BRPI0614724A2 - ep2 receptor agonists - Google Patents

Abstract

EP2 RECEPTOR AGONISTS. A compound of formula (III), or a salt, solvate and chemically protected form thereof, wherein: R5 is an optionally substituted group of C ~ 5-20 ~ aryl or C ~ 4 ~ -C ~ 20 ~ alkyl; L 'is a single bond, -O- or -C (= O) -; A is selected from the group consisting of: formulas (i) (ii) (iii), where X and Y are selected from the group consisting of: O and CR ^ 3 ^; S and CR ^ 3 ^; NH and CR ^ 3 ^; NH and N; O and N; S and N; N and S; and N and O, and where the dotted lines indicate a double bond at the appropriate place, and where Q is either N or CH; D is selected from: formulas (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix); B is selected from the group consisting of: formulas (A) (B), where R ^ P6 ^ is selected from fluorine and chlorine; and R 2 2 is: (i) -CO ~ 2 ~ H; (ii) -CONH ~ 2 ~; (iii) - CH ~ 2 ~ -OH; or (iv) tetrazol-5-yl.

Description

"EP2 RECEIVER AGONISTS"

This invention relates to deEP2 receptor agonists, pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions to treat various diseases.

Background of the Invention

Prostanoids comprise prostaglandins (PGs) and etromboxanes (Txs) and their receptors fall into different five classes (DP, EP, FP, IP and TP) based on their sensitivity to the five naturally occurring prostanoids, PGD2, PGE2, PGF2a, PGl2 and TxA2, respectively (Coleman, RA, Prostanoid Receptors, IUPHAR Compendium of Receptor Characterization and Classification, 2nd Edition, 338-353, ISBN 0-9533510-3-3, 2000). EP receptors (for which endogenous oligant is PGF2) were subdivided into four types called ΕΡχ, EP2, EP3 and EP4. These four types of EP receptors have been cloned and are distinct at both molecular and pharmacological levels (Coleman, R.A., 2000).

EP2 agonists have been shown to be effective in treating various conditions including (but not limited to) dysmenorrhea (WO 03/0374330), premature birth (GB 2 293 101), glaucoma (WO 03/040126), ocular hypertension ( WO 03/040126), immunological disorders (Nataraj, C. et al., J. Clin. In-vest., 108, 1229-1235 (2001)), osteoporosis (WO 98/27976, WO01 / 46140), asthma ( Tilley, et al., Am. J. Physiol. Lung CellMol. Physiol., 284, L599-606 (2003)), Allergy, Bone Disease (WO 02/24647), Fracture Regeneration (WO 98/27976, WO02 / 24647), male sexual dysfunction (WO 00/40248), female sexual dysfunction (US Patent 6,562,868), periodontal disease (WO 00/31084), gastric ulcer (US Patent 5,576,347) and kidney disease (WO 98/34916).

Co-pending application GB 0329620.9 filed December 22, 2003 and a corresponding US provisional application filed December 24, 2003, which are hereby incorporated by reference, have shown that EP2 agonists inhibit lymphocyte activation and release. proinflammatory decitocins of alveolar macrophages. In addition, EP2 activation inhibits monocyte and deneutrophil activation.

Thus, EP2 agonists should prove useful in the treatment of inflammatory and immunological disorders such as psoriasis, dermatitis, rheumatoid arthritis, multiple sclerosis, scleroderma, transplant rejection, allergy, systemic lupus erythematosus, vasculitis, diabetes mellitus. - Type 1 and inflammatory pulmonary diseases such as chronic obstructive pulmonary disease, asthma, water respiratory distress, and cystic fibrosis.

In addition, EP2 agonists may also be used in the treatment of fibrosis, including, but not limited to, idiopathic pulmonary fibrosis, scleroderma and systemic sclerosis, postoperative fibrosis following trabulectomy, recovery and liver regeneration following cirrhosis, liver disease, toxicity, cancer or renal fibrosis. EP2 agonists may also be used to prevent the conversion of fibroblast to myofibroblast to treat asthma and other fibrotic pulmonary diseases. EP2 agonists may also be used to maintain patent ductus arteriosus in children with congenital heart disease.

Compounds that combine the properties of EP2 receptor agonists and EP4 receptor antagonists may prove useful in the treatment of various diseases including myometrial disorders, bone disorders including osteoporosis, osteoarthritis, allergic and immunological disorders. , such as psoriasis, transplant rejection, and so on, inflammatory diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease and acute respiratory disease syndrome, and fibrotic pulmonary diseases.

Summary of the Invention

A first aspect of the present invention provides a compound of formula (I):

<formula> formula see original document page 4 </formula>

or a salt, solvate and chemically protected form, wherein

R5 is an optionally substituted group of C5 -C20 aryl or C4 -C20 alkyl;

L is a single bond, -0- or -C (= 0) -;

A is selected from the group consisting of: <formula> formula see original document page 5 </formula>

where XeY are selected from the group consisting of: 0 and CR3; S and CR3; NH and CR3; NH and N; O and N; S and Ν; N eS; and N and O, and where the dotted lines indicate a double bond at the appropriate location; and where Q is either N or CH;

R 3 is selected from H, F, Cl and optionally substituted groups of C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 1-7 aryl-C 1-4 alkyl;

R4 is selected from H, F, Cl and optionally substituted C1-4 alkyl, C1-4 alkoxy, C5-7 aryl and C1-7 aryl-C1-4 alkyl groups;

R 6 is selected from H, F, Cl and optionally substituted groups of C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl;

D is selected from: <formula> formula see original document page 6 </formula>

B is selected from the group consisting of:

<formula> formula see original document page 6 </formula>

where Rn 'is selected from H and C1-4 alkyl, where one of Rp3 and Rp4 is -Cm alkylene-R2 and the other of Rp3 and Rp4 is H, m and η may be Ooul, and m + η = 1 or 2; Additionally when Rp3 is -Cm alkylene-R2, m may also be 2 or 3, and m + η = 1, 2, 3 or 4, and when R2 is tetrazol-5-yl, m + η may be 0; or where B is selected from the group consisting of:

<formula> formula see original document page 6 </formula> <formula> formula see original document page 7 </formula>

m + η can also be equal to 0;

or where one of Rp3 and Rp4 is -O-CH2-R2, and the other of Rp3e and Rp4 is Η, η is 0;

R11 is H or optionally substituted C1-4 alkyl;

R2 is:

(i) -CO 2 H (carboxy);

(ii) -CONH2;

(iii) -CH 2 -OH; or

(iv) tetrazol-5-yl.

A second aspect of the present invention provides a compound of formula (II):

<formula> formula see original document page 7 </formula>

or a salt, solvate and chemically protected form, wherein

R5 is an optionally substituted group of C5 -C20 aryl or C4 -C20 alkyl;

L 'is a single bond, -0- or -C (= 0) -;

A is selected from the group consisting of: <formula> formula see original document page 8 </formula>

where XeY are selected from the group consisting of: 0 and CR3; S and CR3; NH and CR3; NH and N; 0 and N; S and Ν; N eS; and N and 0, and where the dotted lines indicate a double bond at the appropriate location; and where Q is either N or CH;

R 3 is selected from H, F, Cl and optionally substituted groups of C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl;

R4 is selected from H, F, Cl and optionally substituted C1-4 alkyl, C1-4 alkoxy, C5-7 aryl and C1-7 aryl-C1-4 alkyl groups;

R 6 is selected from H, F, Cl and optionally substituted groups of C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 1-7 aryl-C 1-4 alkyl;

D is selected from: <formula> formula see original document page 9 </formula>

B is selected from the group consisting of:

<formula> formula see original document page 9 </formula>

where Rn is selected from H and C1-4 alkyl, where one of Rp3 and Rp4 is -Cm alkylene-R2 and the other of Rp3 and Rp4 is H, m and η may be O or 1, at + n = lou2; Additionally when Rp3 is -Cm alkylene-R2, m may also be 2 or 3, and m + η = 1, 2, 3 or 4, and when R2 is tetrazol-5-yl, m + η may be 0;

and where B is selected from the group consisting of: <formula> formula see original document page 10 </formula>

m + η may also be equal to zero;

or where one of Rp3 and Rp4 is -O-CH2-R2, and the other of Rp3e and Rp4 is Hf η is 0;

R11 is H or optionally substituted C1-4 alkyl;

R2 is:

(i) -CO 2 H (carboxy);

(ii) -CONH2;

(iii) -CH 2 -OH; or

(iv) tetrazol-5-yl.

A third aspect of the present invention provides a compound of formula (III):

<formula> formula see original document page 10 </formula>

or a salt, solvate and chemically protected form, wherein:

R5 is an optionally substituted group of C5 -C20 aryl or C4 -C20 alkyl;

L 'is a single bond, -0- or -C (= 0) -;

A is selected from the group consisting of: <formula> formula see original document page 11 </formula>

where X and Y are selected from the group consisting of: 0 and CR3; S and CR3; NH and CR3; NH and N; Oe N; S and Ν; N eS; and N and 0, and where the dotted lines indicate a double bond at the appropriate location; and where Q is either N or CH;

R3 is selected from H, F, Cl and optionally substituted C1-4 alkyl, C1-4 alkoxy, C5-7 aryl and C1-7 aryl-C1-4 alkyl groups;

R 4 is selected from H, F, Cl and optionally substituted groups of C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl;

R 6 is selected from H, F, Cl and optionally substituted groups of C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl;

D is selected from: <formula> formula see original document page 12 </formula>

B is selected from the group consisting of where Rp6 is selected from fluorine and chlorine;

where one of Rp3 and Rp4 is -Cm alkylene-R2 and the other of Rp3 and Rp4 is H, m and η may be Ooul, at + n = lou2; Additionally when Rp3 is -Cm alkylene-R2, m may also be 2 or 3, and m + η = 1, 2, 3 or 4, and when R2 is tetrazol-5-yl, m + η may be 0; or where one of Rp3 and Rp4 is -OCH2-R2, and the other of Rp3 and Rp4 is Η, η is 0;

R11 is H or optionally substituted C1-4 alkyl;

R2 is:

(i) -CO 2 H (carboxy)

(ii) -CONH2;

(iii) -CH 2 -OH; or

(iv) tetrazol-5-yl.

A fourth aspect of the invention provides a compound of formula (IV):

<formula> formula see original document page 13 </formula>

or a salt, solvate and chemically protected form, in which:

Wherein T is selected from 0 and S, R1 represents one or more optional substituents selected from F, Cl and optionally substituted groups of C1-4 alkyl, C1-4 alkoxy, C5-7 aryl and C5-7 aryl. C1-4 alkyl; and R represents one or more optional substituents selected from F, Cl and optionally substituted groups of C 3-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl;

D is selected from:

<formula> formula see original document page 14 </formula>

B is selected from the group consisting of: <formula> formula see original document page 15 </formula>

where Rn 'is selected from H and C1-4 alkyl;

where Rp6 is selected from fluorine and chlorine;

where one of Rp3 and Rp4 is -Cm alkylene-R2 and the other of

Rp3 and Rp4 is H, m and η may be Ooul, and m + η = 1 or 2; Additionally when Rp3 is -Cm alkylene-R2, m may also be 2 or 3, and m + η = 1, 2, 3 or 4, and when R2 is tetrazol-5-yl, m + η may be 0; and where B is selected from the group consisting of:

m + η can be equal to 0;

or where one of Rp3 and Rp4 is -O-CH2-R2, and the other of Rp3e and Rp4 is Η, η is 0;

R11 is H or optionally substituted C1-4 alkyl;

(i) -CO 2 H (carboxy): (ii) -CONH 2;

(iii) -CH 2 -OH; or

(iv) tetrazol-5-yl.

