. 66(2H, m), 7.56(1H, brs), 7.33(2H, d, J=8.0Hz), 7.20(1H, dd, J=8.4Hz, 2.4Hz), 6.82(1H, brs), 4.74-4. 68(1H, m), 3. 78(1H, brs), 3.27(1H, brs), 2.62(14, brs), 2.49(3H, s), 2.32(1H, brs). 191 NMR2(400 MHz) : 7.33(14, d, J=2.4Hz), 7.15(1H, dd, J=8.3Hz, 2.4Hz), 6.72(1H, d, J=8.3Hz), 4 .70-4. 63(1H, m), 3.70(14, brs), 3.63-3. 59 (1H, m), 3. 28-3. 21 (1H, m), 3. 18-3. 05(1H, m), 2.71-2. 55(1H, m), 2. 17-2. 06 (1H, m). 192 NMR2 (400MHz) ; 8.48-8. 22(3H, m), 8.04-7. 94 (1H, m), 7. 84-7. 72 (1H, m), 7. 65-7. 56 (3H, m), 7. 27-7. 28 (1H, m), 7. 16-7. 13(1H, m), 6.64-6. 61(1H, m), 5.45(1H, brs), 5.27-4. 67 (2H, m), 3. 22-2. 85 (2H, m), 2.35-1.98 (1H, m). 193 192 NMR2(400MHz) ; 8.75-8. 68(1H, m), 8.43(1H, brs), 8.24-3.10(1H, m), 7.92-7. 85(1H, m), 7. 64-7. 30(3H, m), 7.20-7.10 (2H, m), 6.67-6. 60 (1H, m), 5.30-4. 75(2H, m), 4. 12(1H, brs), 3.15-2. 90(2H, m), 2.17(1H, brs).

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194 192 WMR2 (400MHz) : 8.51-8. 28 (2H, m), 7. 83-7. 25 (4H, m), 7. 20-6. 53 (4H, m), 5. 23-4. 75 (2H, m), 3.30-2. 73 (ZN, m), 2. 55-2. 08(1 H, m). 195 NMR2 (500MHz) ; 8.23-8. 03(2H, m), 7. 88-7. 79 (1H, m), 7. 78-7. 68 (2H, m), 7. 59-7. 49 (1H, m), 7. 49-7. 30 (7H, m), 7. 29-7. 21(1H m), 7.10(1H, dd, J=8.4Hz, 2.1Hz), 6.62-6.51(1H, m), 5.27-4. 91 (1H, m), 4. 90-4. 47 (2H, m), 3.21-2. 82 (2H, m), 2.59–2.00 (1H, m). 196 NMR2(500MHz) I 8.08 (1H, brs), 7.86-7.30 (7H, m), 7.22-7.02 (2H, m), 6.61 (1H, brs), 5.31-5.78 (2H, m), 3.48-2.42 ( 3H, m), 2.37-2.11 (1H, m). 197 192 NMR2 (400 MHz): 8, 47-8. 28 (2H, m), 7. 58-7. 52 (1H, m), 7. 52-7. 29 (3H, m), 7. 10-6. 55 (2H, m), 5. 28-4. 82 (2H, m), 3.20-2. 94 (3H, m), 2.55-2. 17(1H, m). 198 192 NMR2 (400 MHz): 7.88-7. 13(7H, m), 7.08-7, 03(1H, m), 6.58-6. 50(1H, m). 5.80-4. 71 (2H, m), 3. 25-2. 82(3H,m), 2.61-2. 10 (1H, m). 199 NMR1 (500MHz) ; 8.26-7. 67 (4H, m), 7. 57-7. 18 (9H, m), 7. 16-7. 03(1 H, m), 6. 65-6. 48 (1H, m), 5. 30-4. 42(3H, m), 3.35-1.99(3H, m). 200 192 NMR2 (400MHz); 8.75-8. 68(1H, m), 8. 43(1H, br), 8.24-3.10(1H, m), 7.92-7. 85(1H, m), 7. 64-7. 30(3H, m), 7.20-7.10(2H, m), 6.67-6. 60(1H, m), 5.30-4. 75 (2H, m), 4.12 (1H, brs), 3.15-2. 90 (2H, m), 2. 17(1H, brs). 201 NMR2 (400MHz) : 7.90-7. 15 (1OH, m), 7. 14-6. 78 (5H, m), 6. 61-6. 42(1H, m), 5. 36-4. 63 (2H, m), 3.99-3. 27(1H, m), 3.18-2.74(1H, m), 2.62-1. 95 (2H, m). 202 201 NMR2 (400MHz); 7.91-7. 15 (9H, m), 7. 13-6. 90 (5H, m), 6.66-6. 43(1 H. m), 5. 32-4. 66 (2H, m), 3.55-2. 75 (3H, m), 2. 62-1.99 (1H, m).

Table 3

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- 73 040222

21 BUT hq)f F ^F I ) syu 23 but HQ ) _F ^С| ^Y\ ^p F 25 HO HQ ) _F Cl 27 HO HQ ) _F ^with yyy Cl _o ^X WA H 29 HO HQ ) _F

22 HQ hq> _f ci^^^A+Uf T ^F ° yY oW ⁴ F 24 HO HQ )f ^С| xUtr XX J Cl _n N-^ 04 ⁴ 26 HO hq)f F'o^V 28 HO HQ ) _F ^c lxyyZ4-F w F thirty Hq HQ ) _F Cl^^d^-UF F

- 74 040222

- 75 040222

41 HQ _x HO,, / , ^{F 0Ι} γΥΥ ddA 42 HQ but,, / ddy 43 BUT HQ, / G S1chU>4-R < yU F 44 HO HO,, / F CIxyyH-F dvA o 45 BUT HQ,/F cix+Xy-F XX) Ci „N 46 HO HQ,/f ClyyZ+-F 47 HO HQ ) _F Clyyy 48 HO HQ,/f CIsyZ+F+U" 49 HO hq/f ^c, yyv ^F yy F 50 HO hq/f Cixyy+rF yA 51 H.O. HQ / F ^Ci '^4+A“ ^F IT ) .,++ 52 HQ HO„ > F Clx^yy-F 53 HO HQ- J f ckXz4-f y Ay (UHA 54 % ° ZI ^L ky 55 HQ HO,, /F CI'xxXy-F „ - +? d++Cl 56 HO HO,, /F ClyyAf A 57 HO HQ, / F ^ci yyv Μγ^° 58 HO HQ, / F ciyyv .dd-A °x 59 HO HQ, /F CyOy-F FO ₄ 60 HO HQ, / F r ⁰

- 76 040222

- 77 040222

81 HQ hq„> f cix^MMf mA F 83 HO HQ, /F SMUA mA F 85 HO HQ > F Clyy4f MA F 87 HO HQ, /F XX J MM 89 but HQ, / F Clx^xO^F MA 91 1 HQ F HQ/ F J CIkA/M О kA / Α _ο ArA 93 HO hq) F c ^CI VY\ ^F mA F 95 But HQ, /F _Cl^xOH-F ^A F 97 HO HQ/ F CIxAXAUF O LI / naa JT\^O V / nA J ^υ \^j Η N 99 HO HQ,/ F Clx _r x>AA-F mA ο _χ

82 HQ HQ, / F CIx^AMA-F aa 84 HO HQ, / F ^C! vA\~ ^f χΧ F 86 HO HQ, / F mA F 88 HO HQ, / F °Ιχ _Γ χ^M \ F mA F 90 HO HQ ₄ / F ciyO4f Am 92 HO ₄ HQ, / F ^ci vAmA ^f mA 94 HO HQ/Fc ^| x _r A<\ ^F mA 96 HO HQ/ F _c ClyykF AA F 98 HO HQ/Faa 100 HO D _F “M ci o MT (AnXA ^{0 H} 0

- 78 040222

ιοί kLA === o /°T} and ° Df ^D TS 102 I HQ^F. Ci. +++° 103 hq? F xi) In+ 104 but ^H0 7 Г _with CK^/M'-'F Cl kX / -Dur ⁴ F Yo ΤΧ ryvo^* 105 BUT hqJ G \u003d skLHk \ 1 II \ 106 but ^HQ 7 G with Ti ) to /us. X / O ^N ⁷ γΜν+QA H g F Cl _n ^v N 0 +++° F 107 HO HQ) F 01^^7-+-4= 77 F F 108 HO hq) f ci^Ta+p 109 HO HQ,) F aLTL-I T X ) 110 HO HQ,) F ^Ci >rfi ^? >A4' ^F LI ) +++° O =-€+++ 111 , ^H A. sch+Y+ r iT \ 112 HO ₄ I HQ. > F ^C|, ^<4/ ^£ 4' ^F TXT π \ 7 zx ⁵ u) C/lx. IL/ ₀ ^^N- ⁷ OA-OA 113 HO noL G _with skDTH ^ 114 HQU F C1^h+>+4-p F F XX ) +•7 +++° F 115 HO HO,) F 01.^-^++^ U J 116 HO HQ.) F XX 7 +++° 117 HO HQ.) F Clx^IX+'F =-+,++ 118 H.O. ? _F Clx^OH-F ,+++° 119 H.O. ? F CI-^^+H-F +++ F 120 but _h / _f ^c| x^x7+~ ^p +7 F 121 HO? F CI-x^/HF XX7 Cl ₀ oLXXX n g g 122 But. ? _F ^C| h,xl>W-R XX7 C! n hH +++° F

-79040222

123 on g f 125 nC° ⁿ HOj F ΑΧ 127 ψ A X+a F 129 HQ y _o uQ GtLgoA Η ρ F 131 HQ HQ> F ^c lyy4 ^F F 133 H(\ I But, W F C1\AuChu (W F 135 HQ UJ _F Xy^N-^O^° H 137 ^hc Vf Xa-X 139 HO _VF CI^AAF XX 141 HO c.uW 0 xo y ⁷ H ^N F 143 H.Q. ? _F Clx^xjy-F XX”

124 on/ _F Gi^OX-F kA J Cl Λ N F 126 to / f ^c i\^v4-i= F ^F XX / 128 HO HO, / F ci _x A~AA ^f 130 iz ° about 0H. V /Az ⁰ ^+2 'j ¹ ' ¹ 132 but ^but </ r o ^c! ^AaA ^f F ^F kA / χΑ F ^F I 134 HQ HO,> F c|->AaA ^p T 7 LI ) Go F\ ⁰ F 136 BUT HQJ F C1xAA\ OH F 138 on ?' f 140 BUT _H ? F XX kA / /^o ''^X (AxA ⁰ n ^N 142 but _{h? F} ^CI ^AA-F χΧ 144 but ^HQ JF _c F

- 80 040222

- 81 040222

-82040222

187 BUT BUT,} F T T ) g-l CUSA 189 ^H( W ci-^OX-f X-X 191 BUT, ? FxSx X-S>° 193 H<V F Ck^/4-F q ) LH 195 HQ , CkzX%F F-O XX J h ^N F 197 F ^cl vX^X ^F w F 199 HO HQ } F F< P LX / _n ^ N - ⁷ Xa-O^ H F 201 HO ^HC Q Г p Clx^XM-F XX j 203 HO ^HQ J G P Cix^C/Cl-F XX F 205 HO NOL F CSx^T^y-F J? AT F

188 HQ? f Clx^OH-F XX °x 190 hq? F Clxyy>X-F +4X °x 192 H.O.? _F CK^xyH-F °x 194 Knife? F Clx^xX4r-F yX 196 NC f F οΐχ,^ΧΗ-ρ O XX J χχ^νΧΧ^ ⁰ H ^N F 198 HQ P ^H0 X G P 7% 200 HO HO,} F ^ci >XXx ^f F 202 HO HO,} F CI^^XryF mX Cl 204 HO HO, } F CI^TpTPF xx 206 xz ⁰ ?&

- 83 040222

207 HQ^ HQ> F ^Ci >++\ ^F 0V 209 HO HQJ F_++ 211 HQ HQ ) F XIJ Cl + ++ ⁴ °F 213 HO hq,> G _c ++ 215 HQ HQ > F _c ^c, v+++ ^f ++ 217 ^H 4 HO, ) F Clx+^+AF++ 219 HO^F ckAz+f +A+ Cl - N ^ ++ 221 HO HQ,) F ^Ci '^A+ ^-F Ta ) Cl ο N •X+O ϊ>> ^η ci-AU Η < 223 BUT HQ, )F++ 225 HO HQ ) f= P Ta /

208 HQ HQ ) F Clx^AA+F uO l+ +-C+ 210 HO hq) f CfxA+AF XI) A++ 212 & 7a 214 HO HQ ) F ClxX+ApF XIJ o V ++n++ CiAA^j 'Vp 216 HO HQ ) F cix^++- ^F ++ 218 HQ _v _ I HQ.) G -x ^Cl v + 4' ^F + 220 ° ^Άε ++. F/% 222 HO HQ ) _F Clxy+AF +++ 224 HO HQ, ) F ci^^+A-f =++ F /% 226 HO HQ, ) F CI\ _x a+ ^/ +-FF ^F TA /

- 84 040222

227 H(E HQ, /F 228 BUT HO/F sit 229 HO ^H0 A A+a- 230 But H.Q.F Cix^X^-F +L F 231 F+¾ 232 BUT HQ.) F C!\^A+4'- ^p L 7 kA / F y^ ₀ ^^N- ⁷ n ^N ^ R>on 233 but HQ.) F „ SK Λχ-F Г 7 kA / ^^N ⁷ 0+^ ⁴ °°^ g 234 ρ;Ά GuAgO""^ ¹ 8x°n Ά n rG

EX prop Data 1 NMR1 (400MHz) ; 11.19-11.02(1 + m), 8. 33-8. 23 (1H, m), 8.05-7.95(1+m), 7.95-7. 73 (2H, m), 7. 61-7. 36(4H, m), 7.26-7.16(1+m), 6.89-6. 76 (1H, m), 6.36-6.23(1 + m), 5.39-5. 15(1H, m), 5.09-4. 71 (1H, m), 4.22-3.72(2+ m), 3. 10-2. 06 (3H, m). 2 »1 (400MHz) ; 11.25-11.16(1+m), 8.30-8. 26 (1H, m), 8.01-7. 64 (7H, m), 7. 25-7. 18(1H, m), 6.89-6. 79 (1H, m), 6.33-6.24(1 + m), 5. 39-5. 19(1H, m), 5.04-4. 72(1H, m), 4.21-4.07(1+m), 4.04-3. 72(1H, m), 3.07-2. 82 (1H, m), 2.70-2.05 (2+ m). 3 NMR1 (400MHz) ; 11.28-11. 11 (1H, m), 8. 35-8. 22(1H.m), 8.16-7. 74 (3H, m), 7. 64-7. 48 (2H, m), 7. 43-7. 32 (1H, m), 7.27-7. 15(1 + m), 6. 89-6. 77 (1H, m), 6. 37-6. 22 (1H, m), 5.45-5.18(1H, m), 5.08-4. 68 (1+ m), 4. 23-3. 73 (2H, m), 3. 12-2. 78 (1H, m), 2. 61 -2. 05 (2H, m). 4 1 NMR1 (400MHz) ; 11.30-11.15(1+m), 8.36-8.23(1+m), 8.05-7. 75(3H.m), 7.58-7. 38 (3H, m), 7.26-7. 15 (1H, m), 6.90-6. 76(1H, m), 6. 36-6. 23(1H, m), 5. 40-5. 16(1H, m). 5.05-4. 70 (1H, m), 4. 19-4. 09(1H, m), 3.89-3. 72(1H.m), 3. 11-2. 81(1H, m), 2.69-2. 05 (2H, m). 5 1 NMR1 (400MHz) ; 10.95-10. 72 (1H, m), 8. 31 -8. 21 (1H _T m), 8.07-7. 72 (3H, m), 7. 31-7. 08(4H, m), 6.89-6. 77(1H.m), 6.33-6. 17 (1H, m), 5.37-5. 21(1H, m), 5.05-4.70(18, m), 4.22-4.07(1H, m), 4.06-3. 71 (1H, m), 3.11-2.78(1+ m), 2.70-2.03 (8+ m). 6 1 NMR1 (400MHz) ; 9.71-9. 54(1+m), 8.03-7. 74 (2H, m), 7.63-7. 35 (4H, m). 7.28-7. 01(2H, m), 6.94-6. 63 (2H, m). 6.29-6.15(1+ m), 5.37-5.14(1+ m), 5.08-4.71(1+ m), 4.26-3.73(2H, m), 3.68-3. 45 (3H, m), 3.11-2.73(1+ m), 2.67-2.02(2+ m). 7 1 NMR1 (400MHz) ; 9.92-9. 72 (1H, m), 8.01-7.72(2+ m), 7.63-7.51(1+ m), 7.51-7. 41 (1H, m), 7. 41-7. 30 (1H, m), 7.24-7.13(1+m), 7.12-7. 03 (1H, m), 6.91-6.65(2+ m), 6.30-6.19(1+m), 5.36-5. 17(1H, m), 5.07-4. 72 (1H, m), 4. 24-4. 08(1 H, m), 3. 94-3. 75(1H, m), 3.63-3. 43 (3+ m), 3.08-2.78(1+ m), 2.71-2. 03 (2H, m). 8 NMR1 (400MHz) ; 11.50-11. 12(1 H, m). 8.35-8.13(1+ m), 8.10-7.55(7+ m), 7.31-7. 21 (1H, m), 6.96-6. 87 (1H, m), 6.54-6. 32(1H, m), 5.06-4. 67 (1H, m), 3.07-2.55(2+ m), 2.42-2. 07(1+ t), 1.86-1.61 (3H, m).

Table 4

- 85 040222

9 10 eleven 12 13 14 15 8 8 8 8 NMR1 (400MHz) : 11 40-11.07 (1H, m), 8. 40-8. 13 (1H, m), 8. 11-7. 97(18, m), 7. 97-7. 20(6H, m), 6.96-6. 86 (1H, m), 6.52-6.36(18, m), 5.07-4.70(18, m), 3.03-2.55(28, m), 2.44-2.01(18, m), 1.84-1.60(38, m ). NMR1 (400MHz); 10.95-10.73(18, m), 8.34-8. 13(1H, m), 8.11-7.99(18, m), 7.97-7.06(68, m), 6.95-6. 85 (1H, m), 6.50-6. 38(1H, m), 5.07-4.70(18, m), 3.03-2.54(28, m), 2.43-2.00(78, m), 1.87-1.60(38, m). NMR1 (400MHz) ; 9.86-9. 55 (1H, m), 8.05-6.66(108, m), 6.51-6.34(18, m), 5.09-4.68(18, m), 3.97-3.50(38, m), 3.03-2. 53(2H, m), 2. 42-2. 05(1H, m), 1.87-1.46(38, m). NMR1 (400MHz) ; 10.01-9.72(18.00), 8.01-6.00 67(98, m), 6.52-6. 35(1H, m), 5.08-4. 72(1H, m), 3.97-3.50(38, m), 3.03-2.52(28, m), 2.42-2. 04(1H, m), 1.86–1.47(38, m). NMR1 (500MHz) ; 11.46-11.10(18, m), 8.37-8.19(18, m), 8.07-7.54(78, m), 7.29-7.14(18, m), 6.93-6.74(18, m), 6.40-6. 16(1 H, m), 5. 43-5. 11(1H, m), 5.10-4.68(18, m), 4.27-3.70(28, m), 3.11-2.05(38, m). NMR1 (500M8z) ; 11.34-11.12(18, m), 8.35-8.22(18, m), 8.14-7.72(38, m), 7.65-7.48(28, m), 7.44-7.30(18, m), 7.29-7.13(18, m), 6.90-6.75(18, m), 6.39-6.19(18, m), 5.45-5.18(18, m), 5.10-4.68(18, m), 4.24-3.72(28, m), 3.12-2.78(18, m), 2.66-2.03(28, m). NMR1 (500MHz) ; 11.34-11.12(18, m), 8.35-8.22(18, m), 8.14-7.72(38, m), 7.65-7. 48(2H, m), 7.44-7.30(18, m), 7.29-7.13(18, m), 6.90-6.75(18, m), 6.39-6.19(18, m), 5.45-5.18(18, m), 5.10-4. 68 (1H, m), 4. 24-3. 72 (28, m), 3.12-2.78(18, m), 2, 66-2. 03 (2H, m). 16 NMR1 (500MHz) ; 11.45-11.13(18, m), 8.37-7.37(88, m), 7.35-7.15(18, m), 6.97-6.85(18, m), 6.65-6. 21(1H, m), 5.15-4.44(28, m), 3.82-3.55(18, m), 3.29-3. 08(1H, m), 3.07-2. 74 (1H, m), 2. 72-2. 03 (4H, m). 17 NMR1 (500MHz) ; 11.21-11.04(18, m), 8.34-8.21(18, m), 8.05-7.95(18, m), 7.95-7.73(28, m), 7.62-7. 36(4H, m), 7.26-7.16(18, m), 6.90-6.76(18, m), 6.43-6.15(18, m), 5.44-5. 14(1H, m), 5.05-4.71(18, m), 4.22-3. 72 (2H, m), 3.11-2.06(38, m).

- 86 040222

18 17 NMR1 (500MHz) ; 9, 92-9. 72(1H, m), 8.01-7. 72 (2H, m), 7.63-7. 51(1H, m), 7.51-7 41(1H, m), 7. 41-7. 30(1H.m), 7.24-7. 13(1H, m), 7. 13-7. 02(1H, m), 6.91-6. 65 (2H, m). 6.38-6. 10(TH, m), 5.42-5. 13(1H, m), 5.07-4. 72 (1H, m). 4. 24-3. 74 (2H, m), 3. 63-3. 40 (3H.m). 3.08-2. 78 (1H, n0 . 2, 67-2. 02(2H.m). 19 NMR4(500MHz) ; 10.17-9. 78 (1H, m), 8.52-8. 33(1H, m), 8. 18-7. 79 (2H, rn), 7.71-7.62 (1H, id), 7.60-7. 53 (1H, m), 7.49-7. 42(1H, m), 7, 35-7. 26(1H, m), 7.11-7. 03(1H, m). 6.73-6. 51 (1H, m), 5.63-5.34 (1H, m), 5.24-4. 81 (1H, m), 4.52-3. 97(3H.m), 3.20-2. 90 (1H, m), 2.63-2.06(28.m). 20 19 NMR2 (400MHz): 8.80-8. 07(3H, m), 8.04-7. 86(1 H, m), 7.86-7. 72 (2H, id), 7. 72-7. 49 (3H, m), 7. 46-7. 26 (1H, m), 7. 18-7. 02 (1H, id), 6. 72-6. 55 (1H, m), 5. 31-4. 79 (1H, m). 4.60-3. 61(3H, in), 3.20-2. 76(2H, m), 2.63-2. 06 (2H, id) . 21 NMR1 (500MHz) ; 10.87-10. 57(1H.m), 7.92-7. 82 (2H, m), 7. 82-7. 75 (1H, m), 7. 75-7. 65(2H. id). 7.52(2H, d, J=8.7Hz), 7.45-7.29(2H, m). 7.17(1H, dd, J=8.4Hz, 2.4Hz), 6.74-6. 62 (1H, m), 6. 29-6. 02(1H, m), 5.49-5.10(1H, di), 5.10-4. 65 (1H, di), 4. 35-3. 68(2H.m), 3.13-2. 70(1H, di), 2. 64-2. 39(1H, di). 2.39-2. 05(1H.m). 22 21 NMR1 (500MHz) ; 10.76-10. 34 (1H, m), 8. 11-7. 55 (6H, m), 7.55-7. 09(3H, m), 7.05-6. 57 (1H, m), 6. 57-6. 01 (1H, in). 5.50-5. 16(1H, m). 5. 14-4. 63(1H, di), 4. 31-3. 65 (2H, id), 3. 11-2. 74(1H, m). 2.73-2. 44(1H, ni), 2. 43-2. 05(1H.in). 23 NMR1 (500MHz) ; 10.84-10. 57 (1H, tn), 7.96-7, 73 (1H.m). 7.67-7, 59(1H, ni), 7.59-7. 55 (1H, m), 7. 55-7. 48(2H, tn), 7.47-7, 25 (3H, m), 7. 23-7. 08(1H, m), 6.74-6. 57 (1H, m), 6.27-6. 14(1H, m), 5. 43-5. 09(1H, m), 5.09-4. 72(1H, m), 4.30-3. 70(2H, m), 3. 11-2. 73(1H.m), 2.65-2. 40 (1H, m). 2.41-2. O7(1H, in). 24 NMR1 (500MHz) ; 10.61-10. 42(1H, m), 7.94-7. 86 (1H, m), 7.86-7. 75(1H, m), 7. 68-7. 56 (1H, m), 7. 56-7. 5O(1H, m), 7.48-7. 13(4H, in), 6.95-6. 64(1 H, di) , 6. 43-6.U(1H, m), 5.45-5. 13(1H.m), 5.08-4. 67 (1H, m), 4. 27-3. 71 (2H, m), 3. 10-2. 77(1H, m), 2. 71-2. OB(2H. id). 25 NMR2(500MHz) : 8.20-8. 00(1H, m), 7.98(1H, d, J=2.2Hz), 7.86-7.6H1H, m), 7.59-7.28(6H, m), 7.06(1H, dd, J=8, 3Hz , 2.3Hz), 6.73-6. 47 (1H, m), 5. 36-4. 73 (1H, rn), 4. 68-3. 83 (2H, id), 3.62-3. 25 (1H, rn), 3. 25-2. 71 (1H, m). 2.66-2.0H3H, m).

- 87 040222

26 NMR2 (500MHz) ; 8.50-8. 11(2H, m), 7.99(1H, d, J=2.4Hz), 7.78(1H, s), 7.53-7. 31 (3H, m), 7. 31-6. 99(2H, m), 6.75-6. 49 (1H, m), 5. 31-4. 82 (1H, m), 4. 73-3. 81 (2H, m), 3.49-2. 89(2H, m), 2.69-2. 13 (3H, m). 27 21 NMR1 (500MHz) ; 10.87-10. 57(1H, m), 8.04-7. 70 (1H, m), 7. 69-7. 26(7H, m), 7.16(1H, dd, J=8.4Hz, 2.4Hz), 6.74-6. 60 (1H, m), 6.28-6.11 (1H, m), 5.46-5. 10 (1H, m), 5. 10-4. 69 (1H, m), 4. 28-3. 71 (2H, m), 3.11-2. 73(1H, m), 2.63-2. 22 (2H, m). 28 21 NMR1 (500MHz) ; 10.78-10.41 (1H, m), 8.13-7. 71 (2H, m), 7.71-7. 38 (3H, m), 7. 38-7. 00(3H, m), 6.92-6. 63(1H.m), 6.41-6.14(1H, m), 5.42-5. 18(1H, m), 5.04-4. 68(1H, m), 4.28-3. 66 (2H, m), 3.10-2. 77 (1H, m), 2.60-2. 24 (2H, m). 29 19 NMR2 (500MHz); 10.29-9. 93(1H, m), 8.58-8. 31 (1H, m), 8.28-7. 72 (2H, m), 7. 71-7. 55 (1H, m), 7. 45-7. 30 (1H, m), 7.29-7. 16(1H, m), 7.15-6, 96(2H, m), 6.72-6. 50(1H, m), 5.52-5. 27 (1H, m), 5. 23-4. 80 (1H, m), 4. 49-3. 91 (3H, m), 3.21-2. 46(2H, m), 2.45-1. 95 (1H, m). thirty 19 NMR2 (500MHz) ; 8.68-8. 21 (2H, m), 8. 21-8. 08 (1H, m), 8.02-7. 85 (1H, m), 7. 85-7. 70 (2H, m), 7. 43-7. 24 (2H, m), 7.23-7. Ob(2H, m), 6. 73-6. 56 (1H, m), 5. 23-4. 84(1H, m), 4.62-3. 90 (2H, m). 3.71-2. 95 (2H, m), 2.79-2. 07 (2H, m), 1.66-1. 54(1H, m). 31 19 NMR1 C500MHz) I 11.49-11.32 (1H, m), 8.35-8. 23 (1H, rn), 8.07-7.95(1H _T m), 7.94-7. 71 (2H, tn), 7. 59-7. 40 (3H, m), 7.27-7. 16(1H, m), 6.94-6. 78 (1H, m), 6. 34-6. 17(1H, m), 5.40-5.15(1H, m), 5.07-4. 69 (1H, m), 4. 21-3. 72 (2H, m), 3.10-2. 54(2H, m), 2. 39-2. 06(1H, m). 32 19 NMR1 (500MHz); 11.32-11. 10(1 H, m), 8. 35-8. 23(1H, m), 8.10-7. 99 (1H, m), 7. 96-7. 72(2H, m), 7. 39-7. 30 (2H, m), 7.30-7.17(2H.m), 6.93-6. 76 (1H, m), 6. 36-6. 20 (1H, m), 5.40-5.17 (1H, m), 5.07-4. 69 (1H, m), 4. 21-3. 72 (2H, m), 3.11-2.45(2H, m), 2.44-2. 04 (4H, m). 33 NMR4(500MHz) ; 10.00-9.00 73 (1H, m), 8. 51-8. 34(1H, m), 8.22-7. 78 (2H, m), 7. 72-7. 63 (1H, m), 7. 63-7. 52 (1H, m), 7.52-7. 43(1H, m), 7. 36-7. 26 (1H, m), 7. 14-7. 00(1H, m), 6.69-6. 53 (1H, m), 5.54-5. 31 (1H, m), 5. 21-4. 85 (1H, m), 4.46-4. 00 (3H, m), 3. 18-2. 93 (1H, m), 2.55-2. 06 (2H, m). 34 NMR1 (500MHz); 10.00-9.00 75 (1H, m), 8. 25-6. 74 (9H, m), 6. 60-6. 12(1 H, m), 5. 15-4. 40(2H, tn), 4.00-3. 50 (4H, m), 3. 29-2. 56 (3H, m), 2. 46-2. 01 (3H, m).

- 88 040222

35 13 NMR1 (500MHz): 10.96-10. 75 (1H, m), 8. 34-8. 21(1H, m), 8.07-7. 98(14, m), 7. 94-7. 72(2H, m), 7. 49-7. 42(1H, m), 7.42-7. 32(1H.m), 7. 32-7. 16 (3H, m), 6.90-6. 76 (1H, m), 6.42-6. 16(1H, m), 5. 43-5. 13(1H, m), 5. 10-4. 69(1H, m). 4. 24-3.72 (2H, m), 3. 11-2. 07 (6H, m). 36 13 NMR1 (500MHz) : 11.07-10.87(14, m), 8. 33-8. 23(1H, m), 8.04-7. 98 (1H, m), 7. 92-7. 72 (24, m), 7. 38-7. 15 (4H, m), 6.90-6.77(14, m), 6.44-6.17(1H, m), 5.46-5. 16(1H, m), 5.05-4.69(14, m), 4. 22-3. 72(2H, m), 3.12-2.07(64, m). 37 NMR1 (500MHz) ; 10.54-10. 37(1H, m). 8.06-7. 09(9H, m), 6.74-6. 61 (1H, m), 6. 30-6. 03(1H, m), 5. 42-5. 09 (1H, m), 5.08-4.73(14, m), 4.28-3.74(24, m), 3.11-2. 71(1H, m), 2.66-2.05(54, m). 38 37 NMR1 (500M4z) : 10.02-9.72(14, m), 7.99-7.03(84, m), 6.80-6. 57(1H, m), 6.32-5.98(14, m), 5.42-5. 09(14, m), 5.09-4.66(14, m), 4. 28-3. 74 (2H, m), 3.11-2.72(14, m), 2.66-2.04(84, m). 39 37 NMR1 (500MHz) : 10.51-10.00(14, m), 8.08-7. 00(8H, m), 6.90-6.68(14, m), 6.40-6. 07(1H, m), 5. 42-5. 09(1H, m), 5.09-4.66(14, m), 4.26-3. 67(2H, m), 3.10-2.75(14, m), 2.71-2.04(5H, m). 40 37 NMR1 (500MHz) ; 9.56-9.33 (14, m), 8.01-7.70 (24, m), 7.40-6.79(64, m), 6. 79-6. 65(1H, m), 6.35-6.15(14, m), 5.50-5.13(14, m), 5.11-4.66(14, m), 4.30-3.78(24, m), 3.66-3.46(34, m), 3.08-2.78(14, m), 2.66-2.04(24, m). 41 21 NMR1 (500MHz) ; 10.56-10.30(14, m), 8.13-7.72(14, m), 7.57(14, d, J=8.4Hz), 7.53-7.23(64, m), 7.16(14, dd, J=8.4Hz .2.5Hz), 6.75-6. 60(1H, m), 6.29-5.99(14, m), 5.45-5.09(14, m), 5.09-4. 74 (1H, m), 4. 31 -3. 70 (24, m), 3. 13-2. 73 (1H, m), 2.63-2.43(14, m), 2.43-2.21 (44, m). 42 21 NMR1 (500MHz) ; 9.96-9.51(1H, m), 8.19-7.70(14, m), 7.70-7.01(84, m), 6.91-6.47(14, m), 6.40-5. 92 (14, m), 5.40-5.11 (1H, m), 5.11-4. 71 (1H, m), 4.37-3.66(24, m), 3.15-2.77(14, m), 2.67-2.47(14, m), 2.47-2.27(44, m), 2.24-2.09(34, m). 43 21 NMR1 (500M4z) ; 10.36-9.98(14, m), 8.02-7. 75 (1H, m), 7.75-7. 56 (1H, m), 7.56-7.16(74, m), 6.96-6.64(14, m), 6.49-6.00(14, m), 5.42-5.14(14, m), 5.14-4.68(14, m), 4.27-3.68(24, m), 3.09-2.77(14, m), 2.68-2. 41 (1H, m), 2.41-2.06(44, m).