A fifth aspect of the present invention provides a compound of formula (V):

<formula> formula see original document page 16 </formula>

or a salt, solvate and chemically protected form, in which:

R5 is an optionally substituted group of C5-20 aryl or C4-20 alkyl;

L 'is a single bond, -0- or -C (= 0) -;

B is selected from the group consisting of:

<formula> formula see original document page 16 </formula>

where Rn 'is selected from H and C1-4 alkyl, where Rp6 is selected from fluorine and chlorine, where one of Rp3 and Rp4 is -Cm alkylene-R2 and the other of Rp3 and Rp4 is H, m is 1; and, additionally, when R 3 is -C m -alkyl-R 2, m may also be 2 or 3, and when R 2 is tetrazol-5-yl, m may be 0; and where B is selected from the group consisting of:

m may also be 0;

or one of Rp3 and Rp4 may be -O-CH 2 -R 2, and the other of Rp3 and Rp4 is H;

R11 is H or optionally substituted C1-4 alkyl;

R2 is:

(i) -CO 2 H (carboxy);

(ii) -CONH2;

(iii) -CH 2 -OH; or

(iv) tetrazol-5-yl.

Therefore, A (if present) can be one of the following groups:

<formula> formula see original document page 17 / formula> <formula> formula see original document page 18 / formula>

A sixth aspect of the present invention provides a compound of formulas (I) to (V) or a pharmaceutically acceptable salt thereof for use in a method of therapy.

A seventh aspect of the present invention provides a pharmaceutical composition comprising a compound of formulas (I) to (V) as defined in the first to fifth aspects or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.

An eighth aspect of the present invention provides the use of a compound of formulas (I) to (V) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of an agonist-relieved condition of an EP2 receptor.

A ninth aspect of the present invention provides a method for treating a condition that can be alleviated by antagonism of an EP2 receptor, which method comprises administering to a patient in need of treatment an effective amount of a compound of formulas (I) to be treated. (V), or a pharmaceutically effective salt thereof.

In the eighth and ninth aspects of the invention, the EP2 receptor agonism may be selective, or may be accompanied by EP4 receptor antagonism.

Conditions that may be alleviated by agonism of an EP2 receptor are discussed above, and include, in particular, dysmenorrhea, premature birth, glaucoma, ocular hypertension, immune disorders, osteoporosis, asthma, chronic obstructive pulmonary disease, allergy, bone disease, fracture regeneration, male sexual dysfunction, female sexual dysfunction, infertility, periodontal disease, ulceragastric, kidney disease, and psoriasis.

Conditions that may be alleviated by EP2e receptor agonism and EP4 receptor antagonism are discussed above, and include, in particular, myometrial disorders, bone diseases including osteoporosis and osteoarthritis, allergic and immunological diseases, such as comopsoria, transplant rejection, and asthma, diseases. inflammatory diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease and acute respiratory disease syndrome, and fibrotic pulmonary diseases.

EP receptor agonists are known to be capable of inhibiting tea cell activation by proinflammatory cytokine release, although the EP receptor involved in mediating these effects on human T cells has not been previously defined. Some of the present inventors have found that EP2 agonists inhibit the activation (proliferation) of human T cells and inhibit the release of multiple proinflammatory cytokines, including interleukin 2 (IL-2), tumor necrosis factor (TNFα), and interferon. -ron gamma (IFNy) as described in the co-pending North American and International applications under the title "EP2 Agonists" filed December 22, 2004 in the name of Bor-man, RA et al. (W0 2005 / 06144 9), which are incorporated herein by reference. This activity profile emphatically suggests that EP2 receptor agonists will be useful in the treatment of immune and inflammatory disorders including, but not limited to, psoriasis, psoriatic arthritis, dermatitis, rheumatoid arthritis, transplant rejection, inflammatory bowel disease, systemic lupus erythematosus. , Grave's disease, scleroderma, multiple sclerosis, Type I diabetes mellitus, and transplant rejection, and in particular psoriasis (Griffiths, C., Current Drugs Targets - Inflammati-on & Allergyr 3, 157-161, (2004); Lebwohl, M., Lancet, 361,1197-1204 (2003); Salim, A. & Emerson, R. Curr. Opin. Inves-Drugs, 2 (11), 1546-8 (2001)). Therefore, another condition that can be alleviated by agonism of an EP2 receptor is psoriasis.

In addition, some of the inventors of the present invention have also shown that EP2 receptor agonists inhibit the release of proinflammatory cytokine, human monocyte TNFα, and alveolar macrophages, as described in US and co-pending applications. Internationals under the title "EP2 Agonists" filed December 22, 2004 in the name of Borman, RA et al. (WO 2005/061449), which are incorporated herein by reference. This reactivity profile brings further evidence to the view that EP2 receptor agonists will be useful in the treatment of immune and immune disorders and in particular inflammatory lung diseases (including but not limited to asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome). In addition, aspects of the present invention pertain to the use of EP2 agonists to treat conditions attenuated by inhibition of IL-2 TNFα and / or IFNγ production and to the use of an EP2 agonist. in the preparation of a medicament for treating a condition attenuated by inhibiting IL-2 production.

The present invention also provides methods for stimulating EP2 receptors and / or inhibiting IL-2, TNFα and / or IFNγ production in vitro or in vivo, comprising contacting a cell with an effective amount of a first compound. aspect of the present invention.

The compounds of the present invention may be subjected to assays to determine whether they act as antagonists of an EP4 receptor. Suitable assay methods are described in Example 12 below.

The present invention also provides methods of effecting EP2f agonism and possible antagonism of EP4 receptors, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of formulas (I) to (V).

In some embodiments, the compounds described above, which function as EP2 agonists, may be selectable as against modulation of one or more of the other three EP receptors, i.e. EPi, EP3 and EP4. Such selectivity allows to target the effect of the compounds of the invention, with possible benefits in the treatment of certain conditions.

Definitions

Monodentate Group (i.e. groups with a covalent attachment point)

Alkyl: The term "alkyl" as used herein belongs to a monovalent moiety obtained by removal of a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (less than otherwise specified), which may be aliphatic or alicyclic, and which may be saturated or unsaturated. Thus, the term "alkyl" includes the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, etc. subclasses, discussed below.

In the context of alkyl groups, the suffixes (e.g., C 1-4, C 1-7, C 1-20, C 2-1 C 3-7) denote the number of carbon atoms, or range of the number of carbon atoms. For example, the term "C1-4 alkyl" as used herein belongs to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of C1-4 alkyl ("lower alkyl"), C1-7 alkyl and C4-20 alkyl groups. Note that the first suffix may vary according to other limitations; for example, for unsaturated alkyl groups, the first prefix must be at least 2; for cyclic alkyl groups, the first suffix must be minus 3; etc.

Examples of saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), hexyl (C6), heptyl (C7), octyl (C8), nonyl (C9), decyl (C10), undecyl (Cn), dodecyl (C12), tridecyl (C13), tetradecyl (C14), pentadecyl (C15) and eicodecyl (C20) examples. include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), n-butyl (C4), n-pentyl (amyl) (C5), n-hexyl (C6), enheptyl (C7).

Examples of saturated branched alkyl groups include isopropyl (C3), isobutyl (C4), s-butyl (C4), tert-butyl (C4), isopentyl (C5), and neo-pentyl (C5).

Alkenyl: The term "alkenyl" as used herein belongs to an alkyl group having one or more carbon-carbon double bonds. Examples of C 2-4 alkenyl groups include C 2-4 alkenyl, C 2-7 alkenyl and C 2-20 alkenyl. Examples of alkenyl groups include, but are not limited to, ethinyl (vinyl -CH = CH 2), 1-propenyl (-CH = CH-CH 3), 2- propenyl (allyl, -CH-CH = CH 2), isopropenyl (1-methylvinyl, -C (CH 3) = CH 2), butenyl (C 4), pentenyl (C 5), and hexenyl (C 6).

Alkynyl: The term "alkynyl" as used herein belongs to an alkyl group having one or more triple bonds. Examples of groups of alkynyl groups include C 2-4 alkynyl, C 2-7 alkynyl and C 2-20 alkynyl. Examples of alkynyl groups include, but are not limited to, ethinyl (ethinyl, C ^CH), and 2-propynyl (propargyl, -CHCHC2CH).

Cycloalkyl: The term "cycloalkyl" as used herein belongs to an alkyl group which is also a cycloalkyl group; that is, a monovalent moiety obtained by removal of a hydrogen atom from a carbocyclic alicyclic ring atom of a carbocyclic compound, the carbocyclic ring of which may be saturated or unsaturated, whose fraction has from 3 to 7 carbon atoms (unless otherwise mode), including from 3 to 7 ring atoms. Thus, the term "cycloalkyl" includes the cycloalkenyl eccloalquinyl subclasses. Preferably, each ring has from 3 to 7 atoms in the ring. Examples of cycloalkyl groups include C 3-7 cycloalkyl.

Examples of cycloalkyl groups include, but are not limited to, those derived from:

Monocyclic hydrocarbon compounds: cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (C6), cycloheptane (C7), methylcyclopropane (C5), methylcyclobutane (C5), dimethylcyclobutane (C5) ), (C6) methylcyclopentane, (C7) dimethylcyclopentane, (C7) methylcycloexane, (C8) dimethylcyclohexane, (C10) menthane;

unsaturated monocyclic hydrocarbon compounds:

cyclopropene (C3), cyclobutene (C4), cyclopentene (C5), cyclohexene (C6), methylcyclopropene (C4), dimethylcyclopropene (C5), methylcyclobutene (C6), methylcyclopentene (C6), dimethylcyclopentene (C6) ), (C7) methylcyclohexene, (C8) dimethylcyclohexene;

saturated polycyclic hydrocarbon compounds:

thiane (C10), carane (C10), pinane (C10), bornane (C10), norcarane (C7), norpinane (C7), norbornane (C7), ada-mantano (C10), decalin (decai.dronaphthalene) (C10 );

unsaturated polycyclic hydrocarbon compounds: camphene (C10), limonene (C10), pinene (C10).

Heterocyclyl: The term "heterocyclyl" as used herein belongs to a monovalent moiety obtained by removal of a hydrogen atom from a ring atom of a heterocyclic compound whose fraction has 3 to 20 ring atoms (unless otherwise specified) of which 1 to 10 are heteroatoms in the ring. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are non-ring heteroatoms.

In this context, the suffixes (e.g. C3-20, C3-7, C5-6, etc.) denote the number of ring atoms, or the number of ring atoms, whether carbon atoms or hetero atoms. For example, the term "C 5-6 heterocyclyl" as used herein belongs to a heterocyclyl group having 5 or 6 ring atoms. Examples of heterocyclyl group groups include C3-20 heterocyclyl, C5-20 heterocyclyl, C3-15 heterocyclyl, C5-15 heterocyclyl, C5-12 heterocyclyl, C3-10 heterocyclyl, C5-10 heterocyclyl, C3-7 heterocyclyl, C5-7 heterocyclyl, and heterocyclyl. C5_6.

Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from: Ni: (C3) aziridine (C4), pyrrolidine (tetrahydropyrrol) (C5), pyrroline (e.g. 3-pyrroline, 2,5-dihydropyrrol) ) (C5), 2H-pyrrol or 3H-pyrrol (isopyrrol, isoazol) (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine (C7), (C4) oxetane, (C5) oxolane (C5), (C5) oxol (dihydrofuran), (C6) oxane (C6) dihydropyrane, (C6) pyran, (C7) oxepine;

Si: (C3) thiyrane, (C4) thietane, (C5) thiolane (C5), thiophane (tetrahydrothiopyran) (C6), (C7) tympan;

O 2: dioxolane (C6), dioxane (C6), and dioxepane (C7);

O3: trioxane (C6);

N 2: imidazolidine (C 5), pyrazolidine (diazolidine) (C 5), imidazoline (C 5), pyrazoline (dihydropyrazole) (C 5), pi-perazine (C 6);

N101: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (C6);

N1S1: thiazoline (C5), thiazolidine (C5), thiomorpholine (C6);

N20: oxadiazine (C6);

O1S1: oxathiol (C5) and oxathian (thioxane) (C6); and

NO1S1: oxathiazine (C6).

Aryl: The term "aryl" as used herein belongs to a monovalent moiety obtained by removal of a hydrogen atom from an atom of an aromatic ring of an aromatic compound, the fraction of which has 3 to 20 ring atoms (unless otherwise noted). specified). Preferably, each ring has from 5 to 7 ring atoms.