- 89 040222

44 21 NMR1 (500MHz): 9.64-8. 88 (1H, m), 8. 16-7. 73 (2H, in), 7.49-7. 04(6H, m), 6.91-6. 81 (1H, m), 6. 77-6. 66 (1H, m), 6.31-6. 15(1H, m), 5.43-5. 12(1H, m), 5.12-4. 49 (1H, m), 4. 29-3. 70 (2H, m), 3. 70-3. 45 (3H, m), 3.04-2. 80(1H, m), 2.53-2. 44(1H, m), 2. 40-2. 29 (4H, m). 45 37 NMR1 (500MHz) ; 11.33-10. 90 (1H, m), 8. 63-7. 60 (4H, m), 7.50-7.06(4H, m), 6.90-6. 75 (1H, m). 6.41-6. 17(1H, m), 5.55-5. 11(1H, m), 5.09-4. 64 (1H, m), 4. 27-3. 66 (2H, m), 3. 12-2. 73(1H, m), 2.67-2. 01 (5H, m). 46 37 NMR1 (500MHz); 11.16-10. 81 (1H, m), 8. 32-8. 21 (1H, m), 8. 10-7. 96 (1H, m), 7. 94-7. 11 (2H, m), 7.50-7. 06 (5H, m), 6.91-6. 76(1H, m), 6.40-6. 16(1H, m), 5. 47-5. 11 (1H, m), 5.09-4. 67 (1H, m), 4. 27-3. 67 (2H, m), 3. 11-2. 01 (5H, m), 1.14 (3H, t, +7.5Hz). 47 37 NMR1 (500MHz) ; 10.60-10. 31 (1H, m), 7.98-7. 08(10H, m), 6.75-6. 61 (1H, tn), 6. 29-6. 11 (1H, m), 5. 41-5. 08(1H, m), 5. 09-4. 74 (1H, m), 4. 29-3. 74 (2H, m), 3. 11-2. 01 (5H, m), 1.22-1. 08 (3H, m). 48 37 NMR1 (500MHz) ; 9.98-9. 70 (1H, m), 8.6-7. 75 (1H, m), 7.66-6. 60 (9H, m), 6. 35-6. 02 (1H, m), 5. 38-5.11 (1H, m), 5.07-4. 69 (1H, m), 4. 29-3. 74(2H, m), 3.09-2. 01 (8H, m), 1. 23-1.13 (3H, m). 49 37 NMR1 (500MHz) ; 10.38-10. 02(1H, m), 8.00-7. 09(9H, m), 6.90-6. 71 (1H, m), 6. 39-6. 04(1H, m), 5.51-5. 17(1H, m), 5.08-4. 70(1H, in), 4. 26-3. 74(2H, m), 3.11-2. 01(5H, m), 1.21-1.12(3H, m). 50 37 NMR1 (500MHz); 9.34-9. 18(1H, m), 7.94-7. 72 (2H, m), 7.56-6. 62 (8H, m), 6. 35-6. 15 (1H, m), 5. 46-5.15 (1H, m), 5.01-4. 72(1H, m), 4. 30-3. 49(5H, m), 3.09-1. 97(5H, m), 1. 21-1.07(3H, tn). 51 NMR2(500MHz) ; 8.79-8. 56 (1H, m). 8.48-8. 25 (1H, m), 8. 24-8. 11(1H, m), 7.99(0.8H, d, J=2.4Hz), 7.95-7. 71 (1H, m), 7. 71-7. 62 (1H, m), 7.55-7. 42 (1H, m), 7. 42-7. 33 (1H, m), 7.33-7.28 (0.2H, m), 7.19-7. 06 (1H, m), 6.77-6.51 (1H, m), 5.33-4. 82 (1H, m), 4. 66-3. 91 (2H _T m), 3. 48-2. 93 (2H, m), 2.70-2. 08 (3H, m). 52 NMR2(500MHz) ; 9.03-8. 66 (1H, m), 8. 60-8. 23 (1H, m), 8.23-8. 10(1H, m), 8.08-7. 95 (0.8H, m), 7.95-7. 70 (1H, m), 7.67-7. 55 (1H, m), 7. 55-7. 49 (1H, m), 7. 37-7. 29 (0.2H, m), 7.20-7. 07(1H, m), 6. 83-6. 51 (1H, m), 5. 30-4. 83(1H.m), 4.66-3. 90 (2H, m), 3.52-2. 95 (2H, m), 2.68-2. 07 (3H, m).

- 90 040222

53 21, 52 NMR2 (500MHz) ; 9.32-9. 12(1H, m), 9 01-8. 73 (1H, m), 8.41-8. 22(1H, m), 8.16-7. 83 (1H, m), 7. 83-7. 75 (1H.tn), 7.75-7. 57 (3H, m), 7.19-7. 04(1H, m), 6.76-6. 41 (1H, tn), 5.23-4. 82(1H, m), 4. 64-3. 70 (2H, m), 3. 49-2. 96 (3H, m), 2.80-2. 09 (2H, tn). 54 21, 52 NMR2 (500MHz) : 9.31-9. 13(1H, m), 8.99-8. 77 (2H, tn), 8. 17-7. 78(1H, m), 7.53(1H, dd, J=8.3Hz, 3.1Hz), 7.50-7.41 (1H, m), 7.24-7. 17(1H, tn), 7. 17-6. 99(1H, m), 6.68-6.44(1H, m), 5.21-4. 88(1H, m), 4.66-3. 74 (2H, m), 3.55-2. 99 (3H, tn), 2.76-2. 09 (2H, m). 55 21, 52 NMR2 (500MHz) : 8.80-8. 56 (1H, m), 8. 47-8. 25 (1H, m), 8.24-8.10 (1H, m), 8.04-7. 83(1H, m), 7. 80-7. 61 (1.8H, m), 7. 46-7. 28(2.2H, m), 7.20-7. 05(1H, m), 6.77-6. 51 (1H, m), 5. 37-4. 83 (1H, m), 4. 73-3. 89 (2H, m), 3. 48-2. 89 (2H, m), 2.70-2. 07 (3H, tn). 56 21, 52 NMR2(500MHz) : 8.63-8. 38(1H, m), 8. 15-7. 90(2H, m), 7. 84-7. 72 (1H, m), 7. 72-7. 55 (3H, tn), 7. 55-7. 39 (1H, m), 7.1K1H, dd, J=8. 4Hz, 2.5Hz), 6.68-6. 58(1H, m), 6.56(1H, d, J=1.7Hz), 5.33-5. 10 (1H, m), 5.10-4. 87(1H, m), 4.87-4. 64(1H, m), 4.52-4. 23(1H, m), 4.02-3. 83 (1H, m), 3.6K1H, d, J=2.4Hz), 3.35-3. 17 (3H, m), 3. 15-2. 89(2H, m), 2.58-2. 08(2H, tn). 57 NMR1(500MHz); 8.85(1H, s), 7.89(1H, d, J=2.5Hz), 7.83-7.71(1H, m), 7.69-7. 54(1H, m), 7.16(1H, dd, J=8.3Hz, 2.5Hz), 7.12-7. 03(1H, m). 6.97(1H, d, J-1.6Hz), 6.83(1H, d, J=1.1Hz), 6.78-6. 60(1H, m), 6.43-6.16 (1H, m), 5.46-5.17 (1H, m), 5.12-4. 72 (1H, m), 4.24-4. 07(1H, m), 4.07-3. 74 (1H, m), 3. 63-3. 49 (3H, m), 3. 10-2. 75 (1H, m), 2.66-2. 22 (5H, m). 58 NMR2 (500MHz) ; 8.78-8. 53 (1H, m), 8. 52-8. 27(1H, m), 7.97(1H, d, J=2.3Hz), 7.90-7. 70(1H, m), 7.23-7.15(1H, m), 7.15-7.01 (3H, m), 6.78(1H, s), 6.73-6. 55 (1H, m), 5. 40-4. 79 (1H, m), 4. 70-4. 16(1H, m), 4.08-3. 85 (1H, m), 3.80-3.49 (3H, m), 3.38-3. 15 (1H, m), 3.15-2. 86 (1H, m), 2.67-2. 07 (3H, m). 59 58 NMR2(500MHz) ; 8.51-8. 26(1H, m), 8. 23-8. 03(1H, m), 7.97 (1H, d, J=2.4Hz), 7.48-7. 31(1H.m), 7.26-7. 00 (4H, m), 6.86 6.7K1H, m), 6. 71-6. 53(1H.m), 5.32-4. 80(1H, m), 4.66-4.17(1H, m), 4.08-3. 94(1H, m), 3.76-3. 45(3H, m), 3.43-3. 21 (1H, m), 3. 18-2. 92(1H, m), 2.66-2. 07(3H, m).

- 91 040222

60 37 NMR1 (500MHz) : 9 81-9 67(1H, m), 7.98-6. 64(YUN, m), 6.33-6. 05(1 H, m), 5. 42-4. 66 (4H, m), 4. 22-3. 76 (2H, m), 3.30-2. 26(3H, m), 3.08-3. 76 (1H, m), 2.68-2. 04 (2H, m). 61 37 NMR1 (500MHz) ; 9.80-9. 53(1H, m), 7.94-7. 73 (1H, m), 7.68-7. 11(5H, m), 7.03-6. 93 (1H, m), 6. 83-6. 70 (1H, m), 6.46-6. 11 (1H, m), 5. 48-5. 17(1H, m), 5.05-4. 65 (1H, m), 4.25-3.73(2H, m), 3.11-2. 75 (1H, m), 2.67-2. 02 (5H, m). 62 37 NMR1 (500MHz); 8.86-8. 74(1H, m), 8.00-7. 66 (3H, m), 7.24-6. 64(5H, m), 6.44-6. 13 (1H, m), 5. 44-5. 19(1H, m), 5.07-4. 70 (1H, m), 4. 24-3. 70(2H, m), 3.68-3. 55 (3H, m), 3.08-2. 74 (1H, m), 2. 66-2. 02 (5H, m). 63 NMR1 (400MHz); 10.91-10. 69 (1H, m), 8. 22-8. 13(1H, m), 7.92-7. 65(3H, m), 7. 63-7. 13 (1OH, m), 6. 85-6. 71 (1H, m), 6. 38-6.16(1H, m), 5.46-5. 13(1H, m), 5.07-4. 64(1H, m), 4. 24-3. 65 (2H, m), 3.10-2. 01 (3H, m). 64 37, 63 NMR1 (500MHz) ; 10.23-9. 93 (1H, m), 7. 93-6. 61 (9H, m), 6.36-6. 05(1 H, m), 5. 42-5. 15(1H, m), 5.07-4. 71 (1H, m), 4.30-3. 78 (2H, m), 3. 10-2. 08 (6H, m). 65 NMR1 (500MHz) ; 10.01-9. 69 (1H, m), 8. 47-6. 04 (10H, m), 5.10-3.47 (4H, m), 3.29-2.03 (5H, m), 1.90-1.32 (2H, m). 66 NMR1 (500MHz) ; 11.61-11. 20(1H, m), 8.91-8. 73 (1H, m), 8. 43-7. 63(6H, m), 7. 30-7. 13 (1H, m), 6.95-6. 70 (1H, m), 6.43-6. 04(1H, m), 5.50-5.12 (1H, m), 5.08-4. 68(1H, m), 4.27-3. 70(2H, m), 3. 11-2. 00 (3H, m). 67 37, 63 NMR1 (500MHz) ; 8.46-8. 30(1H, m), 8.07-7. 72 (4H, m), 7.62-7. 50 (1H, m), 7. 47-7. 32 (2H, m), 7. 29-7. 15 (1H, m), 6.95-6. 78 (1H, m), 6. 43-6. 18(1H, m), 5. 45-5. 16(1H, m), 5.08-4. 71 (1H, m), 4. 40-3. 74 (4H, m), 3.18-2. 02 (5H, m). 68 37, 63 NMR1 (500MHz) ; 11. 08-10. 69(1H, m), 7.92-6. 07(9H, m), 6.37-6. 04(1H, m), 5. 49-3. 51 (4H, m), 3. 27-2. 02(3H, m). 69 37, 63 NMR1 (500MHz) ; 10.80-10. 51 (1H, m), 7.96-6. 58 (10H, m), 6. 32-6. O2(1H, m), 5. 45-5. 12(1H, m), 5.09-4. 73(1H, m), 4.293.75(2H, m), 3.18-2. 02 (3H, m). 70 37, 63 NMR1 (500MHz) : 10.64-10. 24(1H, m), 8. 15-7. 02(8H, m), 6. 87-6. 62(1H, m), 6. 42-6. 04(1H, m), 5.44-5. 18(1H, m), 5. 10-4. 68 (1H, m), 4. 32-3. 49 (2H, m), 3. 22-2. 02 (3H, m). 71 NMR1 (500MHz) ; 10. 16-9. 86(1H, m), 7.95-7. 07(8H, m), 6.80-6. 60 (1H, m), 6. 37-6. 08(1H, m), 5.45-5. 11 (1H, m), 5. 10-4. 65 (1H, m), 4. 31-3. 72(2H, m), 3.09-2.01(6H, m). 72 71 NMR1 (500MHz) ; 11.04-10. 65(1H, m), 8.00-6. 68 (9H, m). 6.34-5. 99(1H, m), 5.50-3. 93 (4H, m), 3. 12-2. 00(3H, m).