In this context, suffixes (e.g., C320, C5-7, C5-6, etc.) denote the number of ring atoms, or a ring number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C5-6 aryl" as used herein belongs to an aryl group having 5 or 6 ring atoms. Examples of aryl group groups include C3-20 aryl, C5-20 aryl / C5-15 aryl, aryl C5-12, C5-10 aryl, C5-7 aryl, C5-6 aryl, C5 aryl and C6 aryl.

The atoms in the ring can all be carbon atoms, as in "carbaryl groups". Examples of carbaryl groups include C3-20 carb, C5-20 carb, C5-15 carb, C5-12, C5-10, C5-7, C5-6, C5, and C6.

Examples of carbaryl groups include, but are not limited to, those derived from benzene (ie phenyl) (C6), naphthalene (C10), azulene (C10), anthracene (C14), phenanthrene (C14), naphtacene (C16), and pyrene (C16).

Examples of aryl groups comprising fused rings, at least one of which is an aromatic ring, include, but are not limited to, indane (e.g. 2,3-dihydro-1H-indene) (C 9), (C 9) indene groups. ), isoindene (C9), tetraline (1,2,3,4-tetrahydronaphthalene (C 10), acenaphthene (C 12), fluorene (C 13), phenalene (C 13), acefenanthrene (C 15), eaceantrene (C 16).

Alternatively, ring atoms may include one or more heteroatoms, such as "heteroaryl groups". Examples of heteroaryl groups include C3-20 heteroaryl, C5-20 heteroaryl, C5-15 heteroaryl, C5-12 heteroaryl, C5-10 heteroaryl, C5-7 heteroaryl, C5-6 heteroaryl, C5 heteroaryl and C6 heteroaryl .

Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: Νχ: pyrrol (azole) (C5), pyridine (azine) (C6);

Oi: furan (oxol) (C5);

Si: thiophene (thiol) (C5);

NiOi: oxazole (C5), isoxazole (C5), isoxazine (C6);

N 2 O 1: oxadiazole (furazane) (C 5);

NO3: oxatriazole (C5);

N1S1: thiazole (C5), isothiazole (C5);

N2: imidazole (1,3-diazole) (C5), pyrazol (1,2-diazole) (C5), pyridazine (1,2-diazine) (C6), pyrimidine (1,3-diazine) (C6), (C 6) pyrazine (1,4-diazine);

N3: triazole (C5), triazine (C6); and

N 4: tetrazole (C 5).

Examples of heteroaryl groups, including fused rings, include, but are not limited to:

C9 (with 2 fused rings) derived from benzofuran (Οι), isobenzofuran (Oi), indole (Ni), isoindole (Ni), indolinezine (Ni), indoline (Ni), isoindoline (Ni), purine (N4) (e.g., adenine, guanine), benzimidazole (N2), indazole (N2), benzoxazole (N1O1), benzisoxazole (N1O1), benzodioxol (O2), benzofuran (N2Oi) / benzotriazole (N3), benzothiofuran (Si), benzothiazole ( N1S1), benzothiadiazole (N2S);

Cio (with 2 fused rings) derived from chromene (Οι), isochromene (Οι), chroman (Οι), isochroman (Οι), benzo dioxane (O2), quinoline (Ni), isoquinoline (Ni), quinolizine (Ni) benzoxazine (N1O1), benzodiazine (N2), pyridopyridine (N2), quinoxaline (N2), quinazoline (N2), cinnoline (N2), phthalazine (N2), naphthyridine (N2), pteridine (N4); with 2 fused rings) derived from benzodiazepine (N 2);

C13 (with 3 fused rings) derived from carbazole (Ni), dibenzofuran (Oi), dibenzothiophene (Si), carboline (N2), perimidine (N2), pyridoindole (N2); and,

C14 (with 3 fused rings) derived from acridine (Ni), xanthene (Oi), thioxanthene (Si), oxantrene (O2), phenoxyl tiline (OiSi), phenazine (N2), phenoxazine (NiOi), phenothiazine (NiSi) , thiantrene (S2), phenanthridine (Ni), phenanthroline (N2), phenazine (N2).

If a heteroaryl or heterocyclyl group contains a ring nitrogen atom, this ring atom, if possible, may be in an oxidized state, such as an N-oxide.

The above groups, whether alone or part of another substituent, may themselves optionally be substituted with one or more selected groups of themselves, the monodentent substituents added and listed below on alkoxyethylene.

Halo: -F, -Cl, -Br, and -I.

Hydroxy: -OH.

Ether: -OR, where R is an ether substituent, for example, a C1-7 alkyl group (also referred to as a C1-7 alkoxy group discussed below), a C3-20 heterocyclyl group (also referred to as a C3-20 heterocyclyloxy group), or a C5-20 aryl group (also referred to as a C5-20 aryloxy group), preferably a C1-7 alkyl group.

C 1-7 alkoxy: -OR, where R is a C 1-7 alkyl group. Examples of C 1-7 alkoxy groups include, but are not limited to, -OMe (methoxy), -OEt (ethoxy), -O (nPr) (n- propoxy), -O (iPr) (i-sopropoxy), -O (nBu) (n-butoxy), -O (sBu) (s-butoxy), -O (iBu) (isobutoxy), and -O (tBu ) (tert-butoxy).

Oxo (keto, -one): = 0.

Thione (thiocetone): = S.

Imino (imine): = NR, where R is an imino substituent, for example hydrogen, C1-7 alkyl group, C3-201 heterocyclyl group or C5-20f aryl group preferably hydrogen or C1-6 alkyl group 7, Examples of imino groups include, but are not limited to, = NH, = NMe, = NEt, e = NPh.

Formyl (carbaldehyde, caboxialdehyde): -C (= O) H.

Acyl (keto): = C (= 0) R, where R is a substituenteakyl, for example a C1-7 alkyl group (also referred to as C1-7 alkylacyl or C1-7 alkanoyl), a C3-7 heterocyclic group 20 (also referred to as C 3-20 heterocyclylacyl), or a C 5-20 aryl group (also referred to as C 5-20 arylacyl), preferably a C 1-7 alkyl group. Examples of α-scyl groups include, but are not limited to, -C (= 0) CH 3 (acetyl), C (= 0) CH 2 CH 3 (propionyl), -C (= 0) C (CH 3) (t-butyryl), and -C (= O) Ph (benzoyl, phenone).

Carboxy (carboxycyclic acid): -C (= O) OH.

Thiocarboxy (thiocarboxylic acid): -C (= S) SH.

Thiolcarboxy (thiolcarboxylic acid): -C (= O) SH.

Thionocarboxy (thionocarboxylic acid): -C (= S) OH.

Imidic acid: -C (= NH) OH.

Hydroxamic acid: -C (= NOH) OH.

Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C (= O) 0R, where R is an ester substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of ester groups include, but are not limited to, -C (= O) OCH 3, -C (= O) OCH 2 CH 3, -C (= O) OC (CH 3) 3, and -C (= O) 0Ph.

Acyloxy (reverse ester): -O C (= O) R wherein R is an acyloxy substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1 alkyl group -7. Examples of acyloxy groups include, but are not limited to: -0C (= 0) CH3 (acetoxy), OC (= 0) CH2CH3, -0C (= 0) C (CH3) 3, -OC (= 0) Ph, and -0C (= 0) CH 2 Ph.

Starch (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C (= OJNR 1 R 2, wherein R 1 and R 2 are independently amino substituents as defined for amino groups. Examples of starch groups include but are not limited to -C (= 0) NH 2, -C (= 0) NHCH 3, -C (= 0) N (CH 3) 2, -C (= 0) NHCH 2 CH 3, and -C (= 0) N (CH 2 CH 3) 2, as well as starch groups, wherein R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclic structure such as, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholine carbonyl, and piperazinocarbonyl.

Acylamino: -NR1C1 = OJR2, wherein R1 is a substituentamide, for example hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably hydrogen or a C1-7 alkyl group, and R2 is an acyl substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably hydrogen or a C1-7 alkyl group. Examples of acylamide groups include, but are not limited to, -NHC (= 0) CH 3, NHC (= 0) CH 2 CH 3, and -NHC (= 0) Ph, R 1 and R 2 may together form a cyclic structure, as for example. , succinimidyl, ma-leimidyl, and fatlimidyl:

<formula> formula see original document page 32 / formula>

Thioamido (thiocarbamyl): -C (= S) NR 1 R 2, wherein R 1 and R 2 are independently amino substituents as defined for amino groups. Examples of thioamido groups include, but are not limited to, -C (= SJNH 2, -C (= S) NHCH 3, C (= S) N (CH 3) 2, and -C (= S) NHCH 2 CH 3.

Ureido: -N (R 1) CONR 2 R 3, wherein R 2 and R 3 are independently amino substituents as defined for amino groups, and R 1 is an ureido substituent, for example hydrogen, a C 1-7 alkyl group, a C 3-6 heterocyclyl group 20, or a C 5-20 aryl group, preferably hydrogen or a C 1-7 alkyl group. Examples of ureido groups include, but are not limited to, -NHCONH2, -NHCONHMe, -NHCONHEt, -NHCONMe2, -NHCONMe2, -NmeCONH2, -NMeCONHMe, -NMeCONHEt, -NMeCONMe2, and -NMeCONEt2.

Guanidino: -NH-C (= NH) NH 2.

Tetrazolyl: a five-membered aromatic ring containing four nitrogen atoms and one carbon atom,

<formula> formula see original document page 32 / formula> Amino: -NR1R2, where R1 and R2 are independently amino substituents, for example hydrogen, a C1-7 alkyl group (also referred to as C1-7 alkylamino or C 1-7 dialkylamino), a C 3-20 heterocyclic group, or a C 5-20 aryl group, preferably H or a C 1-7 alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 taken together with the atom of nitrogen to which they are attached form a heterocyclic ring having from 4 to 8 ring atoms. Amino groups may be primary (-NH2), secondary (-NHR1), or tertiary (-NHR1R2), and in a cationic form, may be quaternary (-4NR1R2R3). Examples of amino groups include, but are not limited to, -NH 2, -NHCH 3, -NHC (CH 3) 2, N (CH 3) 2, -N (CH 2 CH 3) 2 and -NHPh. Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazine, morpholino, and thiomorpholino.

Amidine (amidino): -C (= NR) NR 2, wherein each R is a substituent, for example hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group, preferably H or a C1-7 alkyl group. Examples of Î ± -minine groups, but without limitation, -C (= NH) NH 2, -C (= NH) NMe 2, and -C (= NMe) NMe 2.

Nitro: -NO2.

Nitrous: -NO.

Cyano (nitrile, carbonitrile): -CN.

Sulfhydryl (thiol, mercapto): -SH.

Thioether (sulfide): -SR, wherein R is a substituentethioether, for example a C1-7 alkyl group (also referred to as a alkylthio group), a C3-20 heterocyclyl group, or a C5-20r group preferably a C1-7 alkyl group. Examples of C1-7 alkylthio groups include, but are not limited to, -SCH3 and-SCH2CH3.

Disulfide: -SS-R wherein R is a disulfide substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group (also referred to herein as C1-7 dealkyl disulfide). Examples of C1-7 alkyl disulfide groups include, but are not limited to, -SSCH3 and -SSCH2CH3-.

Sulfine (sulfinyl, sulphoxide): -S (= O) R wherein R is a sulfin substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of sulphine groups include, but are not limited to, -S (= 0) CH3 and -S (= 0) CH2CH3.

Sulfone (sulfonyl): -S (= O) 2R, where R is a sulfone substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group, including, for example, a fluorinated or perfluorinated C1-7 alkyl group. Examples of sulphone groups include, but are not limited to, -S (= 0) CH3 (methanesulfonyl, mesyl), -S (= 0) 2CF3 (triflyl), -S (= 0) 2CH2CH3 (esyl), - St = (D) 2C4F9 (nonaflil), -S (= 0) 2CH2CF3 (tresyl), S (= 0) 2CH2CH2NH2 (tauryl), -S (= 0) 2Ph (phenylsulfonyl, besi), 4-methylphenylsulfonyl ( tosyl), 4-chlorophenylsulfonyl (closila), 4-bromophenylsulfonyl (brosyl), 4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsila), and 5-dimethylamino-naphthalen-1-sulfonate (dansyl). : -S (= 0) 0H, -SO 2 H.

Sulfonic acid (sulfo): -S (= 0) 20H, -SO3H.

Sulfinate (sulfinic acid ester): -S (= 0) 0R; wherein R is a sulfinate substituent, for example a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group. Examples of sulfinate groups include, but are not limited to, -S (= O) OCH 3 (methoxysulfinyl; methyl sulfinate) and -S (= 0) OCH 2 CH 3 (ethoxysulfinyl; ethyl sulfinate).

Sulfinyloxy: -S (= O) R wherein R is a sulfinyloxy substituent, for example a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 2-20 aryl group, preferably a C 1-7 alkyl group. Examples of sulfinyloxy groups include, but are not limited to, -OS (= 0) CH 3 and -OS (= 0) CH 2 CH 3.

Sulfamyl (sulfamoyl); sulfinic acid amide; sulfinamide): -S (= O) NR 1 R 2, wherein R 1 and R 2 are independently amino substituents as defined for amino groups. Examples of sulfamyl groups include, but are not limited to, -S (= 0) NH 2, -S (= 0) NH (CH 3), -S (= OJN (CH 3) 2, S (= 0) NH (CH 2 CH 3) , -S (= O) N (CH 2 CH 3) 2, and -S (= OJNHPh.

Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide): -Si = OJ2NR1R2, wherein R1 and R2 are independently amino substituents as defined herein. Examples of sulfonamido groups include, but are not limited to, -S (= 0) 2NH2, -S (= 0) 2NH (CH3), -S (= 0) 2N (CH3) 2, S (= 0) 2NH ( CH 2 CH 3), -S (= 0) 2N (CH 2 CH 3) 2, and -S (= 0) 2NHPh.

Sulfonamino: -NR 1 Si = O 2 R 2, wherein R 1 is an amino-substituent as defined for amino groups, and R is a sulfonamino substituent, for example a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or an aryl group C5-20 is preferably a C1-7 alkyl group. Examples of sulphoneone groups include, but are not limited to, -NHS (= 0) 2CH3 and -N (CH3) S (= 0) 2CH5H5.

Sulfinamino: -NR 1 S (= O) R wherein R 1 is an amino substituent as defined for amino groups and R is a sulfinamino substituent, for example a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of sulfonamino groups include, but are not limited to, -NHS (= 0) CH 3 and -N (CH 3) S (= 0) C 6 H 5.

As already mentioned, the groups described above may be substituted, and particular examples include, but are not limited to, C3-20 aryl C1-7 alkyl groups which include benzyl (Phenylmethyl, PhCH2-), benzhydryl (Ph2CH-) , trityl (triphenylmethyl, Ph3C-), phenethyl (phenylethyl, Ph-CH2CH2 -), styryl (Ph-CH = CH-) and cinnamyl (Ph-CH = CH-CH2-).

Bidentate Groups

(i.e. groups with two covalent bonding points; bonding groups)

Alkylene: The term "C1-3 alkylene", as used a-chi, belongs to a bidentate fraction obtained by removing two hydrogen atoms from each of two different carbon atoms of a hydrocarbon compound ranging from 1 to 1. 3 carbon atoms, which may be saturated or unsaturated. Thus, the term "alkylene" includes the subclassesalkenylene and alkynylene. In this context, the suffix C1-3 denotes the number of carbon atoms, or number range of carbon atoms.

Examples of saturated C1-3 alkylene groups include -CH2- (methylene), -CH2CH2- (ethylene) and -CH2CH2CH2- (propylene).

Examples of unsaturated C1-3 alkylene groups (which may be referred to as "c2-3 alkenylene" or "c2-3 alkynylene" as appropriate) include -ch = ch- (vinylene), -ch = ch-ch2-, -ch2- ch = ch-, -ChC-, -csc-ch2- and -ch2-csc-.

The C1-3 alkylene group may be substituted by any monodentate substituent described above.

Alkoxy: The term "alkoxy" as used herein belongs to a bidentate group of formula -O (CH 2) n O-, where η is 1 or 2.

Other Forms Included

Unless otherwise specified, included above are the well-known ionic, salt, desolvate and protected forms of these substituents. For example, a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) (-C00 ") form, a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference An amino group includes the proto-form (-N + HR 1 R 2), an amino group salt or solvate, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Reference to a hydroxyl group also includes the ionic (-0 ") form, a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group. Isomers, Salts, Solvates and Protected Forms

Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including, but not limited to, useful and trans forms; to forms E and Z; forms c, t and er; the endo and exo forms; R, S and meso forms; L shapes; forms d and 1; the (+) and (-) forms; the keto, enol, and enolate forms; yes and anti forms; synclinal and anticline forms; the forms α and β; axial and equatorial shapes, boat shapes, chair, twist, envelope, and half chair; combinations of these, hereinafter collectively referred to as "isomers" (or "isomeric shapes").

Note that, except as discussed below with respect to tautomeric forms, specifically excluded from the term "isomers" as used herein, are structural (or constitutional) isomers (ie isomers that differ in connections between atoms rather than merely atoms). by the position of atoms in space). For example, a reference to a methoxy group, OCH 3, is not to be construed as referring to its structural iomer, a hydroxymethyl group, -CH 2 OH-. Similarly, a reference to ortho-chlorophenyl is not to be interpreted as referring to its structural isomer, meta-chlorophenyl. However, reference to a class of structures may conveniently include structurally isomeric forms that fall within that class (for example, C1-7 alkyl-1a includes n-propyl and isopropyl; butyl includes n-, isomeric). tert-butyl (methoxyphenyl includes ortho, meta and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example keto, enol and enolate forms, such as, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitrous / oxime, thiketone / enetiol, N-nitrous / hydroxyzo, and nitro / aci-nitro.

<formula> formula see original document page 39 </formula>

Note that specifically included in the term "i-somerere" are compounds with one or more isotopic substitutions. For example, H may be any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any formaisotopic, including 12C, 13C, and 14C; 0 may be any isotopic form including 16 O and 18 O; and the like.

Unless otherwise specified, a particular reference to a compound includes all such isomeric forms, including mixtures (wholly or partially) and other mixtures thereof. Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallization, and chromatographic devices) of such isomeric forms are either known in the art or readily obtained by adaptation of methods taught herein, or known methods, in a known manner. Unless otherwise specified, reference to a particular compound also includes ionic forms, salt, solvate, and protected forms thereof, for example, as discussed below.

It may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the active compound, for example a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts are discussed by Berge et al., In J. Pharm. Sci. 66, 1-19 (1977).

For example, if the compound is anionic, or has a functional group which may be anionic (for example, -COOH may be -C00 "), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K +, alkaline earth metal cations such as Ca2 + and Mg2 +, and other cations such as Al3 + Examples of suitable organic cations include, but are not limited to, ammonium ion (ie NH4 *) and ions. Substituted ammonium (e.g. NH3R +, NH2R2 +, NHR3 +, NR4 +) Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine An example of a quaternary ammonium umion is N (CH 3) 4 *.

If the compound is cationic, or has a functional group that may be cationic (for example, -NH2 may be -NH3 +), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to, those derived from the followingorganic acids: 2-acetoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glyceptonic, glyconic, glutamic glycolic, hydroximaleal, carboxylic hydroxynaphthalene, isethionic, lactic, lactobionic, lauic, maleic, malic, methanesulfonic, mycic, oleic, palmitic, pantothenic, phenylacetic, pheenylsulfonic, propionic, pyruvic salicylic, stearic, succinic, sulfanyl, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the compound. The term "solvate" is used herein in a conventional sense to refer to a solute complex (e.g., active compound, active compound salt) and solvent. If the solvent is water, the solvate may conveniently be referred to as hydrate, for example a monohydrate, a dihydrate, a trihydrate, etc.

It may be convenient or desirable to prepare, purify, and / or handle the active compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and belongs to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well-known chemical methods are employed to reversibly render reactive a functional group that would otherwise be reactive under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protective group (also known as a masked group or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed without affecting the protected group; The protective group may be removed, usually at a subsequent stage, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

A wide variety of such methods of "protecting", "blocking", or "masking" are widely used and well-known organic synthesis. For example, a compound that has two non-equivalent reactive functional groups, both of which would be reactive under specific conditions, may be derivatized to make one of the functional groups "protected" and therefore nonreactive under the specified conditions; Thus protected, the compound can be used as a reagent, which has only one reactive functional group. Once the desired assignment (involving the other functional group) has been completed, the protected group can be "unprotected" to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OR (= O) R), for example as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl ether (triphenylmethyl); a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC (= O) CH 3, -OAc).

For example, an aldehyde or ketone group may be protected as an acetal (R-CH (OR) 2 or ketal (R2C (OR) 2), respectively, in which the carbonyl group (> C = 0) is converted to a diether (> C (OR) 2) by reaction with, for example, a primary alcohol The aldehyde or ketone group is readily regenerated by hydrolysis using large excess water in the presence of acid.

For example, an amino group may be protected, for example, as an amide (-NRC0-R) or a urethane (-NRCO-OR), for example as: an acetamide (-NHCO-CH3); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5, -NH-Cbz); as a t-butoxy amide (NHCO-OC (CH 3) 3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC (CH3) 2C6H4C6H5, -NH-Bpoc), such as a 9-fluorenylmethoxyamide (-NH-Fmoc), such as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc) as a 2,2,2-trichloroethyloxy amide (-NH-Troc) as an allyloxy amide (-NH-Alloc) as a 2 (- phenylsulfonyl) ethyloxyamide (-NH-Psec); or, in appropriate cases (eg cyclic amines), as a nitroxide radical (> N-0).

For example, a carboxylic acid group may be protected as an ester, for example as: a C1-7 alkyl ester (e.g. a methyl ester, a t-butyl ester); a C1-7 haloalkyl ester (e.g., a C1-7 alkylthioalkyl ester); a C 1-7 tri-alkylsilyl-C 1-7 alkyl ester; or a C 5-20 aryl alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.

For example, a thiol group may be protected with a thioether (-SR), for example as: a benzyl thioether, an acetamidomethyl ether (-S-CH 2 NHC (= O) CH 3).

The term "treatment" as used herein in the context of treating a condition generally pertains to the treatment of therapy, whether of a human or animal (for example, in veterinary applications), where some desired therapeutic effect is achieved, for example, inhibition. of progress of the condition, and includes a reduction in the rate of progress, a halt in the speed of progress, attenuation of the condition, and cure of the condition. Treatment, as a prophylactic measure (i.e. pro-philaxis), is also included.

The term "therapeutically effective amount" as used herein refers to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective to produce any desired therapeutic effect commensurable with a reasonable risk / benefit ratio when administering a desired treatment regimen. Suitable dose ranges will typically be in the range 0.01 to 20 mg / kg / day, preferably 0.1 to 10 mg / kg / day.

Compositions and their administration

The compositions may be formulated by any means and administration means. Pharmaceutically acceptable carriers and diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, untreated and epidural) administration. ). The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing the active ingredient into association with the carrier constituting one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, conforming the compound.

For solid compositions, conventional non-toxic solid carriers, for example pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talc, glucose, sucrose, magnesium carbonate, and the like may be used. The active compound as defined above may be formulated as suppositories using, for example, polyalkylene glycols, acetylated triglycerides and the like as the carrier. Pharmaceutically administrable liquid compositions, for example, may be prepared by dissolving, dispersing, etc., an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, aqueous saline dextrose, glycerol. , ethanol, and the like to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain small quantities of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate. sorbitan monolaurate, triethanolamine oleate, etc. The actual methods of preparing such dosage forms are known, or will become apparent, to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, 20th Edition, public. Lippincott, Williams & Wilkins, 2000. The composition or formulation to be administered will contain, at any event, an amount of the active compound (s) in an amount effective to alleviate the symptoms of the patient being treated.