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73 71 NMR1 (500MHz) ' 10.60-1027(18, m), 8 04-7. 03 (9H, m), I 6. 77-6. 55(18, m), 6.31-6.14(1H, m), 5.44-5. 09(1H.m). 5.09-4. 72 (1H, m), 4. 29-3. 67(2H, m), 3.10-2.71(18, m), 2.68-2. 02 (5H, m). 74 71 NMR1 (500MHz): 10.81-10. 43(1H, m), 7.96-6. 67 (9H, m), 6. 37-6. 05(1H, m), 5.47-3.54(48, m), 3.27-2. 02 (6H, m). 75 71 NMR1 (500MHz) ; 10.37-10.03(18, m), 8.08-7. 03(8H, m), 6.88-6. 68 (1H, m), 6. 40-6. 17(1H, m), 5.43-5.15(18, m), 5.10-4. 66(18, m), 4.25-3. 7O(2H, m), 3.10-2. 76 (1H, in), 2.69-2. 03 (5H, m). 76 71 NMR1 (500MHz) ; 10.00-9.00 63(1H, m), 8.01-6.94(88, m), 6.82-6. 57 (1H, m), 6.37-6.02(18, m), 5.41-5.14(18, m), 5.11-4.70(18, m), 4.28-3.70(28, m), 3.09-2.72(18, m ), 2. 68-2. 22 (5H, m), 2. 22-2. 03 (3H, m). 77 71 NMR1 (500MHz); 11.47-11. 19(1H, m), 8. 85-8. 69(1H, m), 8.42-8. 23 (1H, m), 8. 23-8. 07(1H, m), 8.07-7.95(18, m), 7.93-7.74(28, m), 7.74-7.60(18, m), 7.33-6.94(28, m), 6.90-6.76(18, m), 6.37-6.20(18, m), 5.48-5.10(18, m), 5.10-4.63(18, m), 4.26-3.64(28, m), 3.10-1.99(38, m). 78 71 NMR1 (500MHz) I 10.72-10. 58 (1H, m), 8. 10-7. 07 (8H, m), 6.75-6.56 (18, m), 6.32-6.02(18, m), 5.43-5.09(18, m), 5.07-4.68(18, m), 4.33-3.71 (28, m ), 3.01-2.75(1H, m), 2. 67-2.04(2H, m). 79 71 NMR1 (500MHz) ; 11.10-10.73(18, m), 8.04-6. 71 (88, m), 6.31-6.01(18, m), 5.42-3.53(48, m), 3.27-2.00(38, m). 80 71 NMR1 (500M8z) I 10.63-10.36(18, m), 8.24-7.00(78, m), 6.86-6.66 (18, m), 6.39-6.12(1H, m), 5.47-5.14(18, m), 5.14-4.66(18, m), 4. 33-3. 62(2H, m), 3.12-2.02(38, m). 81 71 NMR1 (500MHz); 10.25-9.90(18, in), 8.02-7.04(78, m), 6.79-6.61(18, m), 6.27-6.05(18, m), 5.42-5.11(18, m), 5.09-4.68(18 , m), 4.32-3.54(28, m), .320-2.74(18, m), 2.67-2.00(58, m). 82 71 NMR1 (500MHz); 9.87-9. 75 (1 H, m), 8.01-7.69(48, m), 7.22-6.62(48, m), 6.35-6. 18 (1H, m), 5. 45-5. 16(1H, m), 5.08-4.71(18, m), 4.22-3.45(58, m), 3.07-2. 81(1H, m), 2.67-2.03(28, m). 83 71 NMR1 (500MHz) I 10.56-10. 33(1H, m), 7.96-7. 72 (1H, m), 7.72-7. 28 (6H, m), 7. 22-7. 08(1H, m), 6.74-6.60(18, m), 6.28-6. 05(1H, m), 5.39-5.10(18, m), 5.08-4.70(1H, m), 4.28-3.73(28, m), 3.09-2.73(18, m), 2.68-2.00(58, m).

- 93 040222

84 71 NMR1(500MHz) : 6.30-6. 02(1H, 10 88-10 44 (1H, w), 7. 93-6. 68 (8N. t). t), 5. 44-3. 49 (4H, m), 3. 27-2. 01 (6H, m). 85 71 NMR1 (500MHz) ; 7.55-7.29(4H, 6.27-6.14(1H, 4.30-3.72(2H, 10.76-10, 60(1H, m), 8.04-7. 74(3H, m), m), 7. 19-7.10(1H, m), 6. 74-6. 61 (1H, m), m), 5. 46-5. 10 (1H, m), 5. 08-4. 69 (1H, m), m), 3. 10-2. 75 (1H, m), 2. 66-2. 01 (2H, m). 86 71 NMR1 (500MHz); 6.30-6. 05(1 Η, 11.12-10. 74(1H, m), 8.10-6. 70(8Η, m), m), 5. 44-3. 52 (4H, m), 3. 27-2. 01 (ZN, m). 87 71 NMR1 (500MHz); 6.85-6. 67(1H, 5.08-4.67(1H, 10. 62-10 40 (1H, m), 8. 18-7. 09(7H, m), m), 6.38-6. 18 (1H, m), 5. 42-5. 1 7 (1H, m), m), 4. 25-3. 69 (2H, m), 3. 10-2. 03 (ZN, m). 88 71 NMR1 (500MHz): 6.77-6.61(1H, 5.09-4.69(1H, 2.66-2.02(6H, 10.24-9. 95(1 H, m), 8.06-7. 08 (7Η, m), m), 6. 30-6. 02(1H, m), 5. 41-5. 13 (1H, m), m), 4. 27-3. 70(1H, m), 3.12-2. 74(1H, m), m). 89 71 NMR1 (500MHz); 5.39-5. 16(1H, 3.20-2.00(5H, 7.97-6. 72 (10H, m), 6. 34-6. 05(1H, m), m), 5.11-4. 69(1 H, m), 4. 22-3. 44 (7H, m), m). 90 21, NMR1 (500MHz) ; 1 1.52-1 1.07 (1H, m), 9. 48-8. 24 (2H, m), 52 7.92-7. 70 (1H, 7.04-6. 66 (1H, 4.30-3. 54 (2H, m), 7. 70-7. 55 (2H, m), 7. 55-7. 07 (8H, m), m), 6. 50-5. 99(1H, m), 5.50-4. 63 (2H, m), m), 3.17-2. 87 (1H, m), 2.70-2. 02 (2H, m). 91 NMR1 (500MHz); 7.94-7. 30(9H, 6.38-6.16(1H, 4.19-3.44(2H, 10.93-10. 71(1H, m), 8. 24-8. 11 (1H, m), m), 7.29-7. 11 (3H, m), 6. 87-6. 70 (1H, m), m), 5.41-5.11 (1H, m), 5.04-4. 65 (1H, m), m), 3.09-2. 01 (3H, m). 92 71 NMR1 (500MHz); 6.85-6.71(1H, 5.05-4.68(1H, 2.66-2.01(5H, 10, 29-10. 15(1H, m), 7.92-7. 13(7H, m), m), 6.35-6. 20 (1H, m), 5. 42-5. 17 (1H, m), m), 4. 29-3. 68(2H, m), 3.09-2. 78 (1H, m), m). 93 71 NMR1 (500MHz) ; 6.76-6. 63(1 N, 5.07-4.70(1 N, 2.65-2.05(8N, 9.83-9. 75(1H, m), 7.93-7. 08 (7H, m), m), 6.31-6.16(1H, m), 5. 39-5.15(1H, m), m), 4. 25-3. 74 (2H, m), 3, 08-2. 77 (1H, m), m). 94 71 NMR1 (500MHz); 7.23-6. 79 (ZN, 5.37-5.14(1 N, 3.65-3.44 (ZN, 9.56-9. 42(1H, m), 7.95-7. 31 (4H, m), m), 6.77-6.62 (1H, m), 6.32-6. 20(1H, m), m), 5.07-4. 72 (1H, m), 4. 27-3. 74 (2H, m), m), 3.10-2. 79(1H, m), 2.66-2.01(511, m).

- 94 040222

95 96 NMR1 (500MHz) ; 11.72-11. 11 (1H, m), 9. 37-8. 24 (2H, m), 7.97-7. 66 (1H, m), 7. 67-7. 06(9H, m), 7.00-6. 68 (1H, m), 6.44-5. 81(1H, m), 5.53-4. 41 (2H, m), 4. 41-3. 54 (2H, m), 3.09-2. 90 (1H, m), 2.68-2. 14 (2H, m). 96 NMR1 (500MHz) ; 11.20-10. 76(1H, m), 8.30-8.12(1H, m), 7.88(1H, d, J=2.5Hz), 7.85-7. 63 (2H, m), 7. 59-7. 04 (9H, m), 6.90-6.72(1H, m), 6.37-6. 00(1H, m), 5.44-5.11(1H, m), 5.08-4. 63 (1H, m), 4. 21-3. 68 (2H, m), 3. 11-2. 76(1H, m), 2. 71-2. 03 (2H, m). 97 NMR1 (500MHz) ; 1 1. 36-10. 85 (1H, m), 8.74 (1H, dd, J=4.8Hz, 1.5Hz), 8.31-8. 14(1H, m), 8. 10-7. 02 (10H, m), 7.25-7.14 (1H, m), 6.88-6. 69 (1H, m), 6. 35-6. 13 (1H, m), 5.41-5. 09(1H, m), 5. 08-4. 67(1H, m), 4. 23-3. 60(2H, m), 3. 11-2. 75 (1H, m), 2.68-2. 07 (2H, m). 98 58 NMR1 (500MHz) ; 11.80-11. 14(1 H, m), 9. 64-8. 28 (3H, m), 8.23-7. 97 (1H, m), 7. 95-7. 73 (1H, m), 7. 73-7. 31 (6H, m), 7.31-7. 03 (1H, in), 7.03-6.61 (1H, m), 6.43-5. 92 (1H, m), 5.37-4. 58 (2H, m), 4. 29-3. 57 (2H, m), 3. 25-2. 83 (1H, m), 2.78-2. 08 (2H, m). 99 NMR1 (500MHz) ; 9.72-9. 54(1H, m), 8.07-6. 61 (1OH, m), 6.30-6. 16 (1H, m), 5.41-5. 13(1H, m), 5.07-4. 69 (1H, m), 4.25-4. 10(1H, m), 3.93-3. 73 (1H, m), 3. 66-3. 44 (3H, tn), 3. 10-2. 73(1H.m), 2.67-2. 02 (2H, m). 100 NMR1 (500MHz) : 9.85-9. 75(1H, m), 7.92-7. 86 (1H, m), 7.69-7. 66 (1H, m), 7. 59-7. 54 (1H, m), 7. 48-7. 44 (1H, m), 7.39-7. 32 (1H, m), 7. 25-6. 97 (1H, m), 6.91-6. 75 (1H, m), 4.91-4. 60(1H, m), 3. 65-3. 54(3H, m), 2.98-2. 90 (1H, m), 2.86-2. 70(1H, m), 2. 21-2.12(1H, m). 101 NMR1 (500MHz) ; 9. 81-9. 71(1H, m), 7. 84-7. 78 (2H, m), 7.76-7. 71 (1H, m), 7. 70-7. 65 (2H, m), 7. 24-6. 82 (4H, m), 6.81-6. 56(1H, m), 4.91-4. 60(1H, m), 3. 65-3. 50(3H, m), 3.02-2. 90 (1H, m), 2.86-2. 70 (1H, m), 2. 22-2. 10 (1H, m). 102 NMR1 (500MHz) ; 10.45-10. 11(1H, m), 8.05-7. 53 (2H, m), 7. 53-6. 78 (7H, m), 6.58-6.24" m), 5.07-4. 68 (1 H, m), 3.03-2. 05 (6H, m), 1.90-1.43 (3H, m). 103 102 NMR1 (500MHz) ; 10.39-10. 06(1H, m), 8.05-6. 78(9H, m), 6.56-6. 24 (1H, m), 5. 17-4. 65(1H, m), 3.04-2. 03 (6H, m), 1.86–1.41 (3H, m).

- 95 040222

104 91 NMR1 (500MHz): 10 37-10 25 (1H, m). 7.87-7. 75 (1 H, m), 7. 60-7. 22(13H, m), 7.16-7. 11 (1H, m), 6. 67-6. 60 (1H, m), 6.19 (1H, s), 5.35-4. 75 (2H, m), 4. 16-3. 76(2H, m), 3.03-2.76(18, m), 2.57-2.07(28, m). 105 91 NMR1 (500MHz) : 10. 23-9. 99(1H.m), 7.90-7. 76 (1H, m), 7. 64-7. 28 (1OH, m), 7. 23-7. 10(3H, m), 6.79-6. 68 (1H, m), 6. 31-6. 19(1 Η, m), 5.36-4. 71 (2H, m), 4. 17-3. 75(2H, m), 3.05-2. 80(1H, m), 2.61-2.08(28, m). 106 91 NMR1 (500MHz) ; 10.60-10. 34 (1H, m), 7.97-7.71 (28, m), 7.61-7. 37 (4H, m), 7. 33-7. 13 (3H, m), 6. 84-6. 69 (1H, m), 6.35-6. 07(1H, m), 5. 39-4. 72 (2H, m), 4. 22-3. 73 (2H, m), 3.07-2. 81 (1H, m), 2.65-2. 07 (2H, m). 107 91 NMR1 (500MHz) ; 10.85-10. 72(1H, m), 7.91-7.72(28, m), 7.57-7.51(1H, m), 7.48-7. 17 (5H, m), 6. 84-6. 74 (1H, m), 6.33-6. 07(1H, m), 5.38-4. 73 (2H, m), 4.19-3. 77 (2H, m), 3.07-2. 82 (1H, m), 2.65-2. 08 (2H, m). 108 91 NMR1 (500MHz) : 10.65-10. 55 (1H, m), 7.90-7. 76(1H, m), 7.63-7.31(8H, m), 7.19-7. 13(1H, m), 6.72-6.63(18, m), 6.24-6.18 (1H, m), 5.36-4. 77 (2H, m), 4. 20-3. 79 (2H, m), 3.05-2. 78 (1H, m), 2.59-2. 08 (2H, m). 109 91 NMR1 (500MHz) : 10.93-10.84(18, m), 7.89-7. 77 (1H, m), 7.59-7. 33 (7H, m), 7.19-7.14(18, m), 6.73-6. 65(1H, m), 6.23-6. 19 (1H, m), 5.36-4. 76 (2H, m), 4.19-3. 78 (2H, m), 3.05-2. 80 (1H, m), 2.59-2. 08 (2H, m). 110 91 NMR1 (500MHz) ; 8.42-8. 36(1H, m), 7.99-7.76(48, m), 7.53-7.44(28, m), 7. 25-7. 17 (1H, m), 6.90-6. 81 (1H, m), 6.35-6. 25(1H, m), 5.46-4.76(28, m), 4.19-3. 77 (4H, m), 3.10-3. 05(2H, m), 2.94-2. 85 (1H, m), 2.64-2. 09 (2H, m). 111 91 NMR1 (500MHz) ; 10.97-10.71(18, m), 7.88-7.80(18, m), 7.75-7. 67 (1H, m), 7. 65-6. 76 (8H, m), 6.26-6.07(18, m), 5.37-3.58(48, m), 3.24-2.07(38, m) 112 91 NMR1 (500M8z) ; 10.71-10.41(18, m), 7.86-7.14(138, m), 7.01-6.70(28, m), 6.22-6. 05(1H, m), 5.36-3.58(48, m), 3.24-2. 07 (3H, m). 113 91 NMR1 (500M8z) ; 7.90-7.78(18, m), 7.65-7.16(88, m), 6.78-6.71(18, m), 6.27-6. 20 (1H, m), 5. 36-4. 76(2H, m), 4.18-3.80(48, m), 3.18-2.99(2H, m), 2.91-2. 82(1H, m), 2.64-2.10(28, m). 114 102 NMR2 (400MHz) : 8.40-8.25(18, m), 8.10-7.30(78, m), 7.25-6.90(28, m), 6.68-6.58(18, m), 5.23-4. 35 (1H, m), 3.20-2.48(38, m), 2.45-2.08(18, in), 2.00-1.70(38, m).