Dosage forms or compositions containing the active ingredient in the range of about 0.25 to 95% may be prepared with the balance being made of a nontoxic carrier.

For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the commonly employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, croscarmellose sodium, starch, magnesium stearate. sodium saccharin, talc, glucose, sucrose, magnesium carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, constant release formulations, and similars. Such compositions may contain from 1% to 95% of the active ingredient, more preferably 2 to 50%, most preferably 5 to 8%.

Parenteral administration is generally characterized by subcutaneous, intramuscular or intravenous injection. Injectables may be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid, prior to injection or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be administered may also contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate. triethanolamine oleate, sodium triethaneamine acetate, etc.

The percentage of active compound contained in such parenting compositions is highly dependent upon their specific nature as well as the activity of the compound and the patient's needs. However, percentages of the active ingredient from 0.1% to 10% in solution are employable, and will be higher if the composition is a solid that will dilute at the above percentages. Preferably, the composition will comprise from 0.2 to 2% of the active agent in solution.

Ointments are typically prepared from the compound and a base for paraffinic or water-soluble ointment.

Creams are typically prepared from the active compound and a water-in-oil cream base. If desired, the cream base phase may include, for example, at least about 30% w / w of a polyhydric alcohol, ie, an alcohol having two or more hydroxyl groups such as propylene glycol, butane. 1,3-diol, mannitol, sorbitol glycerol and polyethylene glycol and mixtures thereof. Topical formulations may desirably include a compound that enhances the absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active compound, such carriers as are known in the art to be appropriate.

General Synthesis Methods

Compounds of the present invention where R2 is tetrazol-5-yl may be synthesized from compounds where R2 is cyano by treatment with sodium azide, thiomethyl tin azide or trimethylsilyl azide. It is carboxy and may be synthesized from compounds where R is an ester by hydrolysis reaction, for example using sodium hydroxide.

The compounds of formulas (I) to (IV), as well as their precursors and protected forms, may be represented as:

<formula> formula see original document page 49 / formula>

where Ra represents R5-L-A-, A 'or protected precursors and forms thereof, and R8 represents - (CH2) n-B, or protected precursors and forms thereof.

Compounds of formula 1 where D is -C (= O) -N (Rn) -can be synthesized by coupling the compounds of Formula 2 and Formula 3, wherein the groups Ra and Rb are as defined above.

<formula> formula see original document page 49 / formula>

Such a coupling step may be carried out using a coupling agent or agents, for example, O- (7-azabenzotriazol-1-yl) -Ν, Ν, Ν ', N'-tetramethyluronium, TBTU and DIPEA hexafluorophosphate, or EDC and HOAt.

Compounds of Formula 1, where D is -N (Rn) -C (= o), may be synthesized by coupling the compounds of Formula 1a and Formula 5, wherein the groups Ra and Rb are as defined. above.

<formula> formula see original document page 50 </formula>

Such coupling step may be performed using agent or coupling agents as described above.

Compounds of Formula 1, where D is -CH 2 -O or -CH 2 -S, may be prepared by coupling compounds of Formula 6 and 7, wherein the groups Ra and Rb are as defined above.

Formula 6

<formula> formula see original document page 50 </formula>

Formula 7

where X 'is 0 or S, using NaH in an organic solvent, such as DMF and heptane or THF.

A key step in the synthesis of compounds of Formula 1a, where D is - (C (= 0) -CH 2 -) is the coupling of the remainder of the molecule to Ra. This can be accomplished by coupling a compound of Formula 8:

<formula> formula see original document page 50 </formula> or precursor to Ra by a suitable method.

For example, when A is:

<formula> formula see original document page 51 </formula>

Coupling may occur in an organic solvent in the presence of P2O5.

The compounds of Formula 1, where D is -CHOH-CH 2 - may be synthesized by reduction of a compound of Formula 1, where D is -C (= 0) -CH 2 -, for example, using disodium borohydride in an organic solvent. .

The compounds of Formula 1, where D is -CH 2 = CH 2 -, may be synthesized by dehydration of a compound of Formula 1, where D is -CH (OH) -CH 2 -, for example, using methanesulfonyl chloride in an organic solvent.

The compounds of Formula 1, where D is -S-, may be prepared by coupling the compounds of Formula 9 and 10, wherein the groups Ra and R8 are as defined above.

<formula> formula see original document page 51 </formula>

using K 2 CO 3 in an organic solvent, such as acetone, with heating, for example, in a microwave. Compounds of Formula 1, where D is -C (= NH) -NH-, may be prepared by coupling the compounds. of Formulas 11 and 12, wherein the groups Ra and Rb are as defined above.

<formula> formula see original document page 52 </formula>

by adding triethylaluminum solution to the compound of formula 12 in an organic solvent, followed by addition of the compound of formula 11 with heating.

The compounds of the present invention, where R 5 is an aryl group and L is a single bond, may be synthesized from compounds where R 5 is bromo by coupling Suzuki with a compound of formula 13a (or equivalent ester of formula 13b) :

<formula> formula see original document page 52 </formula>

Suzuki coupling may be obtained using, for example, bis (diphenylphosphino) ferrocene] dichloropalladium (II) as the palladium catalyst. Alternatively, coupling may be obtained using CsCO3, with Pd (PPh3) 4 as the palladium catalyst. In this reaction, other functional groups, for example carboxy, should be suitably protected. The compounds of the present invention, where R 5 is an alkyl group and L is a single bond, and where A is:

can be synthesized from compounds where A is:

<formula> formula see original document page 53 </formula>

by reaction with R5-Br in the presence of AlCl3 in an organic solvent such as ortho-dichlorobenzene followed by acid group protection. This method can be readily adapted for other groups A.

The compounds of formula V may be represented by Formula 14:

<formula> formula see original document page 53 </formula>

where Rb is B or a precursor thereof, and R is R-L- or a precursor thereof.

The compounds of Formula 14 may be synthesized by coupling the compounds of Formula 15 and 16: <formula> formula see original document page 54 </formula>

by reacting them together under appropriate conditions, for example with heating in NMP followed by basification with potassium carbonate.

Preferences

The following preferences may be combined with each other, and may differ for each aspect of the present invention.

R 5 may be a C 1-1 aryl group such as furan-2-yl and phenyl.

R5 is preferably a C6 aryl group, and is more preferably phenyl. R5 may be substituted, and preferred substituents include C1-7 alkoxy groups, more preferably C1-4 alkoxy groups, for example -OMe, -OCF3, -OEt, -OCHF2, where -OCHF2 is most preferred. .

When R5 is phenyl, preferred substituents include: C1-4 alkyl (e.g. methyl, -CF3, isopropyl), C1-4 alkoxy (e.g. methoxy, -OCF3) including substituted C1-4 alkoxy (e.g. benzyloxy); C 5-6 aryl (e.g. phenyl); halo (e.g., Cl, F, di-Cl); acyl (e.g. -COMe); amino (e.g., -NH2, -NMe2); alkoxy (e.g. -O-CH 2 -O). In some embodiments, C1-4 alkyl (e.g. methyl, -CF3, isopropyl); C1-4 alkoxy (e.g. methoxy, -OCF3); halo (e.g. Cl, F, di-Cl), acyl (e.g. -COMe); and alkoxyethylene (e.g. -O-CH 2 -O-) are preferred.

The substituents may be in any position of the phenyl ring, for example 2, 3 and 4, and when there are substituents (for example dichloro), they may be, for example, in: 2, 3; 2,4; 3, 5 or 3,4.

R 5 may preferably be a C 9 -C 10 aryl group, for example naphthyl (more preferably naphth-1-yl) and indolyl (more preferably indol-4-yl).

When R5 is a C4-20 alkyl group, it may be a C4-10 alkyl group, and preferably a branched C4-10 alkyl group, for example t-butyl, -CH2-CH (CH3) 2 or a cyclic alkyl group such as as cyclohexyl or adamantyl.

Of these cyclic groups are more preferred, where ada-mantle is most preferred.

In the compounds of formulas (II), (III) and (V), L 'is preferably a single bond.

In some embodiments, R 4 is selected from H, F, Cl, C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl groups.

In some embodiments, R 3 is selected from H, F, Cl, C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl groups.

When A is a five membered ring: (i) R3 (if present) is preferably selected from H and optionally substituted C1-4 alkyl (in particular methyl) and is more preferably H; and

(ii) R4 is preferably selected from H and is optionally substituted C1-4 alkyl (in particular methyl) and is more preferably H.

When A is a six membered ring, it is preferred that:

(i) R3, R4 and R6 (if present) are H; or

(ii) one of R3, R4 and R6 (if present) is Cl or F.

A preferred option when A is:

<formula> formula see original document page 53 </formula>

is for R to be F.

A is preferably selected from

<formula> formula see original document page 56 </formula>

and is most preferably selected from:

<formula> formula see original document page 53 </formula> <formula> formula see original document page 57 </formula>

Most preferably selected from:

<formula> formula see original document page 57 </formula>

The most preferred option for A is:

<formula> formula see original document page 57 </formula>

In the compounds of formulas (III) to (V), D is preferably selected from:

<formula> formula see original document page 57 </formula> <formula> formula see original document page 58 </formula>

In the compounds of formula (I) and (III) to (V), D is more preferably selected from:

<formula> formula see original document page 58 </formula>

and is more preferably: Rn is preferably H or methyl, and is more preferably H.

In the compounds of formula (II), D is preferably selected from:

<formula> formula see original document page 59 </formula>

and in some modalities D is:

<formula> formula see original document page 59 </formula>

In the compounds of formulas (IV) and (V), B is preferably selected from: <formula> formula see original document page 60 </formula>

In the compounds of formulas (I), (II), (IV) and (V), B is most preferably selected from:

<formula> formula see original document page 60 </formula>

and more preferably:

<formula> formula see original document page 60 </formula>

In the compounds of formula (III), B is preferably:

<formula> formula see original document page 60 </formula> In the compounds of formula (IV), T is preferably

0. In some embodiments, A 'is unsubstituted.

R 2 is preferably carboxy or tetrazol-5-yl, where carboxy is more preferred.

When Rp4 is H, Rp3 is preferably -CH = CH-R2.

In some embodiments, m and η may only be 0or 1, and m + η may be only 1 or 2. In such embodiments, preferably η + m = 1, and more preferably η 0 and m is 1.

In other embodiments, it is preferred that η is 0, one of R 3 (preferably R 3) is -O-CH 2 -R 2, wherein R 2 is preferably carboxy or tetrazol-5-yl, more preferably carboxy.

Particularly preferred compounds include:

3- {3 - [(5-phenoxy-furan-2-carbonyl) amino] -phenyl} -acrylic acid (5);

3- {3 - [(5-benzoyl-furan-2-carbonyl) -amino] -phenyl} -acrylic acid (11);

3- {3- (6-Phenyl-pyridin-2-ylsulfanyl) -phenyl] -acrylic acid (16);

3- {3 - [(dibenzofuran-2-carbonyl) -amino] -phenyl} -acrylic acid (20);

3- {3- [2-Hydroxy-2- (5-phenyl-furan-2-yl) -ethyl] -phenyl} -acrylic acid (28);

3- {3- [2- (5-phenyl-furan-2-yl) -vinyl] phenyl} -acrylic acid (29);

3- [3- (5-phenyl-benzoxazol-2-yl) -phenyl] -acrylic acid (34); 3- {6 - [(5-phenyl-furan-2-carbonyl) -amino] -pyridinic acid 2-yl} acrylic (40);

3- {4-Fluoro-3 - [(5-phenyl-furan-2-carbonyl) -amino] -phenyl} -acrylic acid (45);

3- {4-chloro-3 - [(4-fluoro-biphenyl-3-carbonyl) -amino] -phenyl} -acrylic acid (52);

3- {3 - [(4-Fluoro-biphenyl-3-carboximidoyl) -amino] -phenyl} -acrylic acid (58).

The selectivity of the compound to modulate EP2 receptors over one or more of the other EP receptors (i.e.EPi, EP3, EP4) can be quantified by dividing the Ki to EP2 (see below) by Ki for the other EP receptors (see below). The resulting ratio is preferably 10 or more, more preferably 100 or more.