- 96 040222

115 91 NMR1 (500MHz) : 11 05-10. 79(1H, m), 7.90-7. 81 (1H, m), 7.75-7. 69(1H, m), 7. 62-6. 76(7H, m), 6. 25-6. 06(1H, m), 5. 36-3. 58 (4H, m), 3. 24-2. 06 (6H, m). 116 91 NMR1 (500MHz) ; 10.73-10. 63 (1H, m), 7.90-7. 77(1H, m), 7.58-7. 51 (2H, m), 7. 43-7. 31 (3H, m), 7.19-7. 11 (3H, m), 6.72-6. 65(1H, in), 6.21(1H, s), 5.36-4. 77 (2H, m), 4.20-3. 79(2H, m), 3.05-2. 77(1H, m), 2.64-2. 08 (5H, m). 117 91 NMR1 (500MHz); 7.93-7. 78 (2H, m), 7. 52-7. 36(4H, m), 7.31-7. 09(3H, m), 6. 86-6. 69 (1H, m), 6. 27-6.19 (1H, m), 5.46-4. 75 (2H, m), 4. 18-3. 80 (4H, m), 3. 13-2. 82 (3H, m), 2.64-2. 08 (2H, m). 118 102 NMR2 (400MHz); 8.04-7. 29(6H, m), 7.05(1H, dd, J=8.4Hz, 2.5Hz), 7.00-6. 93 (2H, m), 6. 61 (1H, d, J=8.4Hz), 5.22-4. 93(1H, m), 3.14-2. 79(2H, m), 2. 78-2. 51 (1H, m), 2.47, 2.49(total 3H, each s), 2.42-2. 06 (1H, m), 1.90, 1.80(total 3H, each s). 119 102 NNR2(400MHz): 8.38-8. 18(1H, m), 8. 17-7. 30(6H, m), 7.26-7. 01 (3H, m), 6.59 (1H, d, J=8.4Hz), 5.25-4. 70 (1H, m), 3.40-2. 50 (3H, m), 2.45-2. 05(1H, m), 1.95-1. 70 (3H, m). 120 102 NMR2(400MHz) : 8.10-7. 65 (2H, m), 7. 58-6. 95 (8H, m), 6.60 (1H, d, J=8.4Hz), 5.25-4. 80(1 H, m), 3. 30-2. 50 (3H, m), 2.48-2. 08(4H, m), 1.92-1. 70 (3H, m). 121 102 NMR2(400MHz) ; 8.44-8. 30(2H, m), 8.09-6. 92(7H, rn), 6.67-6. 59(1H, m), 5. 20-4. 88 (1H, m), 3.14-2. 81(2H, m), 2.74-2. 57(1H, m), 2. 45-2. 07(1H, m), 1.91, 1.80(total 3H, each s). 122 102 NMR2 (400MHz) : 8.75-7. 26 (7H, m), 7. 26-6. 65 (5H, m), 5. 10-4. 65(1H, m), 4.00-2. 05(5H, m), 1.90-1. 60 (5H, in). 123 102 NMR2 (400MHz) ; 8.09-7. 76 (3H, m), 7. 52-7. 44 (3H, m), 7. 36-7. 00 (4H, m), 6.60 (1H, d, J=8.4Hz), 5.20-4. 94 (1H, m), 3.07-2. 82(2H, m), 2.76-2. 59 (1H, m), 2. 41-2.15 (1H, m), 1.90, 1.80 (total 3H, each s). 124 102 NMR2(400MHz) ; 8.37-8. 31(2H, m), 8.06-7. 52(2H, m), 7.38-6. 94(5H, m), 6.64-6. 60 (1H, m), 5. 18-4. 92 (1H, m), 3.08-2. 81(2H, m), 2.74-2. 55 (1H, m), 2. 42-2. 16 (1H, m), 1.91, 1.80(total 3H, each s). 125 NMR2(500MHz); 8.51-8. 20 (2H, m), 8. 20-7. 75 (3H, m), 7.70-7. 58 (4H, rn), 7. 31-7. 22 (1H, m), 7. 15-7. 10 (1H, m), 6.70-6. 62 (1H, m), 5.20-4. 90(1 H, m), 3. 90-3. 61(2H, m), 3.32-2. 80 (5H, m), 2.65-2. 30 (2H, in), 2.10-2. 00 (1H, m)

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126

102

NMR2 (400MHz) ; 8.04-7. 25 (1 OH, m), 7.07(14, dd, J=8.4Hz, 2.1Hz), 6.6K1H, d, J-8.34z), 5.18-4.92(14, m), 3.13-2.57 ( 34, m), 2.40-2.13(14, m), 1.89, 1.79(total 3H, each s).

127

NMR1 (500MHz); 7.79-7. 69 (14, 7.19-7.14 (1 Η, 5.36-4.76 (24, 2.64-2.06(24,

10.76-10.66(14, m), 7.97-7.85(24, m), m), 7.60-7.46(34, tn), 7.43-7. 32(2H, m), m), 6. 72-6. 65(1H, m), 6. 21(1H, s), m), 4.20-3.79(24, m), 3.05-2.79(14, m), m).

128 91 NMR1 (500MHz); 7.44-7.09(64, 5.38-4.72(24, 2.64-2.07(54, 10.58-10.47(14, m), 7.92-7.71(24, m), m), 6.84-6.74(14, tn), 6.32-6.21(14, m), m), 4.19-3.75(24, m), 3.06-2.82(14, tn), m). 129 91 NMR1 (500M4z); 6.26-6.07(14, 11. 10-10.81 (14, m), 8.00-6. 76(9H, m), m), 5.36-3.57(44, tn), 3.25-2.06(34, tn). 130 102 NMR2 (400M4z): 7.85-7. 75(1H, 6.70-6.60(1H, 8.70-8. 55 (1H, m), 8.35-7.90(34, m), m), 7.70-7.40(44, m), 7.18-7.08(14, tn), m), 5.22-2.00(54, m) , 1.80-1.75(34, m). 131 91 NMR1 (500MHz) ; 7.91-7. 70(24, 6.44-6.28(14, 3.09-2.89(14, 10.83(1H, brs), 8.24-8.20(14, m), m), 7.36-7. 21 (44, m), 7.00-6.88(1H, m), m), 5.39-4.70(24, m), 4.18-3.74(24, m), tn), 2.67-2.09(54, m). 132 NMR1(500MHz); 7.33-7. 17(3H, 5.47-4.68(2H, 2.68-2.09(24, 10.62-10.48(14, tn), 8.16-7.44(54, m), tn), 6.84-6.73(14, m), 6.33-6. 23 (1H, m), m), 4.20-3.74(24, in), 3.12-2. 75 (1H, m), m). 133 91 NMR1 (500MHz); 7.91-7.69(24, 7.42-7.37(14, 6.44-6.28(14, 3.09-2.88(14, 11.06(14, brs), 8.23-8. 18(1H, m), tn), 7.61-7.57(14, m), 7.50-7. 47 (1H, m), m), 7. 28-7. 21 (1H, tn), 6.98-6.88(14, tn), m), 5.39-4.70(24, m), 4.17-3.74(2H, m), m), 2.66-2.1 1 (24, m). 134 91 NMR1 (500MHz); 7.90-7.79(14, 6.95-6.83(14, 4.15-3.72(2H, 10.83(14, brs), 8.10(14, brs), m), 7.64-7.57(14, m), 7.50-7.19(94, m), m), 6.42-6. 26(1H, m), 5.39-4.68(24, m), m), 3.08-2. 86(1H, tn), 2.64-2.07(24, m). 135 91 NMR1 (500MHz); 7.71-7. 64(14, 6.72-6.64(14, 4.20-3.78(24, 10.73-10. 63(1H, m), 7.90-7.77(34, tn), m), 7.53-7. 31 (4H, m), 7.19-7.14(14, m), m), 6.23-6.18(14, m), 5.36-4.77(24, tn), m), 3.06-2. 79(1 H, m), 2. 64-2. 08(2H,tn).

- 98 040222

136 91 NMR1 (500MHz): 10.56-10. 46(1H, m). 7.90-7. 62(5H.m), 7.32-7. 14(3H, m), 6.86-6. 73 (1H, m), 6. 34-6. 23 (1H, m), 5. 45-4. 58 (2H, m), 4. 18-3. 77(2H, m), 3.06-2. 82(1 H, m), 2. 64-2. 07 (2H, m). 137 102 NMR2(400MHz) ; 9. 12-9. 04(1H, m), 8. 62-8. 57(1H, m), 8.04-7. 30(11H, m), 7.09-6. 95(1H, m), 6.60-6. 43(1H, m), 6.33(1H, s), 5.15-4. 86(1H, m), 3. 26-2. 96(2H, m), 2.73-2. 07(1H, m), 1.84-1. 73 (3H, m). 138 102 NMR2 (400MHz) ; 8.01-7. 79 (2H, m). 7.63-7. 35 (8H, m), 7. 25-6. 89 (4H, m), 6. 79-6. 42(2H, m), 5.06-4. 77 (1H, m), 3. 15-2. 58 (3H, m), 2. 40-2. 05 (1H, m), 1.88, 1.70 (tota 1 3H, etach s). 139 102 NMR2 (400MHz) : 9.10-7. 25 (13H, m), 7. 12-7. 00 (1H, m), 6.68-6. 50 (1H, m), 5. 20-4. 75(1H, m), 4.10-2. 00 (4H, m), 1.73–1.50 (3H, m). 140 102 NMR2 (400MHz) ; 8.05-7. 99 (14H, m), 7. 10-7. 06(1H, m), 6.56-6. 59(1 H, m), 5. 14-4. 89(1 H, m), 3. 14-2. 55 (3H, m), 2.40-2. 08(1H, m), 1.88, 1.73(totaI 3H, etach s). 141 1 NMR2 (500MHz): 8.30-7. 02 (14H, m), 6. 65-6. 51 (1H, m), 5.28-3. 90 (3H, m), 3. 29-2. 90(2H,m), 2.61-2. 02 (3H, m). 142 102 NMR2 (400MHz): 8.80-8. 60 (1H, m), 8. 35-8. 25 (1H, m), 8.07-7. 46 (2H, m), 7. 45-7. 35 (1H, m), 7. 20-6. 73 (4H, m), 6.70-6. 55(1H, in), 5.25-4. 90 (1H, m), 3.76-3. 62 (3H, m), 3.15-2. 10(4H, m), 1.92-1. 77 (3H, m). 143 102 NMR2 (400MHz) ,- 8.82(1H, dd, J=9.6Hz, 3.8Hz), 8.73, 8.60(total 1H, eachs), 8.19-7. 86 (4H, m), 7. 63-7. 53 (2H, m), 7. 25-7. 00(1H, m), 6.65(1H, dd, J=8.4Hz, 2.4Hz), 5.17-4. 87(1H, m), 3.51-2. 58 (3H, m), 2. 42-2. 08 (1H, m), 1.82, 1.77 (tota I 3H, etach s). 144 91 NMR1 (500MHz); 10.80-10. 50(1H, m), 7. 87-7. 71(1H, m), 7.68-7.15(11H, rn), 7.03-6. 69 (2H, m), 6. 22-6. 06(1H, m), 5.35-3. 55 (4H, m), 3. 22-2. 05 (3H, m). 145 102 NMR1 (400MHz): 10.25-9. 95(1H, m), 8.00-6. 25 (11H, m), 5. 10-4. 70(1H, m), 3.00-1.40(1 OH, m). 146 91 NMR1 (400MHz) ; 10.77-10. 66(1H.m), 8.15-8.10(1H, brs), 7.90-7. 79 (1H, m), 7. 66-7. 19(11H, m), 6.95-6. 84(1H, m), 6.42-6. 27 (1H, m), 5. 38-4. 69 (2H, m), 4. 15-3. 73 (2H, m), 3.07-2. 86 (1H, m), 2.64-2. 08 (2H, m). 147 102 NMR2 (400MHz) ; 8.04-7. 44 (5H, m), 7. 35-7. 20(1H, m), 7.07(1H, dd, J=8.3Hz, 2.4Hz), 6.60(1H, d, J=8.4Hz), 5.18-4. 89( _1Htm ), 3.27-2. 57 (3H, m), 2.40-2.12 (1H, m), 1.89, 1.79 (tota I 3H, etach s).

- 99 040222

148 102 NMR2 (400MHz) : 8. 30-7. 52 (4H, m), 7. 36-6. 94(5H, m), 6.64-6. 61(1H.m), 5.17-4. 90(1H, m), 3.08-2. 58 (3H, m), 2. 41-2. 12 (1H, m), 1.90, 1.79 (tota I 3H, etach s). 149 102 NMR2 (400MHz); 7.34-7. 17 (7H, m), 7. 28-7. 21(3H, m), 7.07-7. 04 (1H, m), 6.61 (1H, d, J=8.4Hz), 5.20-4. 95 (1H, m), 3.06-2. 58 (3H, m), 2.48, 2.46 (tota! 3H, each s), 2.40-2.15 (1H, m), 1.89, 1.80 (tota I 3H, etach s). 150 102 NMR2 (400MHz); 8.37 (1H, t, J=8.1Hz), 8.06-6. 96 (9H, m), 6.64-6.61 (1H, m), 5.19-4. 91(1H, rn), 3.09-2. 51 (3H, m), 2.50, 2.49(total 3H, each s), 2.43-2. 13 (1H, m), 1.91, 1.79 (totaI 3H, etach s). 151 102 NMR2 (400MHz); 8.04-7. 70 (3H.m), 7.55-7. 29(7H, m), 7.09-7. 02 (1H, m), 6.60 (1H, d, J=8.3Hz), 5.22-4. 93 (1H, m), 3.09-2. 77 (2H, nt), 2. 74-2. 56 (1H, m), 2. 43-2. 12 (1H, m), 1.88, 1.80 (tota I 3H, etach s). 152 102 NMR2 (400MHz); 8.42-8. 26(2H, m), 8.08-7. 27 (6H, m), 7.32-6. 92(2H, m), 6.66-6. 59 (1H, m), 5. 20-4. 90 (1H, m), 3.09-2. 75 (2H, m), 2.75-2. 53 (1H, m), 2. 45-2. 10 (1H, m), 1.91, 1.80 (tota I 3H, etach s). 153 NMR1 (500MHz) ; 10.64-10. 33 (1H, m), 7.95-7. 75 (1H, m), 7. 74-7. 22 (12H, m), 7. 21-7. 07(1H, m), 6.69-6. 56(1H, m), 6.20(1H, s), 5.47-4. 69(2H, m), 4. 22-3. 73(2H, m), 3.08-2. 72(1H, tn), 2.59-2. 04(2H, m). 154 91 NMR1 (500MHz) ; 10.21-10. 12(1H, m), 7. 89-7. 77 (1H, m), 7.59-7. 29 (9H, m), 7. 24-7. 12(3H.m), 6.78-6. 68 (1H, m), 6.31-6. 22 (1H, m), 5.37-4. 70 (2H, m), 4.16-3. 75 (2H, m), 3.04-2. 82 (1H, m), 2.60-2. 05 (2H, m). 155 102 NMR1 (400MHz) : 10.95-10. 60(1H, m), 8. 26-7. 20 (13H, m), 7.05-6. 93(1H, m), 6.61-6. 40(1H, m), 5.00-4. 64(1H, m), 3.04-2. 06(3H, m), 1.93-1. 60 (3H, m). 156 91 NMR1 (500MHz) ; 10.72-10. 64(1H, m), 7.90-7. 08(10H, m), 6.86-6. 68(1H, m), 6.25-6. 18(1H, m), 5. 47-4. 58 (2H, m), 4. 21-3. 74(2H, m), 3.06-2. 70(1H, m), 2. 60-2. 06 (2H, m). 157 NMR1 (500MHz) ; 10.52(1H, s), 8.03-7. 39 (5H, m), 7.39-7.08(4H, m), 6.86-6. 70(1H, m), 6. 37-6. 20(1H, m), 5.44-4. 70 (2H, m), 4. 22-3. 74 (2H, m), 3. 10-2. 77 (1H, m), 2.67-2. 05 (2H, m). 158 91 NMR1 (500MHz) ; 10.46-10. 38 (1H, m), 7. 88-7. 76 (1H, m), 7. 52-7. 16(12H, m), 6.67-6. 60(1H, m), 6.19(1H, s), 5.35-4. 75 (2H, m), 4.16-3. 77(2H, m), 3.04-2. 78 (1H, m), 2.56-2. 10 (2H, m).

- 100 040222

159 102 NMR2 (400MHz): 8.42-8.25 (1H.m), 8.10-6.90 (8H.m), 6.69-6. 58 (1H, m), 5.22-4.85(1 + m), 3.15-2.06(4+ m), 1.95-1. 70(3H, m). 160 NMR2(400MHz) ; 8.06-7. 78 (2H, m), 7. 62-7. 30 (9H, m), 7.16-6.81 (5H, hi), 6.60-6. 44(1 + m), 5. 21-4. 85 (1H, m), 3. 12-2. 45 (3H, m), 2. 43-2. 01 (1H, m), 1.92-1.72 (3H, m). 161 102 NMR2 (400MHz) : 8.20-6.98 (10+ m), 6.65-6. 54 (1H, m), 5. 20-4. 78(1H, m), 3.85-2.03(4H, m), 1.95-1.74(3+ m). 162 102 NMR2 (400MHz) : 8.35-6. 90 (1OH, m), 6.67-6. 55 (1H, m), 5. 23-4. 85(1H, m), 3. 15-2. 07(4H, m), 1.95-1. 73 (3H, m). 163 102 NMR2(400MHz) : 8.40-8. 20 (1H, m), 8. 11-6. 90 (1OH, m), 6.70-6. 55 (1H, m), 5. 23-4. 85 (1H, m), 3. 15-2. 08(4H, m), 1.95-1. 73 (3H, m). 164 91 NMR1 (500MHz) ; 10.82-10. 53 (1H, m), 7. 87-7. 15(11H, m), 7.05-6. 72 (2H, m), 6. 23-6. 07(1H, m), 5.35-3. 55 (4H, m), 3.23–2.04(3+ m). 165 NMR1 (500MHz); 11.25-10.84(1+m), 8.27-8. 16(1H, m), 7.92-7. 65 (3H, m), 7. 63-7. 29 (5H, m), 7. 27-7. 11 (3H, m), 6.87-6. 73(1 + m), 6. 33-6. 19(1H, m), 5. 39-4. 70(2H, m), 4. 19-3. 70 (2H, m), 3.10-2. 77(1H, in), 2.66-2. 06 (2H, m). 166 91 NMR1 (500MHz) : 10.84-10. 67 (1H, m), 8. 21-8. 15 (1H, m), 7. 89-7. 79 (1H, m), 7. 72-7. 62 (2H, m), 7.50-7. 45 (1H, m), 7.39-7.25 (2+ m), 7.21-7. 08(5H, m), 6. 82-6. 73 (1H, m), 6.29-6. 22(1 H, in), 5. 35-4. 71 (2H, m), 4.13-3.73(2+ m), 3.05-2. 81 (1H, m), 2.59-2. 04 (5H, m). 167 160 NMR2(400MHz) ; 8.24-7.95, 7.85-7. 22(total 14H, each), 7.15-7. 02(1H, m), 6. 63-6. 51 (1H, m), 5. 22-4. 81(1H, m), 3.14-2.50(3+ m), 2.42-2. 03(1H, m), 1.85, 1.73(total 3H, etach s). 168 NMR1 (500MHz) ; 10.38-10. 09(1H, m), 7.90-7. 73 (1H, m), 7.63-7. 30 (6H, m), 7.28-7. 08(5H, m), 6. 81-6. 65 (1H, m), 6.34-6.19(1 + m), 5.39-4.66(2+ m), 4.19-3. 71(2H, m), 3.07-2.74(1H, m), 2.67-2. 06 (2H, m). 169 NMR1 (500MHz) ; 10.66-10. 32(1H, m), 7. 89-7. 74 (1H, m), 7. 73-7. 43 (3H, m), 7. 40-7. 07(9H, m), 6.69-6. 58 (1H, m), 6.19(1+ s), 5.48-4. 73(2H, m), 4. 21-3. 72(2H, m), 3. 23-2. 74(1H, m), 2.58-2. 04(2H.m). 170 102 NMR2 (400MHz) : 8.55-8. 25 (1H, m), 8.08-7.15(7+ m), 7. 11-6.98(1H, m), 6.59(1+ d, J=8, 4Hz), 5. 23-4. 80(1H, m), 3.55-2. 05(4H, m), 1.94-1. 73 (3H, m).

- 101 040222

171 102 NMR2 (400MHz) : 8.60-6. 90 (9H, m), 6 61 (1H, d, +8.4Hz), 5.22-4. 83 (1H, m), 3. 18-2. 06(4H, nt), 1.95-1. 73(3H, m). 172 102 NMR2(400MHz) : 8.50-7. 93 (4H, m), 7. 63-7. 53 (1H, m), 7. 52-7. 36(2H, m), 7. 35-7. 28(1H, m), 7. 28-7. 20(1H, m), 7.17-7. 06(1H, m), 6.64(1H, d, +8.4Hz), 5.23-4. 87(1H, m), 3. 28-2. 92(2H, m), 2.84 (2H, q, +7.5Hz), 2.77-2. 03(3H, m), 1.80-1. 60(3H, m), 1.30-1.20(3H, m). 173 102 NMR2(400MHz) ; 8. 17-6. 60 (1OH, m), 5.21-4. 55 (1H, m), 4. 27-3. 86(4H, m), 3.32-2. 18 (6H, m). 174 91 NMR1 (500MHz) ; 10.70-10. 50 (1H, m), 8. 23-8. 16 (1H, m), 7.91-7. 60 (3H, m), 7. 47-7. 13(6H, m), 7.01-6. 85 (2H, m), 6.82-6. 71 (1H, m), 6. 33-6. 22 (1H, m), 5. 46-4. 58 (2H, m), 4.16-3. 73 (2H, m), 3. 61-3. 41(3H, m), 3.07-2. 82 (1H, m), 2.61-2. 07 (2H, m). 175 91 NMR1 (500MHz) ; 11. 17-11.03(1H, m), 8. 31-8. 25(1H, m), 8.00-7. 76 (3H, m), 7. 71-7. 61 (2H, m), 7. 52-7. 44 (2H, m), 7.23-7.17(1H, m), 6.87-6. 78 (1H, m), 6. 33-6. 24 (1H, m), 5.37-4. 74 (2H, m), 4. 17-3. 77(2H, m), 3.08-2. 85(1 H, m), 2.64-2. 08 (2H, m). 176 37 NMR2 (400MHz) ; 7.98-6. 46 (15H, m), 5. 19-4. 51(1H, m), 4.22(1H, d, +10.4Hz), 4.04(1H, d, +10.4Hz), 3.60, 3.58(tota I 3H, each s), 3 .31-3. 23(1H, m), 3.08-2. 92(1H, m), 2.59-2. 04 (3H, m). 177 37 NMR2 (400MHz); 8.29-6. 50(14H, m), 5. 22-4. 56(1H, m), 4.23-3. 88 (2H, m), 3.63, 3.61 (total 3H, each s), 3.25-3. 16(1H, m), 3. 13-2. 94(1H, m), 2.59-2. 05 (3H, m). 178 102 NMR2 (400MHz): 8.08-6. 88(10H, m), 6.61(1H, d, +8.3Hz), 5.25-4. 87(1H, m), 3.15-2. 10(10H, m), 1.93-1. 75 (3H, m). 179 102 NMR2 (400MHz) : 8.10-7. 23 (6H, m), 7. 10-6. 86 (3H, m), 6.6K1H, d, +8.3Hz), 5.24-4. 86(1H, m), 3.13-2. 07(10H, m), 1.93-1. 73 (3H, m). 180 102 NMR2 (400MHz) : 8. 08-6. 90(11H, m), 6.62(1H, d, +8.3Hz), 5.23-4. 83 (1H, m), 3.15-2. 50 (3H, m), 2.45-2. 25(1H, m), 2.17(3H, s), 1.89(1H, brs), 1.84-1. 57(4H, m). 181 102 NMR1 (400MHz) ; 10.00-9.00 98(1H, m), 8.03-6. 90(9H, m), 6.78(1H, t, +8.8Hz), 6.45-6. 25(1H, m), 5.06-4. 70 (1H, m), 3.00-2. 73 (4H, m), 2.40-2. 24(1 H, m), 2. 23-2. 05(3H, m), 1. 96(1H, s), 1.83-1. 60 (3H, m).

- 102 040222

182 102 NMR2 (400MHz) ; 8.06-7=18(78, m), 7.12-6.97 (28, w). 6.59(18, d, J=8.4Hz), 5.21-4. 90(1H, m), 3.08-2.79(28, m), 2.75-2.56(18, m), 2.45-2. 08 (4H, m), 1.90, 1.80(totaI 3H, each s). 183 102 NMR2 (400MHz) I 8.51-8.22(18, m), 8.09-7.50(48, m), 7.21-7. 08(2H, m), 7.18-7.08(18, m), 7.03-6. 63 (1H, m), 5.21-4. 90(1H, m), 4. 32-4. 20(2H, m), 3.13-2.58(58, m), 2.44-2.12(18, m), 1.89, 1.79(total 38, etach s). 184 37 NMR1 (500MHz); 7.88(18, d, J=2.2Hz), 7.80-7. 75(1H, m), 7.48-7.38(48, m), 7.30-7. 15 (3H, m), 6.78-6. 71 (1H, m), 6. 27-6. 21 (1H, m), 5. 36-4. 76(2H, m), 4.18-3.80(4H, m), 3.11-2.82(38, m), 2.64-2.08(28, m). 185 99 NMR1 (500MHz) ; 7.93-7.78(28, m), 7.55-7.25(78, m), 7.19-7.14(18, m), 6.78-6.71(18, m), 6.26-6.21(18, m), 5.36-4.77(28 , m), 4.18-3.81(48, m), 3.13-2.81(38, m), 2.64-2.08(28, m). 186 99 NMR1 (500MHz) ; 7.95-7.79(28, m), 7.69-7.60(28, m), 7.51-7.38(38, m), 7.19-7.14(18, m), 6.78-6. 70 (1H, m), 6. 26-6. 20(1H, m), 5.36-4.77(28, m), 4.18-3. 81 (4H, m), 3.06-2. 81(1H, m), 2.64-1.92(88, m). 187 NMR1 (500MHz) ; 7.91-7.55(28m), 7.53-7.36(48m), 7.35-7. 24(2H, m), 7. 22-7. 11(1H, m), 6.81-6.66(18, m), 6.30-6.05(18, m), 5.39-4.74(28, m), 4.22-3. 76 (4H, m), 3.20-2.77(38, m), 2.66-2.06(28, m). 188 102 NMR2(400MHz) ; 8.09-7.40(78, m), 7.22-6.55(48, m), 5.25-4.90(18, m), 3.80-3.50(38, m), 3.20-2.50(38, m), 2.50-2.07(18 , m), 1.92-1.72 (38, m). 189 102 NMR2(400MHz) ; 8, 32 (1H, brd, J=8.38z), 8.20-7.48(28, m), 7.25-6.54(78, m), 5.28-4.93(18, m), 3.80-3. 60 (3H, m), 3.18-2.07(78, m), 1.93-1.73 (38, m), 190 102 NMR2 (400MHz); 8.40-7.40(48, m), 7.43-6.56(68, m), 5.30-4.90(18, m), 3.83-3.58(38, m). 3.20-2. 55(3H, m), 2.54-2.46(38, m), 2.45-2. 08(1H, m), 1.93-1. 74 (3H, m). 191 102 NMR2(400MHz) ; 8.34-7.45(48, m), 7.40-6.55(68, m), 5.27-4.86(18, m), 3.80-3.50(38, m), 3.20-2. 08(4H, m), 1.93-1.70(38, m). 192 102 NMR2 (400MHz) ; 8.78-8.50(18m), 8.43-8.24(18m), 8. 10-7. 46(2H, m), 7.24-6.55(68, m), 5.26-4. 90(1H, m), 3.83-3.55(38, m), 3.15-2.53(38, m), 2.47-2.10(1H, m), 1.95-1.70(38, m).

- 103 040222

193 102

194 102

195 160

196 160

197

198

199

200

201

102

NMR2 (400MHz) : 8.13-7. 30 (5H, m), 7. 25-6. 85(4H, m), 6.60(1H, brd, J=8.4Hz), 5.25-4. 86(1H, m), 3.20-2. 50(3H, m), 2.48-2. 28(1 H, m), 2. 27-2. 1 7 (3H, m), 1.93-1. 72(3H, nil) 1H, d, J=8.4Hz), 5.22-4.82(1H, m), 3.20-2.53(3H.m), 2.50-2.41(3H, tn), 2.40 -2.07 (1H, tn), 1.96-1.70 (3H, m).

NMR2 (400MHz) ; 8.29-7. 76 (4H, m), 7. 54-7. 44 (2H, m), 7. 44-7. 29 (4H, m), 7. 32-7. 13 (1H, tn), 7. 13-6. 97(2H,m),

6.63-6. 55 (1H, m). 5.17-4. 88 (1H, m), 3.10-2. 54 (3H,m),

2.44-2. 08 (1H, m), 1.84, 1.74(total 3H, etachs).

NMR2 (400MHz) ; 8.22-7. 75(3H, m), 7.69(1H, s),

7.55-7. 30(8H, tn), 7. 31-7. 20(1H, m), 7.12-7. 03(1H,m),

7.02-6. 53 (1H, tn), 5. 16-4. 87(1H, m), 3.08-2. 53 (3H,m),

2.39-2. 04 (1H.tn), 1.82, 1.73 (tota I 3H, etach s).

NMR2 (400MHz) ; 8.1 5-6. 93(11H, m), 6.59(1H, d, J=8.4Hz),

5.22-4. 78 (1H, m), 3.30-2. 50 (3H, m), 2.45-2. 05 (1H,m),

1.94-1.70(3H, m).

NMR1 (400MHz) ; 10.28-10. 18(1H, m), 7. 89-7. 76 (1H, m), 7. 61-7. 36 (5H, tn), 7. 27-7. 10 (6H, m), 6. 80-6. 68(1H.m),

6.33-6. 23(1H, m), 5.38-4. 69 (2H, tn), 4. 17-3. 74 (2H,m),

3.06-2, 86(1H, m), 2.62-2. 05 (2H, m).______________________________

NMR1 (400MHz) ; 10.50-10. 40(1H, m), 7. 88-7. 76(1H, m), 7.57-7. 24 (8H, m), 7. 21-7. 09 (4H, tn), 6. 67-6, 60 (1H,m),

6.21(1H, s), 5.46-4. 58 (2H, tn), 4. 17-3. 76 (2H, m), 3.05-2. 77 (1H, m), 2.58-2. 05 (2H, tn).

NMR1 (400MHz) ; 11.05-10. 88(1H, m), 8. 24-8. 16(1H, m), 7, 91-7. 67 (3H, m), 7. 54-7. 32 (4H, m), 7. 22-7. 10 (4H,m),

6.83-6. 74 (1H, m), 6. 30-6. 21 (1H, m), 5. 37-4. 71 (2H,m),

4. 16-3. 73 (2H, tn), 3.08-2. 80 (1H, tn), 2.68-2. 05(2H,m).

NMR1 (400MHz) ; 7.88(1H, d, J=2.5Hz), 7.85(1H, d,

J=2. 1Hz), 7.60 (1H, dd, J=8.1Hz, 2.2Hz), 7.48-7. 38 (3H, tn), 7. 31-7. 25(2H, m), 7. 20-7.14(1H, m), 6. 77-6. 70(1H, m), 6.25(1H, brs), 5.38-4. 76 (2H, m), 4. 19-3. 80(4H, m), 3.11-2. 81(3H, m), 2.68-2. 08(2H, in).

202 99

NMR1 (400MHz); 7. 91(1H, d, J=7.7Hz), 7.88(1H, d, J=2.5Hz), 7.69 (1H, d, J=7.2Hz), 7.48-7. 37 (3H, m), 7. 32-7. 25 (2H, m), 7.19-7. 14(1H, m), 6.78-6. 70(1H, m), 6.27-6. 22(1H, m), 5.37-4. 76 (2H, m), 4.19-3. 80 (4H, m), 3. 13-3. 11 (2H, m), 3.08-2. 81 (1H, m), 2.68-2. 07 (2H, m).