Synthesis Examples

Abbreviations

For convenience, many chemical fractions are represented using well-known abbreviations including, but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), i-sopropyl (iPr), n-butyl (nBu), s-butyl (sBu), isobutyl (iBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph) methoxy (MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).

For convenience, the following abbreviations are used:

d doublet

DCM dichloromethane

dd doublet of doubletsDIPEA Ν, N-diisopropylethylamine

4- (dimethylamino) -pyridine DMAP

DME 1,2-dimethoxyethane

N, N-dimethylformamide DMF

1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide EDC hydrochloride

eq equivalent

EtOAc ethyl acetate

EtOH Ethanol

HCl hydrogen chloride

HOAt 1-hydroxy-7-azabenzotriazole

K2CO3 potassium carbonate

m multiplet

MeCN acetonitrile

Methanol MeOH

MgSO4 Magnesium Sulphate

NaOH sodium hydroxide

NaHCO3 baking soda

Na2SO4 sodium sulfate

NMP 1-methyl-2-pyrrolidine

what quartet

s singlet

sept septeto

triplet t

tlc thin layer chromatography

TBME tert-butyl methyl ether

TBTU o-benzotriazol-1-yl-N, N, N ', N'-tetramethylammonium THF tetrahydrofuran tetrafluorborate

νο1 volume

General Methods

Commercially available reagents and solvents (HPLC grade) were used without further purification.

Microwave irradiation was performed using a CEM Discover focused microwave reactor.

1 H NMR spectra were recorded on a Bruker 400 MHz Av spectrometer in deuterated solvents. Chemical shifts (δ) are in parts per million and coupling constants are expressed in Hz. Thin layer chromatography (TLC) analysis was performed with Kieselgel plates (Merck) and UV light visualization.

Analytical HPLC-MS was performed on Agi-Ient HP1100, Waters 600 or Waters 1525 LC systems using reversed phase Hypersil BDS C18 (5 μπι, 2.1 χ 50 mm) columns, gradient 0-95% B (A = water / 0.1% TFA), B = acetonitrile / 0.1% TFA) for 2.10 minutes, flow rate = 1.0 mL / min. NoUV spectra were recorded at 215 nm using a Gilson G1315A Diode Series Detector, Gs214A UVsimple wavelength detector, 2487 Wa-ters dual UV wavelength detector, Waters2488 dual UV wavelength detector, or UV detector. Waters 2996 series diode. Mass spectra were obtained in the 150 to 850 m / z range at a sampling rate of 2 scans per second or 1 scan for 1.2 seconds using Micromass LCT with Z-Spray or Micromass Interfaces. LCT with Z-spray or Mux interface. Data were integrated and reported using OpenLynx and OpenLynx Browser software.

Purification of compounds by preparative HPLC was performed on Gilson systems using ThermoHypersil-Keystone HyperpreP HS C18 columns (12 μπι, 100X 21.2 mm), gradient 20 to 100% B (A = water / 0.1% T FA, B = acetonitrile / 0.1% TFA) for 9.5 minutes, flow rate = 30 mL / min, 2: 1 DMSO: acetonitrile injection solvent (1.6 mL), UV detection at 214 nm.

Common Methods

<formula> formula see original document page 65 </formula>

The nitro derivative was dissolved in EtOH (5 vol) and SnCl 2 -2H 2 O (50 eq) was added as a solid. The resulting solution was then stirred at 60 ° C for 2 hours. After cooling to room temperature, a premixed solution of saturated Rochelle salt (10 vol) and saturated NaHCO3 solution (10 vol) was added to the reaction mixture and the aqueous layer was extracted with EtOAc (3 x 20 vol). . The combined organic layers were dried (MgSO4) and the solvent removed under vacuum.

<formula> formula see original document page 65 </formula> To a stirred solution of carboxylic acid (1 eq) and amino acid ester (1 eq) in DMF (20 vol) was added DIPEA (1 eq) followed by TBTU (1 eq ). The reaction was stirred overnight or until complete by LC / MS at room temperature. To the reaction mixture was added EtOAc (30 vol) and the organic layer was washed with 2M HCl (2 x 50 vol), brine (2 x 50 vol), saturated aqueous NaHCO 3 (2 x 50 vol) and brine (2 x 50) vol). The organic layer was dried (MgSO 4), filtered and the solvent removed under vacuum.

<formula> formula see original document page 66 </formula>

To a solution of ethyl ester in EtOH or MeOH (5vol) was added IM NaOH (5vol) and the resulting solution was stirred for 30 minutes at room temperature. EtOH was then removed under vacuum and the residue redissolved in TBME (50 vol) and water (50 vol). The aqueous layer was extracted with TBME (2 x 50 vol), then acidified with 2M HCl until a white precipitate formed. This was then extracted with EtOAc (3 χ 50 vol). The organic layer was washed with brine, dried (Na 2 SO 4), filtered and the solvent removed under vacuum.

<formula> formula see original document page 66 </formula>

Carboxylic acid (1 eq), EDC (1.2 eq), and HOAt (1.2 eq) were added to a flask as solids. The amino ester (1.2 eq) was dissolved in DMF (10 vol) and added to the flask. The reaction was stirred at room temperature overnight or until complete by LC / MS. Water (20 vol) was added and the mixture was extracted with EtOAc (3 x 10vol). The organic layer was then washed with water (10 vol), dried (MgSO 4), filtered and concentrated under vacuum. Column chromatography using a stepped gradient of EtOAc in heptane yielded the product.

<formula> formula see original document page 67 </formula>

To a suspension of aryl bromide (1 eq), Cs2CO3 (1.2 eq) and boronic acid (1.1 eq) in toluene (15 vol) and Me-OH (4 vol) was added Pd (PPh3) 4 ( 0.1 eq). The resulting mixture was heated in a CEM Discover microwave for 30 minutes at 120 ° C (150 W, 15.58 kgf / cm2 (250 psi). Analysis was performed by LC-MS and, if required, the reaction was reheated to bring reaction to completion Once complete, the reaction mixture was filtered through Celite and the solvents removed in vacuo.The crude residue was redissolved in EtOAc and washed with water (3x5 vol). The combined organic layers were dried (Na 2 SO 4), filtered and the solvents removed under vacuum The compounds were then purified by column chromatography If the ester group was ethyl then EtOH was used in place of MeOH. -MS showed partial hydrolysis during the reaction, in which case the solvents were removed under vacuum, the residue was redissolved in EtOAc (1.5 vol) and the organic layer was washed with HCl IM (2x1 vol), dried (Na 2 SO 4), filtered and the solvent removed under vacuum. Duo was triturated comTBME (1.5 vol).

<formula> formula see original document page 68 </formula>

To a suspension of aryl bromide (1.2 eq), Cs2CO3 (4.0 eq) and boronic acid (1 eq) in toluene (5 vol) and EtOH (5 vol) under N2 was added Pd (PPh3) 4 (0 0.05 eq) and the resulting mixture was heated to 85 ° C for 3 hours. Solvents were removed under vacuum and the solids resuspended in EtOAc (10 vol). Water (10 vol) was then added and all solids dissolved. The layers were separated and the aqueous layer was washed with EtOAc (3x5 vol) and acidified to pH 4 with 2M HCl whereby a precipitate formed. This was then extracted with EtOAc (2 x 10vol). The combined organic layers were dried (Na 2 SO 4) and removed under vacuum to give the product.

Example 1: 3- {3 - [(5-Phenoxy-furan-2-carbonyl) amino] -phenyl} -acrylic acid (5) <formula> formula see original document page 69 </formula>

(a) 3- (3-Amino-phenyl) -acrylic acid ethyl ester (2)

Ethyl 3-nitrocynamate (1) (2.0 g, 9.04 mmols) was reduced using method A, except that SnCl2.2H20 (10.2g, 45, 20 mmols) was EtOH (20 mL) was used and After reaction the solvent was concentrated under vacuum, Rochelle salt and saturated NaH-CO 3 (1: 1, 80 mL) were added, and the aqueous portion was basified with 1 N NaOH. The aqueous portion was extracted with EtOAc (3 x 40 mL), washed with Rochelle salt / saturated NaHCO 3 solution (2 x 40 mL), dried (MgSO 4) and the solvent concentrated under vacuum to give the title compound. Yield: 1.77 g,> 100%; LCMS rt 0.89 min; MS (ES +) mlz 192 (M + H)

(b) 3- {3 - [(5-Phenoxy-furan-2-carbonyl) -amino] -phenyl-acrylic acid ethyl ester (4)

5-Phenoxy-2-furic acid (3) (313 mg, 1.05 mmol) was coupled to aniline (2) (2) (200 mg, 1.05 mmol) using Method B, except that DIPEA (270 mg, 2.09 mmol) and DMF (2 mL) were used to give the title compound. Yield: 178mg, 96%; LCMS r t 1.65 min; HPLC purity: 95%; MS (ES +) m / z 378 (M + H) (c) 3- {3 - [(5-Phenoxy-furan-2-carbonyl) -amino] -phenyl} -acrylic acid (5)

Ester (4) (100 mg, 0.27 mmol) was hydrolyzed using Method C, except that EtOH (1 mL), THF (0.5 mL) and NaOH IM (1 mL) were used, and the reaction was stirred for 2 hours. 4 hours. The solvent was removed under nitrogenous stream and the aqueous residue was acidified to pH 5 using 1N HCl, extracted with EtOAc (2x2 mL), dried (MgSO 4), filtered and the concentrated solvent under vacuum to give the title compound as a solvent. Pale solid. Yield: 89 mg, 96%; LC-MS R t 1.47 min; HPLC purity: 100%; MS (ES +) mlz 350 (M + H)

7.20-7.30 (m, 3H), 7.35-7.60 (m, 6H), 7.80 (d, 1H), 8.00 (s, 1H), 10.15 (s, 1H), 12.50 (br. S, 1H)

1H-NMR (400 MHz; DMSO): δ 5.95 (d, 1H), 6.45 (d, 1H)

Example 2: 3- {3 - [(5-Benzoyl-furan-2-carbonyl) -amino] -phenyl} -acrylic acid (11)

<formula> formula see original document page 70 </formula>

(a) 5-Benzoyl-furan-2-carboxylic acid methyl ester (8) Methyl 2-furate (7) (100 mg, 0.79 mmol), iron (III) chloride (193 mg, 1 19 mmol) and benzoic anhydride (6) (180 mg, 0.79 mmol) were combined and stirred in DCM at room temperature overnight. The reaction mixture was filtered and the organic layer was washed with saturated NaHCO 3 solution, dried (MgSO 4), filtered and the solvent concentrated under vacuum. The crude product was partially purified using column chromatography eluting with 10 to 20% EtOAc in heptane. Excess benzoic acid was removed by dissolving the product in DCM and washing with saturated NaHCO 3 solution (x 3). The organic layer was dried (MgSO 4), filtered and the solvent concentrated in vacuo to give the title compound. Yield: 80 mg crude, 44%; LC r t 1.29 min.

(b) 5-Benzoyl-furan-2-carboxylic acid (9)

The crude ester (8) (80 mg, 0.35 mmol) was hydrolyzed using Method C except MeOH (0.8 mL) and NaOH IM (0.8 mL) and NaOH IM (0.8 mL). ) was used. After the reaction, the solvent was removed under a stream of nitrogen gas, acidified using 1N HCl, extracted with EtOAc, dried (MgSO 4), filtered and the solvent concentrated under vacuum to the crude title compound. Yield; 48 mg; HPLC purity:> 66%; LC rt 1.09 min.

(c) 3- {3 - [(5-Benzoyl-furan-2-carbonyl) -amino] -phenyl} -acrylic acid ethyl ester (10)

Acid (9) (48 mg, 0.22 mmol) was coupled to aniline (2) (43 mg, 0.22 mmol) using Method B except that DIPEA (57 mg, 0.44 mmol) and DMF (0.5 mL) were used. The crude product was purified by preparative HPLC to give the title compound. Yield: 28 mg; LC-MS R t 1.54 min; MS (ES +) m / z 389 (M + H)

(d) 3- {3 - [(5-Benzoyl-furan-2-carbonyl) -amino] -phenyl} -acrylic acid (11)

Ester (10) (28 mg, 0.072 mmol) was hydrolyzed using Method C, except that EtOH (0.15 mL) and NaOH IM (0.15 mL) were used. After the reaction, the solvent was removed under nitrogen stream. gas and the acidified residue to pH 5 using 1N HCl. The precipitate was filtered and dried to give the title compound. Yield: 8 mg, 31%; LCMStr 1.95 min; HPLC purity: 98%; MS (ES +) m / z 362 (M + H); 1H NMR (400 MHz; DMSO): δ 6.4 (d, 1H), 7.10 (d, 1H), 7.20-7.40 ( m, 2H), 7.55 (m, 1H), 7.60-7.80 (m, 3H), 7.80-7.90 (d, 1H), 7.95 (s, 1H), 7 95-8.10 (m, 3H)

Example 3: 3- [3- (6-Phenyl-pyridin-2-ylsulfanyl) -phenyl] -acrylic acid (16)

<formula> formula see original document page 72 </formula>

(a) 2-Bromo-6-phenylpyridine (13) To Ν, N-dimethylethanolamine (0.8 mL, 8.00 mmols) in heptane (10 mL) externally cooled to 0 ° C was added dropwise. - Drop a 2.5M n-butyl lithium solution (6.40 mL) and the reaction mixture is stirred for 30 minutes. 2-Phenylpyridine (12) (412 mg, 2.66 mmol) in heptane (5 mL) was then added and the reaction mixture stirred for a further 1 hour. The reaction was then cooled and carbon tetrabromide (3.18 mg, 9.60 mmols) was added while maintaining the temperature at -78 ° C. The reaction was kept at -78 ° C for 1 hour and then allowed to warm to room temperature. Water was carefully added and extracted with TBME (X 2), dried (Na 2 SO 4) and the solvent concentrated under vacuum. The crude product was purified by column chromatography eluting with 5% EtOAc in heptane to give the title compound. Yield: 300 mg, 48%; LC-MS R t 1.63 min; HPLC purity: 97%; MS (ES +) mlz 234, 236 (M + H)

(b) 2- (3-Bromo-phenylsulfanyl) -6-phenyl-pyridine (14)

2-Bromo-6-phenylpyridine (13) (100 mg, 0.43 mmol), K 2 CO 3 (117 mg, 0.85 mmol) in acetone (2 mL) was added 3-bromothiophenol and the reaction mixture was added. heated in a CEM Discover microwave for 1 χ 30 minutes at 90 ° C, then 4x2 hours at 130 ° C, followed by 1x8 hours at 130 ° C. The crude product was partially purified by column chromatography with 10% EtOAc in heptane to give the title compound. Yield: 100 mg, 68%; LC-MS R t 1.97 min; Purezapor HPLC: 55%; MS (ES +) mlz 342, 344 (M + H) (c) 3- [3- (6-Phenyl-pyridin-2-ylsulfanyl) -phenyl] -acrylic acid methyl ester (15)

Crude Aryl Bromide (14) (100 mg, 0.18 mL), methyl α-crylate (18 mg, 0.21 mmol), triethylamine (71 mg, 0.70 mmol), tri (o-tholi) phosphine (5 mg, 0.016 mmol) and palladium (II) acetate (12 mg, 0.54 mmol) in acetonitrile (2 mL) were heated in a CEM Discover microwave for 45 minutes at 90 ° C. More tri (o-tholi) phosphine (3 mg) and palladium (II) acetate (3 mg) were added and the reaction mixture re-treated in the microwave for 20 minutes; Palladium (II) acetate was then added and the process repeated for a further 25 minutes. The solvent was removed under gaseous nitrogen stream, water was added, and the organics extracted with EtO-Ac, washed with water, dried (Na 2 SO 4) and the solvent concentrated under vacuum. The crude product was partially purified by column chromatography. Yield: 51 mg, 60%; LC-MStr 1.82 min; HPLC purity: 70%; MS (ES +) mlz 348 (M + H)

(d) 3- [3- (6-phenyl-pyridin-2-ylsulfanyl) -phenyl] -acrylic acid (16)

Ester (15) (51 mg, 0.11 mmol) was hydrolyzed using Method C, except that the reaction was stirred for 2 hours. The crude solid was purified by preparative HPLC to afford the title compound. Yield: 3 mg, 10% LC-MS r t 1.65 min; HPLC purity: 100%; MS (ESt) mlz 334 (M + H); 1H-NMR (400 MHz; MeOH): δ 6.65 (d, 1H), 7.05 (d, 1H), 7.45-7.55 (m, 3H), 7.60-7.65 (dd 1H), 7.65-7.85 (m, 5H), 8.00 (m, 3H) Example 4: 3- {3 - [(Dibenzofuran-2-carbonyl) -amino] -phenyl} -acrylic acid (20)

<formula> formula see original document page 75 </formula>

(a) Dibenzofuran-2-carboxylic acid (18)

To dibenzofuran-2-carboxaldehyde (17) (200 mg, 1.02 mmol) was added solid NaOH (49 mg, 1.22 mmol) then 10% NaOH solution (1.8 mL). Silver nitrate (173 mg, 1.02 mmol) was then added, the reaction mixture warmed to 60 ° C for 1.5 h and then stirred overnight at room temperature. The reaction mixture was then filtered and washed with water. The filtrate was acidified to pH 2 using concentrated HCl and the precipitated product filtered and dried to give the title compound as a pale solid. Yield: 83 mg, 38%; LC-MS R t 1.31 min; HPLC purity: 100%; MS (ES +) undetectable m / z (M + H)

(b) 3- {3 - [(Dibenzofuran-2-carbonyl) -amino] -phenyl} -acrylic acid ethyl ester (19)

Acid (18) (50 mg, 0.24 mmol) was coupled to α-niline (2) (54 mg, 0.28 mmol) using Method D, except that DMF (1 mL) was used. The product was further purified by trituration in DCM / heptane to give the title compound.

Yield: 46 mg, 51%; LC-MS R t 1.70 min; HPLC purity: 97-100%; MS (ES +) mlz 386 (M + H)

(c) 3- {3 - [(dibenzofuran-2-carbonyl) -amino] -phenyl} -acrylic acid (20)

Ester (19) (46 mg, 0.12 mmol) was hydrolyzed using Method C, except that MeOH (1 mL) and THF (1 mL) were used, and the reaction mixture was heated to 40 ° C for 1 hour. After the reaction, TBME was added and the mixture was acidified using 6N HCl. The aqueous portion was extracted with TBME (x 3), EtOAc (x 3), dried (MgSO 4) and the solvent concentrated under vacuum. The crude solid was triturated with DCM, filtered, washed with heptane and dried to give the title compound. Yield: 34 mg, 81%; LC-MS R t 2.08 min; Purezapor HPLC: 100%; MS (ES +) mlz 358 (M + H); 1H-NMR (400 MHz; DMSO): δ 6.60 (d, 1H), 7.55-7.75 (m, 5H), 7.9 (d, 1H), 7.95-8.05 (m , 2.H), 8.25 (S7IH), 8.30 (d, 1H), 8.40 (d, 1H), 8.95 (SfIH), 10.65 (SfIH)

Example 5: 3- {3- [2-Hydroxy-2- (5-phenyl-furan-2-yl) -ethyl] -phenyl} -acrylic acid (28) <formula> formula see original document page 77 </ formula >

(a) 2-Phenyl-furan (23)

Furan-2-boronic acid (22) (3.6 g, 32.14 mmols) was coupled to bromobenzene (21) (4.2 g, 26.79 mmols) using Method E, except that Cs2CO3 (17.47 g , 53.58 mmols), Pd (PPh3) 4 (6.20 g, 0.54 iranol), toluene (25 mL) and EtOH (25 mL) were used and the reaction heated in a CEMDiscover microwave at 140 ° C (200 ° C). W, 14.06 kg f / cm2 (200 psi) The product was purified by dry flash chromatography eluting with EtOAc in heptane to yield the title compound Yield: 2.94 g, 62%; MS r t 1.50 min; HPLC purity: 84%

(b) 2- (3-Bromo-phenyl) -1- (5-phenyl-furan-2-yl) -ethanone (25)

Phosphorus pentoxide (2.02 g, 14.20 mmol) suspended in 1,2-dichlorobenzene (60 mL) was added to a mixture of 2-phenyl furan (23) (500 mg, 2.84 mmols) and 3-bromophenylacetic acid (24) (1.34 g, 2.65 mmols). The reaction mixture was heated to 80 ° C for 2 hours and then cooled to room temperature. DCM was added, the organic layer washed with water and partially reduced under vacuum. The crude product was purified by Flash Master Jones Chromatography using 50 g silica cartridge and initially eluting with heptane to remove excess 1,2-dichlorobenzene. then 5 to 10% EtOAc in heptane to give the title compound. Yield: 278 mg, 38%; LC-MS R t 1.73min; HPLC purity: 100%; MS (ES +) mlz 341, 343 (M + H)

(c) 3- {3- [2-Oxo-2- (5-phenyl-furan-2-yl) -ethyl] -phenyl} -acrylic acid methyl ester (26)

Tri (o-tholi) phosphine (25 mg, 0.082 mmol) and palladium (II) acetate (9 mg, 0.041 mmol) in acetonitrile (1 mL) were added to a mixture of methyl acrylate (84 mg, 0, 98 mmol) and triethylamine (329 mg, 3.26 mmol). Dearyl bromide (25) (278 mg, 0.82 mmol) in acetonitrile (3 mL) was then added and the reaction mixture heated in microwave Discover for 45 minutes at 90 ° C. The solvent was concentrated under vacuum, and the crude product was purified by Flash Master Jones Chromatography using a 25 g silica cartridge eluting with 5-17% EtOAc in heptane. Yield: 222 mg, 78%; LC-MS R t 1.62 min; HPLC purity: 100%; MS (ES +) m / z 347 (M + H)

(d) 3- {3- [2-Oxo-2- (5-phenyl-furan-2-yl) -ethyl} -phenyl} -acrylic acid (27)

Ester (26) (222 mg, 0.64 mmol) was hydrolyzed using Method C, except that MeOH (1 mL), THF (1 mL) and NaOHIM (1 mL) were used, and the reaction was stirred for 1 min. After preparation, the crude product was triturated with DCM / heptane. (χ 3) to provide the title compound. Yield: 134 mg; LC rt 1.39 min; HPLC Purity: 92%

(e) 3- {3- [2-Hydroxy-2- (5-phenyl-furan-2-yl) -ethyl] -phenyl} -acrylic acid (28)

To the ketone (27) (33 mg, 0.10 mmol) dissolved in Me-OH (2 mL) was added sodium borohydride (8 mg, 0.21 mmol). Subsequent additions of sodium borohydride (2 mg) were added until the reaction was complete. The reaction mixture was acidified to pH 5 by dropwise addition of 1 N HCl and extracted with TBME (x 3). The organic layer was dried (MgSO 4) and the solvent concentrated under vacuum to give the title compound as a white solid. Yield: 20 mg, 61%; LC-MS R t 2.02 min; HPLC purity: 100%; MS (ESt) m / z335 (M + H); 1H-NMR (400 MHz; CDCl3): δ 3.20-3.30 (d, 2H), 5.0 (t, 1H), 6.3 (d, 1H), 6.40 (d, 1H), 6.60 (d, 1H), 7.20-7.50 (m, 7H), 7.65-7.80 (m, 3H)

Example 6: 3- {3- [2- (5-Phenyl-furan-2-yl) -vinyl] phenyl} -acrylic acid (29)