- 104 040222

203 91 NMR1 (400MHz) ; 11.04-10. 75 (1H _S m), 7. 89-7. 43 (6H, m), 7.39-6. 75 (4H, m), 6. 28-6. 08(1H, m), 5. 37-3. 57 (4H, m), 3.27-2. 05 (3H, m). 204 99 NMR1 (400MHz) ; 10.99-10. 84(1H, m). 8.26-8. 20(1H, m), 7.9K1H, d, J=8.7Hz), 7.9O(1H, d, J=2.5Hz), 7.86-7. 74(1H, m), 7. 40-7. 32(2H, m), 7. 25-7. 17 (2H, m), 6.99(1H, d, J=7.7Hz), 6.88-6. 78(1H, m), 6. 34-6. 23(1H, m), 5. 38-4. 74 (2H, m), 4. 18-3. 76(2H, m), 3.08-2. 83(1H, m), 2. 68-2. 09(3H, m), 0.94-0. 81 (2H, m), 0.72-0. 61(2H, m). 205 91 NMR1 (400MHz); 10.25-10.14(1H, m), 7.89 (1H, d, J=2.4Hz), 7.82-7. 65(1H, m), 7. 47-7. 16(6H, m), 6.99(1H, d, J=7. 7Hz), 6.84-6. 73(1H, m), 6. 34-6. 23 (1H, m), 5.38-4. 73(2H, m), 4. 21-3. 77(2H, m), 3.07-2. 80 (1H, m), 2.64-2. 08(3H, m), 0.97-0. 84 (2H, m), 0.75-0. 60 (2H, m). 206 91 NMR1 (400MHz) (; 10.50-10.41(1H, m), 7.88(1H, d, J=2.5Hz), 7.58(2H, d, J=8.5Hz), 7.41- 7.30 (4H, m), 7.26-7.13 (2H, m), 6.99(1H, d, J=8.OHz), 6.71-6.64 (1H, m), 6. 21(1H, brs), 5.37-4.77(2H, m), 4.20-3.79(2H, m), 3.06-2.78(1H, m), 2.68-2 .07(3H, m), 0.95-0.82(2H, m), 0.74-0.60(2H, m). 207 99 NMR1 (400MHz) ; 7.88 (1H, brs), 7.78 (1H, d, J=7.4Hz), 7.49-7. 36 (3H, m), 7. 33-7. 22(3H, m), 7. 20-7. 14(1H, m), 6.79-6. 70(1H, m), 6. 27-6. 18 (1H, m), 5. 36-4. 76(2H, m), 4.20-3. 79 (4H, m), 3. 10-2. 81 (3H, m), 2.68-2. 07 (5H, m). 208 99 NMR1 (400MHz) ; 7.88(1H, d, J=2.5Hz), 7.81-7. 71 (1H, m), 7.47-7. 22 (6H, m), 7.19-7. 14(1H, m), 6.78-6. 71 (1H, m), 6.26-6.21 (1H, m), 5.36-4. 76 (2H, m), 4.19-3. 81 (4H, m), 3.07-2.81 (3H, m), 2.63-2. 09 (5H, m). 209 91 NMR1 (400MHz); 8.43-8. 35 (1H, m), 7.93-7. 76(4H, m), 7.62(1H, dd, J=8.1Hz, 2.2Hz), 7.44(1H, d, J=8.1 Hz), 7.25-7. 18(1H, m), 6.91-6. 81 (1H, m), 6. 37-6. 30(1H, m), 5. 39-4. 74 (2H, m), 4. 20-3. 77 (4H, m), 3.10-2. 84 (3H, m), 2.68-2. 07 (2H, m). 210 91 NMR1 (400MHz) J 7.95(1H, dd, J=8.6Hz, 6.0Hz), 7.90-7. 79 (1H, m), 7. 38-7.17 (6H, m), 6. 89-6. 78 (1H, m), 6.36-6. 24(1H, m), 5.37-4. 71 (2H, m), 4.19-3. 78 (4H, m), 3.15-2. 83 (3H, m), 2.68-2. 07 (2H, m). 211 91 NMR1 (400MHz) : 8. 08-7. 86 (1H, m), 7. 80-7. 26 (6H, m), 7.20-7. 12(1H, m), 6.83-6. 70(1H, m), 6. 29-6. 23 (1H, m), 5.37-4. 72 (2H, m), 4. 22-3. 61 (4H, m), 3. 12-2. 84 (3H, m), 2.67-2. 07 (2H, m).

- 105 040222

212 91 NMR1 (400MHz); 8.05-7.74 (2H _; m) _; 7.70-6. 79 (7N _: , 6.30-6.09(1 N, t), 5.37-3.58(6N, t), 3.28-2.89 (ZN, t), 2.70-2 .05(2H, t). 213 91 NMR1 (400MHz) ; 8.42-8. 34(1 N, ha), 8.06-7. 74(4H, ha), 7.30-7. 18 (ZN, t), 6. 90-6. 80(1H, t), 6. 36-6. 26 (1H, ha), 5.40-4. 74 (2H, t), 4. 22-3. 75 (4H, t), 3.12-2. 83 (ZN, t), 2.69-2. 07 (2H, t). 214 91 NMR1 (400MHz); 7.98-7. 82 (2H, t), 7. 70-6. 79 (7H, t), 6. 30-6. 09 (1H, t), 5.37-3. 58 (6H, t), 3. 30-2. 91 (ZN, t), 2. 70-2. 05 (2H, t). 215 91 NMR1 (400MHz) ; 7.91-7. 78 (2H, t), 7. 53-7. 43 (2H, ha), 7.38-7. 17(4H, t), 6.89-6. 77(1H, t), 6. 37-6. 25(1H, ha), 5.38-4. 71 (2H, t), 4. 17-3. 77 (4H, t), 3. 15-2. 82 (ZN, t), 2.68-2. 07 (2H, t). 216 91 NMR1 (400MHz); 7.93-7. 80(2H, t), 7.54(1H, td, J+. 5Hz, 1.2Hz), 7.43-7. 18(6H, Ch), 6. 89-6. 79(1H, t), 6. 36-6. 24(1H, t), 5. 37-4. 73(2H, t), 4. 19-3. 78(4H, ha), 3.15-2. 84(ZN, t), 2. 69-2. 08(2H, ha). 217 91 NMR1 (400MHz) : 7.91-7. 79(1H.t), 7.60(1H, dd, J=9.2Hz, 2.5Hz), 7.49-7. 18 (6H, m), 6. 89-6. 78(1H, m), 6.36-6.24(1H, m), 5.38-4. 72(2H, m), 4.19-3. 77(4H, m), 3.14-2.84(3H, m), 2.65-2. 07 (2H, m). 218 99 NMR1 (400MHz) ; 10.22-10. 13(1H, m), 8. 47(1H, d, J=4.0Hz), 7.90-7. 62 (5H, m), 7. 49-7. 40 (2H, m), 7. 32-7.14 (4H, m), 6.79-6. 69 (1H, m), 6. 33-6. 24(1H, m), 5. 37-4. 72 (2H, m), 4. 18-3. 75(2H, m), 3.07-2. 81 (1H, m), 2. 67-2. 07 (2H, m). 219 NMR1 (400MHz); 10.55(1H, s), 7.94-7. 90(2H, m), 7.81-7. 77(2H, m), 7.53(1H, d, J=8.6Hz), 7.20(1H, d, J-11.4Hz), 7.07-7.00(2H, m), 4.80-3.60(2H, br) , 2.78-2.65 (2H, br). 220 NMR1 (500MHz); 11.25-11. 16(1H, m), 8. 31-8. 28(1H, m), 7.99-7. 78 (3H, m), 7. 59-7. 52 (2H, m), 7. 39-7. 35 (1H, m), 7.24-7.19(1H, m), 6.87-6. 80(1H, m), 5.00-4. 75(1H, m), 4.16-3. 78(2H, m), 3.07-2. 86 (1H, m), 2.64-2. 13 (5H, m). 221 220 NMR1 (500MHz) ; 11.23-11. 13(1H, m), 8. 31-8. 28(1H, m), 7.99-7. 73 (4H, m), 7. 61-7. 59(1H, m), 7. 53-7. 51 (1H, m), 7.23-7.19 (1H, m), 6.87-6. 80(1H, m), 5.00-4. 75(1H, m), 4.15-3. 98(1H, m), 3.79(1H, br d, J+0.9Hz), 3.07-2. 86 (1H, m), 2. 64-2.10(5H, m).

- 106 040222

222 220 NMR1 (500MHz) : 11 25-11. 16(1 _Hr m), 8.31-8.28(18, m), 7.99-7. 77(3H, m), 7.59-7.52(28, m), 7.39-7. 35 (1H, m), 7.24-7.19 (18, m), 6.87-6. 80(1H, tn), 5.00-4.75(18, m), 4.16-3. 78(2H, in), 3.07-2.86(18, m), 2.64-2. 13 (5H, m). 223 NMR1 (500MHz) ; 11.28-11. 18(18, m), 8.31-8.28(18, m), 7.98-7. 77 (5H, m), 7.23-7.19 (1H, m), 6.87-6. 80(1H, m), 4.99-4. 75(1H, m), 4.15-3.78(28, m), 3.07-2. 86(1H, m), 2.64-2. 12 (2H, m). 224 220 NMR1 (500MHz) ; 11.28-11. 18 (1H, m), 8.32-8.28(18, m), 7.98-7.77(58, m), 7.23-7.19 (18, tn), 6.87-6. 80(1H, m), 4.99-4. 75(1H, m), 4.15-3.78(28, m), 3.07-2. 86(1H, m), 2.64-2. 12 (5H, m). 225 220 NMR1 (500MHz) ; 10.85-10.74(18, m), 8.19-8.16(1H, m), 7.88-7. 67 (3H, m), 7. 57-7. 54(2H, m), 7.47-7.27(7H, m), 7.22-7.17(1H, m), 6.82-6.76(18, m), 4.98-4. 74(1H, m), 4. 12-3. 76(2H, m), 3.05-2.84(18, m), 2.64-2. 11 (5H, m). 226 223 NMR1 (500MHz) ; 11.41-11. 31(1H, m), 8. 84-8. 83(1H, m), 8.32-8.19(28, m), 7.98-7. 79(4H, m), 7.24-7.20(18, m), 6.88-6. 81 (1H, m), 5.00-4.75 (18, m), 4.15-3.78(28, m), 3.07-2.13 (38, m). 227 220 NMR1 (500M8z) ; 11.41-11. 31 (1H, m), 8. 84-8. 83 (1H, m), 8.32-8.19 (28, m), 7.98-7. 79 (4H, m), 7.24-7.20(18, m), 6.88-6.81 (1H, m), 5.00-4.75(18, m), 4.16-3.78(28, m), 3.07-2.13 (68, m ). 228 223 NMR1 (500M8z); 11.26-11.17(18.00), 8.30-8.26(18.00), 7.98-7. 66 (7H, m), 7.24-7.20(18, m), 6.88-6.81(18, m), 5.00-4.75(18, m), 4.15-3.78(28, m), 3.07-2.86(18, m ), 2.62-2. 13 (2H, m). 229 220 NMR1 (500M8z) ; 11.27-11.17(18, m), 8. 30-8. 27(18, m), 7.98-7. 66 (7H, tn), 7.24-7.19(18, m), 6.88-6.81(18, m), 5.00-4.76(18, m), 4.16-3.78(28, m), 3.07-2. 86(1H, m), 2.62-2.10(58, m). 230 223 NMR1(500M8z); 11.25-11.16(18, m), 8. 31-8. 28(1H, m), 7.99-7.77(38, tn), 7.63-7.52(28, nt), 7.39-7.35(18, m), 7.24-7.13(1H, m), 6.93-6.80(18, m ), 5. 00-4. 75(1H, m), 4.18-3.77(28, m), 3.22-2.12(38, m). 231 220 NMR1 (500MHz) ; 11.25-11.16(18, m), 8.31-8.28(18, m), 7.99-7.77(38, m), 7.64-7. 52 (2H, m), 7. 39-7. 35 (1H, m), 7.24-7.15 (1H, m), 6.93-6. 80(1H, m), 5.00-4.75(18, m), 4.16-3.78(28, m), 3.23-2. 10 (6H, m). 232 220 NMR1 (500M8z) : 11.01-10.89(18, m), 8.24-8.20 (1H. m), 7.88-7.68(38, m), 7.55-7.33(58, m), 7.23-7.15 (38, m), 6.84-6.77(18, m), 4.99-4.74(18, m), 4.13-3.76(28, m), 3.05-2.85(1H, m), 2.60-2.11(58, m). 233 220 NMR1 (500MHz) ; 10.97-10.87(18, m), 8.21-8.17(18, m), 7.88-7. 68(3H, m), 7.48-7.17(98, m), 6.82-6. 75 (1H, m), 4.98-4.73(18, m), 4.12-3.76(28, m), 3.05-2.84(18, m), 2.59-2.11(58, m). 234 220 NMR1 (500MHz) ; 11.14-11.03(18, m), 8.77-8.76 (18, m), 8.22-7. 17(128, m), 6. 83-6. 76(1H, m), 4.98-4.74(18, m), 4.13-3.76(2H, m), 3.06-2.85(18, m), 2.60-2.12(5H, m).

Test Cases

Test Example 1: Binding Affinity for Vasopressin V _1a and V2 Receptors

Various compounds were tested for binding affinity to vasopressin receptors with an indicator of inhibition of rat ³ H-arginine vasopressin (AVP) vasopressin V1a receptor and V2 vasopressin receptor binding (NET800, manufactured by PerkinElmer Inc., Life Sciences).

(1) Rat V _1a receptor binding inhibition test (rV _1a R) μg of V _1a receptor fractions obtained from rat liver membranes were diluted with a reaction solution (100 mM Tris-HCl (pH 8.0), 0.1% BSA , 5 mm MgCl ₂ , 1 mm EDTA) and added to each well in a 96-well plate. Compound was added to each well at various concentrations (0.3 nM to 100 nM) and 3H-AVP was added thereto in the range of 1 to 3 nM. Reactions were carried out at 4°C for 2 hours in a plate. After the reaction, V1a receptor fractions were collected using a 96-well glass filter (Unifilter GF/B), washed three times with a wash solution (10 mM Tris-HCl (pH 8.0), 5 mM MgCl ₂ , 1 mM EDTA), and then scintillation counter measured the radioactivity of ³ H-AVP.

- 107 040222 (2) Rat V ₂ receptor binding inhibition test (rV ₂ R)

Rat V ₂ receptor-expressing CHO cells (rV ₂ R-CHO) were incubated in a 24-well plate in DMEM/F12 containing 10% FBS and washed twice each well in D-PBS. A reaction solution (D-PBS containing 0.1% BSA and 0.05% sodium azide) containing the compound at various concentrations (from 0.3 to 100 nM) was added to each well, and a certain amount of ³ H- AVP (100-fold dilution). Reactions were carried out at 4°C for 2 hours in a plate. Each well was then washed twice in D-PBS and 0.1N NaOH was added to each well. Cells were harvested and 3H-AVP radioactivity was measured with a scintillation counter.

(3) Calculation of IC ₅₀

The degree of ³ H-AVP binding in the presence of the compound was calculated according to the following equation:

Degree of binding (%)=(B-NSB)/(TB-NSB)x100 (B: Amount of bound ³ H-AVP in the presence of each compound, NSB: Amount of bound ³ H-AVP in the presence of 1 μM unlabeled AVP, TB: Amount bound ³ H-AVP in the absence of 1 μM unlabeled AVP)

The concentration (IC ₅₀ ) at which each compound inhibits the amount of bound ³ H-AVP by 50% was calculated using the extent of ³ H-AVP binding and compound concentrations.

The results are presented below.

___________________________________________________________ Table 5

Binding affinity for vasopressin V _la and V ₂ receptors (1C ₅₀ : nM) Connection (EX) _{rVla RV2} 2 3.4 2.1 3 9.5 2.1 15 2.9 ι, ο 23 2.6 ι, ο 24 2.7 1.5 51 16.1 1.7 52 8.8 h, o 58 9.3 1.3 63 1.4 1.1 66 21.1 3.5 96 2.0 5.0 97 5.4 1.4 127 7.2 1.8 132 5.2 2.3 153 3.6 4.5 157 12.0 3.2 165 1.7 3.4 168 2.2 4.7 169 1.6 h, h 187 2.6 0.4

Test Case 2: Metabolic Stability Test

Reaction system and incubation

According to the methods of Obach and Jones, et al. (methods described in R. S. Obach, Drug Metab. Dispos. 1999 (27): 1350-1359 and H. Jones and J. B. Houston, Drug Metab. Dispos. 2004 (32): 973-982) the following reaction system was prepared and the metabolic stability of test compounds (compounds of the present invention and tolvaptan) using the reaction system below. Human liver microsomes manufactured by Corning Inc. were used. The test compounds were dissolved in DMSO at a concentration of 10 mmol/l, and then diluted with acetonitrile to obtain a 100 μmol/l solution for use in the test. Solutions at a concentration of 100 µmol/L were used in the experiment.

reaction system

Test compound 1 µmol/l

Human liver microsomes 1 mg/ml

Cofactors (NADPH and NADH) 1 mmol/l each

Magnesium chloride 5 mmol/l

100 mmol/l potassium phosphate buffer (pH 7.4)

Number of samples: n=4

- 108 040222

Reaction conditions

The reaction mixture without cofactors was pre-incubated at 37°C for 5 min and then the reaction was initiated by adding cofactors. The mixture was incubated for 0, 5, 10, 20, 30 and 60 minutes after the addition of the cofactors. An aliquot of the reaction mixture was taken, added to a methanol solution containing an internal standard (IS), and stirred until the reaction was subsequently stopped at a predetermined time.

Analytical method

After stopping the reaction, the mixture was separated by centrifugation, and the supernatant was injected into a liquid chromatograph coupled to the mass spectrometer (LC-MS/MS) to measure the unchanged substances remaining in the reaction system. The mass spectrometer operated in positive ion detection mode with electrospray ionization (ESI). Unchanged species and IS were determined by multiple reaction monitoring (MRM) transitions using a selected set of precursor ion and product ions.

Analysis Data

The percentage of unchanged test compounds was calculated using the following equation.

Percentage unchanged = (Ratio of peak areas of test compound and IS at t minutes after incubation)/(Ratio of peak areas of test compound and IS at 0 min)

The slope of the x-axis (incubation time) and the y-axis (log of the proportion of unchanged compounds) was calculated by a non-linear least squares method. Liver intrinsic clearance (CLint) was calculated according to the following equation:

CL _int (µl/min/mg)=-(Slope (min ^-1 ))-1(mg/ml)x1000

The results are presented below.

Table 6

Intrinsic liver clearance for test compounds as measured in the human liver microsome metabolic stability test Compounds tested CLi _nt (µl/min/mg) mean±8p EX2 <4 EXZ <4 EX15 <4 EX23 1.11±2.21 EX24 <4 EX51 <4 EX52 <4 EX58 1.81±2.10 EX63 3.10±3.58 EX66 <4 EX96 0.953±1.905 EX97 6.98±4.77 EX127 <4 EX132 <4 EX153 1.91±2.22 EX157 <4 EX165 3.61±2.43 EX168 7.48±1.50 EX169 5.09±0.32 EX187 <4 Tolvaptan 105±11 n=4 SD: Standard deviation

Test Case 3: PK Study in Mice

Test method

To compare the oral absorption properties of the compounds of the present invention with tolvaptan, a pharmacokinetic (PK) study was performed using male ICR mice. Those

- 109 040222 the compounds to be tested were suspended in a solution of 1% hydroxypropyl methylcellulose (HPMC) to a concentration of 4.5 mg/ml. The compounds of the present invention were used in the form obtained in the above examples (including amorphous form) for the test compound, or used after spray drying, if necessary.

Male ICR mice (7 weeks old) were fed and watered ad libitum and weighed on an electronic scale. Then, the test compound was orally administered at a dose of 30 mg/kg (15 ml/kg). After oral administration, blood was collected from the inferior vena cava under isoflurane anesthesia using a 1 ml heparinized syringe with a 26G injection needle. The blood was separated by centrifugation at 4°C, 3000 rpm for 10 min to obtain plasma in the supernatant. Plasma test compound concentration was measured by LC-MS/MS.

Test results

The following PK parameters were calculated using mean plasma concentrations of unchanged substances obtained from two animals at the same time point.

C _max : Peak plasma concentration (mcg/ml) t _max : Time to peak plasma concentration (h)

AUCinf: Area under the plasma concentration-time curve from administration to infinity (µg h/mL)

The results showed that the C _max and AUC _inf values for the compounds of the present invention were higher than those for tolvaptan. The results are presented below.

Table 7

Pharmacokinetic parameters after a single oral administration of 30 mg/kg of tested compounds to male ICR mice Tested Stakh t _max (hours) AUC _inf connections (µg/ml) (µg hours/mL) EX2 9.232 1 95.68 EXZ 4.819 1 38.91 EX15 6.182 1 63.07 EX23 5.420 4 71.32 EX24 4.081 4 44.05 EX51 5.068 1 53.78 EX52 5.571 1 62.68 EX58 5,888 1 44.86 EX63 4.436 1 14.41 EX66 4.553 1 38.31 EX96 5.551 4 42.96 EX97 3.131 1 8.313 EX127 7.952 1 93.76 EX132 3.589 4 56.52 EX153 5.482 1 33.96 EX157 6.212 1 80.54 EX165 7.716 1 41.49 EX168 7.111 1 40.91 EX169 5.651 1 32.25 EX187 2.043 1 5.438 Tolvaptan 0.6815 1 1.783

Test case 4.

The pharmacological effects of some compounds of the compounds of the present invention on polycystic kidney disease were evaluated according to the tests disclosed in WO 2015/056805 using a PKD animal model, PCY mice and CCK rats, and positive results were obtained for the compounds of the present invention, which confirm the test results in Test Cases 1-3.

Industrial Applicability

The vasopressin antagonist compound of the present invention may be useful in the diagnosis, prevention and/or treatment of various diseases associated with vasopressin receptors.

Claims (18)

CLAIM 1. Benzazepine compound of formula (1) 0) where R ¹ is deuterium or C _1-6 alkyl optionally substituted with 1-3 OH groups; L is a direct bond or -C(=O)-NH-; Ring A ¹ is a phenyl ring or a partially unsaturated or unsaturated 5-15-membered monocyclic, bicyclic or tricyclic heterocycle containing from 1 to 5 heteroatoms as ring atoms independently selected from the group consisting of nitrogen, oxygen and sulfur, Ring A ² is a phenyl ring or a partially unsaturated or unsaturated 5-15-membered monocyclic, bicyclic or tricyclic heterocycle containing from 1 to 5 heteroatoms as ring atoms independently selected from the group consisting of nitrogen, oxygen and sulfur; Ring A ¹ may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkyl-O—, halo and oxo; And Ring A ² may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyl-O-, optionally substituted C3-6 cycloalkyl, halogen, oxo, optionally substituted phenyl, and optionally substituted pyridyl , with the proviso that when Ring A ² contains multiple substituents on the ring carbon atoms, the substituents may be combined together with the carbon atoms to form C3-6 cycloalkyl; where in Ring A ¹ each substituent of optionally substituted C _1-6 alkyl or optionally substituted C _1-6 alkyl-O- independently represents 1-3 identical or different groups selected from the group consisting of halogen and C _1-6 alkyl- O-; in Ring A ² each substituent of optionally substituted C _1-6 alkyl or optionally substituted C _1-6 alkyl-O- is independently the same or different 1-3 halogens, the substituent of optionally substituted C _3-6 cycloalkyl is 1-3 the same or different 1-3 halogens, the optionally substituted phenyl substituent is 1-3 groups independently selected from the group consisting of halogen, C _1-6 alkyl and C _1-6 alkyl-O—, and the optionally substituted pyridyl substituent is the same or different 1-3 halogens, or its salt. 2. The compound according to claim 1, where Ring A ¹ is a phenyl ring, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing from 1 to 4 nitrogen atoms as a ring heteroatom, a partially unsaturated or unsaturated 7-15-membered a heterobicycle containing from 1 to 5 nitrogen atoms as a ring heteroatom, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing 1 or 2 oxygen atoms and at least one nitrogen atom as a ring heteroatom, or a partially unsaturated or unsaturated 5 - or a 6-membered heteromonocycle containing 1 or 2 sulfur atoms and at least one nitrogen atom as a ring heteroatom; Ring A ² is a phenyl ring, a partially unsaturated or unsaturated 5 or 6-membered heteromonocycle containing from 1 to 4 nitrogen atoms as a ring heteroatom, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing 1 or 2 as a ring heteroatom oxygen atoms, a partially unsaturated or unsaturated 7-12-membered heterobicycle containing from 1 to 3 oxygen atoms as a ring heteroatom, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing 1 or 2 sulfur atoms as a ring heteroatom, partially unsaturated or an unsaturated 7-15-membered heterobicycle containing from 1 to 5 nitrogen atoms as a ring heteroatom, a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing 1 or 2 oxygen atoms as a ring heteroatom and at least one nitrogen atom, or a partially unsaturated or unsaturated 5- or 6-membered heteromonocycle containing having as a ring heteroatom 1 or 2 sulfur atoms and at least one nitrogen atom; Ring A ¹ may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkyl-O—, halo and oxo; And Ring A ² may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkyl-O-, optionally substituted C _3-6 cycloalkyl, halo, oxo, optionally substituted phenyl and optionally substituted pyridyl, with the proviso that when Ring A ² contains multiple substituents on the ring - 111 040222 carbon atoms, substituents can be combined together with carbon atoms to form C ₃ . ₆ cycloalkyl; where in Ring A ¹ each substituent of optionally substituted C _1-b alkyl or optionally substituted C _1-b alkyl-O- independently represents 1-3 identical or different groups selected from the group consisting of halogen and C _1-b alkyl- O-; in Ring A ² each substituent of optionally substituted C _1-b alkyl or optionally substituted C _1-b αalkyl-O- independently represents the same or different 1-3 halogens, the substituent of optionally substituted C _3-b cycloalkyl represents 1-3 identical or different 1-3 halogens, the optionally substituted phenyl substituent is 1-3 groups independently selected from the group consisting of halogen, C ₁ . ₆ alkyl and C ₁ . ₆ αalkyl-O-, and the optionally substituted pyridyl substituent is the same or different 1-3 halogens, or a salt thereof. 3. The compound according to claim 1 or 2, wherein Ring A ¹ is benzene, pyridine, pyrazine or tetrahydroisoquinoline and Ring A ¹ may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C ₁ . ₆ alkyl optionally substituted with C ₁ . ₆ αalkyl-O-, halogen and oxo; Ring A ² is benzene, pyridine, furan, thiophene, or tetrahydroisoquinoline, and Ring A ² may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C ₁ . ₆ alkyl optionally substituted with C ₁ . _b alkyl-O-, optionally substituted with C ₃ . _b cycloalkyl, halogen, oxo, optionally substituted phenyl and optionally substituted pyridyl, where in Ring A ¹ each substituent is optionally substituted C ₁ . ₆ alkyl or optionally substituted C ₁ . _b alkyl-O- independently represents 1-3 identical or different groups selected from the group consisting of halogen and C ₁ . ₆ alkyl-O-; in Ring A ² each substituent of optionally substituted C1.6 alkyl or optionally substituted C1.bαalkyl-O- independently represents the same or different 1-3 halogens, the substituent of the optionally substituted C3.b-cycloalkyl represents 1-3 identical or different 1-3 halogens, the optionally substituted phenyl substituent is 1-3 groups independently selected from the group consisting of halogen, C1.6 alkyl and C1_bαalkyl-O-, and the optionally substituted pyridyl substituent is the same or different 1-3 halogens, provided that, if Ring A ² contains many substituents on its carbon atoms, then the substituents can combine together with carbon atoms to form C3_ _b cycloalkyl; or its salt. 4. A compound according to any one of claims 1 to 3, wherein R ¹ is C ₁ . ₆ αkyl substituted with 1-3 OH groups, or a salt thereof. 5. A compound according to any one of claims 1 to 4, wherein Ring A ¹ is benzene optionally substituted with halogen, C ₁ . ₆ alkyl, halo-C ₁ . ₆ alkyl, C ₁ . ₆ alkyl-O-, halo-C ₁ . _b alkyl-O-, C ₁ . ₆ alkyl-OC ₁ . _b αalkyl-O-, halogen-C ₁ . _b alkyl-OC ₁ . _b alkyl-O-, C ₁ . _b αalkyl-O-halogen-C ₁ . _b alkyl-O- or halo-C ₁ . ₆ alkylO-halogen-C ₁ _ _b αalkyl-O-; pyridine optionally substituted with halogen; pyrazine; or tetrahydroisoquinoline optionally substituted with oxo; And Ring A ² is benzene optionally substituted with 1-3 groups independently selected from the group consisting of halo, C ₁ . ₆ alkyl, halo-C ₁ _ _b alkyl, C ₁ . _b alkyl-O-, halo-C ₁ _ _b αalkyl-O-, C ₃ . _b cycloalkyl, optionally substituted phenyl and pyridyl, wherein the optionally substituted phenyl is phenyl optionally substituted with halogen, C ₁ . ₆ αalkyl, halogen-C ₁ . ₆ alkyl, C ₁ . ₆ alkyl-O- or halo-C ₁ . _b alkyl-O-; pyridine optionally substituted with C ₁ . ₆ alkyl, halo-C ₁ . _b alkyl or phenyl; furan optionally substituted with C ₁ . ₆ alkyl; thiophene optionally substituted with C ₁ . ₆ αkyl; or tetrahydroisoquinoline optionally substituted with 1-3 groups independently selected from the group consisting of halo, C ₁ . ₆ alkyl and oxo, provided that if the tetrahydroisoquinoline contains many C ₁ . _b alkyl groups on their ring carbons, then C ₁ . _b αalkyl groups can combine together with carbon atoms to form C ₃ . _b cycloalkyl, or its salt. 6. The compound according to any one of claims 1-5, where R ¹ is C ₁ _ _b αkyl substituted with 1-3 OH groups, Ring A ¹ is benzene optionally substituted with halogen, C ₁ _ ₆ alkyl, C ₁ . ₆ alkyl-O- or C ₁ _ ₆ alkyl-OC ₁ . ₆ alkyl-O-; or pyridine optionally substituted with halogen, and Ring A ² is benzene optionally substituted with 1-3 groups independently selected from the group consisting of halo, C ₁ . ₆ alkyl, halo-C ₁ - ₆ alkyl, C ₁ . ₆ alkyl-O-, halo-C ₁ . ₆ αlkyl-O-, C ₃ . ₆ cycloalkyl, optionally substituted phenyl and pyridyl, wherein the optionally substituted phenyl is phenyl optionally substituted with halogen, C ₁ . ₆ αalkyl, halogen-C ₁ . ₆ alkyl, C ₁ . ₆ alkyl-O- or halo-C ₁ . ₆ alkyl-O-, or a salt thereof. 7. A compound according to any one of claims 1 to 5, wherein R ¹ is C ₁ . ₆ αkyl substituted with 1-3 OH groups, Ring A ¹ is benzene optionally substituted with halogen, C ₁ _ ₆ alkyl-O- or ha - 112 040222 logen-C _1-6 alkyl-O-; or pyridine, and Ring A ² is benzene optionally substituted with 1-3 groups independently selected from the group consisting of halogen, C _1-6 alkyl, halo-C _1-6 alkyl and phenyl optionally substituted with halogen; pyridine optionally substituted with phenyl or halo-C _1-6 alkyl; or tetrahydroisoquinoline optionally substituted with 1-3 groups independently selected from the group consisting of halogen and oxo, or a salt thereof. 8. A compound according to any one of claims 1 to 7, wherein L is -C(=O)-NH-, or a salt thereof. 9. A compound or salt thereof selected from the following group of compounds: - 113 040222 10. A vasopressin receptor antagonist, which is a compound according to any one of claims 1 to 9 or a salt thereof. 11. Pharmaceutical composition for the treatment and/or prevention of a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, syndrome of inappropriate vasopressin secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, kinesia, water metabolism disorder and ischemic disorder, comprising as an active ingredient a compound according to any one of claims 1 to 9 or a salt thereof. 12. Pharmaceutical composition for diagnosing a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, syndrome of inappropriate vasopressin secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory insufficiency, kinesia, water metabolism disorders and ischemic disorders, comprising as an active ingredient a compound according to any one of claims 1 to 9 or a salt thereof. 13. A method for treating and/or preventing a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, syndrome of inappropriate vasopressin secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, kinesia, water metabolism disorder, and ischemic disorder, comprising administering to a subject a compound according to any one of claims 1 to 9, or a salt thereof. 14. Method for diagnosing a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, syndrome of inappropriate vasopressin secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure , kinesia, water metabolism disorders, and ischemic disorders, comprising administering to a subject a compound according to any one of claims 1 to 9, or a salt thereof. 15. Use of a compound according to any one of claims 1 to 9 or a salt thereof for the treatment and/or prevention of a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease , syndrome of inappropriate secretion of vasopressin, cirrhosis of the liver, hyponatremia, hypokalemia, diabetes, circulatory failure, kinesia, impaired water metabolism and ischemic disorders. 16. Use of a compound according to any one of claims 1 to 9 or a salt thereof for diagnosing a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease, inappropriate secretion syndrome vasopressin, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, kinesia, water metabolism disorder and ischemic disorder. 17. The use of a compound according to any one of claims 1 to 9 or a salt thereof for the manufacture of a medicament for the treatment and/or prevention of a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure , polycystic kidney disease, syndrome of inappropriate vasopressin secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, kinesia, disorders - 114 040222 water metabolism and ischemic disorders. 18. The use of a compound according to any one of claims 1 to 9 or a salt thereof for the manufacture of a medicament for diagnosing a disease selected from the group consisting of Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease , syndrome of inappropriate secretion of vasopressin, cirrhosis of the liver, hyponatremia, hypokalemia, diabetes, circulatory failure, kinesia, impaired water metabolism and ischemic disorders.