To the acid (28) (9.2 mg, 0.028 mmol) in DCM (1 mL), externally cooled to -78 ° C, was added methanesulfonyl chloride (20 mg, 0.17 mmol) and triethylamine (29 mg, 0.29). mmol). The solution was then allowed to warm to room temperature and stirred for a further 2 hours. The solvent was concentrated under vacuum and the residue purified by Flash Master Jones Chromatography using a 2 g silica cartridge and eluting with 50% EtOAc in heptane to give the title compound as a pale solid. Yield: 3.6 mg, 41%; LC-MS R t 1.77 min; HPLC purity:> 85%; MS (ES +) mlz 317 (M + H); 1H-NMR (400 MHz; DMSO): δ 6.70-6.80 (m, 2H), 7.15 (d, 1H), 7.25-7.35 (d, 1H), 7.35-7 , 45 (m, 2H), 7.50-7.60 (m, 4H), 7.65-7.75 (m, 3H), 7.90 (d, 2H), 8.10 (s, 1H )

Example 7: 3- [3- (5-Phenyl-benzoxazol-2-yl) -phenyl] -acrylic acid (34);

<formula> formula see original document page 80 </formula>

(a) 2- (3-Bromo-phenyl) -5-phenyl-benzoxazole (32)

2-Amino-4-phenylphenol (30) (250 mg, 1.20 mmol) 3-bromo-benzoylchloride (31) (265 mg, 1.20 mmol) heated in NMP at 150 ° C overnight . The reaction was cooled to room temperature, then K 2 CO 3 (aqueous) and brine were added, and the aqueous portion extracted with EtOAc (x 5). The organic layer was washed with brine, dried (Na 2 SO 4), and the solvent concentrated under vacuum. The product was purified by column chromatography eluting with a 1: 1 mixture of DCM in heptane to yield the title compound. Yield: 210 mg, 49%; LC-MS R t 2.02 min; HPLC pure: 67%; MS (ES +) mlz 350, 352 (M + H)

(b) 3- [3- (5-Phenyl-benzoxazol-2-yl) -phenyl] -acrylic acid methyl ester (33)

Tri (o-tolyl) phosphine (9 mg, 0.030 mmol), depalladium (II) acetate (6 mg, 0.027 mmol), methyl acrylate (31 mg, 0.34 mmol), triethylamine (116 mg, 1, 14 mmol) and dearyl bromide (32) (100 mg, 0.29 mmol) in acetonitrile (3 mL) heated in a CEM Discover microwave for 90 minutes at 90 ° C. The solvent was removed under gaseous nitrogen stream, water was added and the organics extracted with EtO-Ac. The organic layer was dried (Na 2 SO 4) and the solvent concentrated under vacuum. The crude product was purified by column chromatography eluting with 20% EtOAC in heptane. Yield: 41 mg, 40%; LC-MS R t 1.86 min; HPLC purity: 67%; MS (ES +) mlz 356 (M + H)

(c) 3- [3- (5-Phenyl-benzoxazol-2-yl) -phenyl] -acrylic acid (34)

Ester (33) (41 mg, 0.12 mmol) was hydrolyzed using Method C, except MeOH (3 mL), THF (3 mL) and NaOHIM (5 mL) were used and the reaction was stirred for 2 hours. Yield: 21 mg, 53%; LC-MS R t 1.74 min; HPLC purity: 96%; MS (ES +) mlz 342 (M + H); 1H-NMR (400 MHz; DSMO): δ 6.7 (d, 1H), 7.4 (t, 1H), 7.45-7.55 (t, 2H), 7.70-7.80 (m , 5H), 7.9 (d, 1H), 8.05 (d, 1H), 8.10 (s, 1H), 8.30 (d, 1H), 8.50 (s, 1H), 12 , 55 (br. S, 1H) Example 8: 3- {6 - [(5-Phenyl-furan-2-carbonyl) amino] -pyridin-2-yl} -acrylic acid (40)

<formula> formula see original document page 82 </formula>

(a) 5-phenyl-furan-2-carboxylic acid (36)

To 5-phenyl-2-furidide (35) (690 mg, 4.01 mmol) was added NaOH (176 mg, 4.40 mmol), then 10% NaOH solution (6.2 mL). Silver nitrate (680 mg, 4.00 mmol) was added and the reaction mixture heated to 60 ° C for 4.5 hours, then cooled to room temperature. The reaction mixture was then filtered and washed with water. The filtrate was acidified to pH 2 using 2N HCl and the precipitated product filtered and dried to give the title compound.

Yield: 527 mg, 70%; LC-MS R t 1.57 min; Purezapor HPLC: 98%; MS (ES +) mlz 189 (M + H)

(b) 3- (6-Amino-pyridin-2-yl) -acrylic acid methyl ester (38)

Tri (o-tholi) phosphine (26 mg, 0.086 mmol), depalladium (II) acetate (214, 0.96 mmol), methyl acrylate (90 mg, 1.04 mmol), triethylamine (351 mg, 3.47 mmols) and 2-amino-6-bromopyridine (37) (150 mg, 0.87 mmol) in acetonitrile (3mL) were heated in a CEM Discover microwave for 1 hour at 90 ° C. The solvent was removed under a stream of nitrogen gas. 4N HCl was added and the aqueous portion extracted with TBME (x 2). The aqueous layer was then basified to pH9 / 10 using K 2 CO 3 (aq) and extracted with EtOAc (x 5). The organic layer was washed with brine, dried (Na 2 SO 4) and the solvent concentrated under vacuum. The crude product was partially purified by column chromatography eluting with 50% EtOAc in heptane to give the title compound. Yield: 95 mg, 61%; LC-MS R t 0.76 min; HPLC purity: 42%; MS (ES +) mlz 179 (M + H)

(c) 3- {6 - [(5-Phenyl-furan-2-carbonyl) -amino] -pyridin-2-yl} -acrylic acid methyl ester (39)

To the acid (36) (100 mg, 0.53 mmol) was added thionyl chloride (0.5 mL), a catalytic amount of DMF (1 drop) and the reaction heated to 50 ° C for 30 minutes. After cooling, The solvent was concentrated under vacuum and azeotroped with toluene to afford acid chloride in situ. To the acid chloride was added amine (38) (95 mg, 0.53 mg) and DIPEA (69 mg, 0.53 mmol) in DCM (2 mL), and the reaction mixture stirred at room temperature overnight. . K 2 CO 3 (aq) was then added and the aqueous layer extracted with DCM. The organic layer was washed with water, dried (Na 2 SO 4) and the solvent concentrated under vacuum. The residue was partially purified using column chromatography eluting with 50% EtOAc in heptane to give the title compound. Yield: 35 mg, 19%; LC-MS R t 1.67min; HPLC purity: 52%; MS (ES +) mlz 349 (M + H)

(d) 3- {6 - [(5-phenyl-furan-2-carbonyl) -amino] -pyridin-2-yl} -acrylic acid (40)

Ester (39) (35 mg, 0.10 mmol) was hydrolyzed using Method C, except that EtOH (2 mL), THF (1 mL) and NaOH (2 mL) were used, and the reaction was stirred for 2 hours. . After preparation, the crude product was purified by preparative HPLC to give the title compound. Yield: 9.8mg, 29%; LC-MS R t 2.00 min; HPLC purity: 97%; MS (ES +) mlz 335 (M + H); 1H NMR. (400 MHz, MeOH): δ 6.95 (d, 1H), 7.05 (d, 1H), 7.35-7.55 (m, 5H), 7.65 (d, 1H), 7, 85-8.00 (m, 3H), 8.30 9 (d, 1H)

Example 9: 3- {4-Fluoro-3 - [(5-phenyl-furan-2-carbonyl) -amino] -phenyl} -acrylic acid (45)

<formula> formula see original document page 84 </formula>

(a) 3- (4-Fluoro-3-nitro-phenyl) -acrylic acid methyl ester (42)

Trimethyl phosphonoacetate (182 mg, 1.00 mmol) in THF (1.70 mL) was added dropwise (caution - vigorous reaction!) To sodium hydride (60% in oil) (60 mg, 1.50 mmol) in THF (1.70 mL) under a nitrogen atmosphere at 0 ° C. Reaction mixture was stirred for 15 minutes at 0 ° C and then 4-fluoro-3-nitrobenzaldehyde (169 mg, 1.00 mmol) in THF (0.50 mL) was added. After 1 hour, EtOAc / water was added and the organic layer is washed with more water, dried (Na 2 SO 4) and the solvent concentrated under vacuum. The crude product was purified by column chromatography with 35% EtOAc in heptane to give the title compound. Yield: 160mg, 71%; LC-MS R t 1.31 min; HPLC purity:> 75%; MS (ES +) undetectable m / z (M + H)

(b) 3- (3-Amino-4-fluoro-phenyl) -acrylic acid methyl ester (43)

Crude nitro compound (42) (160 mg, 0.71 mmol) was reduced using Method A, except that SnCl2.2H20 (0.80g, 3.55 mmols) and EtOH (3.2 mL) were used. The crude product was purified by column chromatography eluting with 25% EtOAc in heptane to give the title compound. Yield: 65 mg, 47%; LC-MS R t 1.14 min; HPLC purity: 88%; MS (ES +) mlz 195 (M + H)

(c) 3- {4-Fluoro-3 - [(5-phenylfuran-2-carbonyl) -amino] -phenyl} -acrylic acid methyl ester (44)

5-Phenyl-2-furic acid (36) (18 mg, 0.15 mmol) was coupled to aniline (43) (30 mg, 0.15 mmol) using Method B, except that DIPEA (40 mg, 0.31 mmol) and DMF (2 mL) were used and the reaction was stirred at room temperature for 2.5 hours, then at 40 ° C for 24 hours. Thereafter, TBTU (1 eq) and acid (1 eq) were added and the reaction heated at 60 ° C for a further 6 hours to give the title compound after preparation. The residue was purified using column chromatography eluting with 20% EtOAC in heptane to give the title compound. Yield: 18 mg, 32%; LC-MStr 1.55 min; HPLC purity: 83%; MS (ES +) mlz 366 (M + H)

(d) 3- {4-Fluoro-3 - [(5-phenyl-furan-2-carbonyl) -amino] -phenyl} -acrylic acid (45)

Ester (44) (18 mg, 0.049 mmol) was hydrolyzed using Method C, except that MeOH (1 mL), THF (1 mL) and NaOHIM (2 mL) were used, and the reaction was stirred for 1 hour. : 3 mg, 17%; LC-MS R t 1.44 min; HPLC purity: 91%; MS (ES +) mlz 352 (M + H): 1 H NMR (400 MHz; MeOH): δ 6.50 (d, 1H), 7.05 (d, 1H), 7.25-7.60 ( m, 6H), 7.70 (d, 1H), 7.95 (d, 2H), 8.15 (d, 1H)

Example 10: 3- {4-Chloro-3 - [(4-fluoro-biphenyl-3-carbonyl) -amino] -phenyl} -acrylic acid (52)

<formula> formula see original document page 86 </formula>

(a) 3- (4-Chloro-3-nitro-phenyl) -acrylic acid methyl ester (47) Trimethyl phosphonoacetate (245 mg, 1.35 ramol) in THF (2.5 mL) was added dropwise. -drout, (caution - vigorous reaction!) to sodium hydride (60% in oil) (83 mg, 2.02mmols) under a nitrogen atmosphere at 0 ° C. The reaction mixture was stirred for 15 minutes at 0 ° C and then 4-chloro-3-nitrobenzaldehyde (46) (250 mg, 1.35 mmol) in THF was added dropwise. After 2 hours, water was added and the solvent concentrated under vacuum. The solid was filtered and dried to afford the crude title product. Yield: 190 mg

(b) 3- (3-Amino-4-chloro-phenyl) -acrylic acid methyl ester (48)

Crude nitro compound (47) (190 mg, 0.79 mmol) was reduced using Method A, except that SnCl2.2H20 (0.89g, 3.94 mmols) and MeOH (2 mL) were used and the reaction was then heated for 3 hours. The crude product was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound as a pale solid. Yield: 69 mg, (24% yield in two steps); LC-MS tr1.32 min; MS (ES +) mlz 212 (M + H)

(c) 4-Fluorobiphenyl-3-carboxylic acid (50)

5-Bromo-2-fluoro acid (49) (2.0 g, 9.00 mmols) was coupled to phenyl boronic acid (1.23 g, 10.0 mmols) using method F, except that after 2 hours reaction , water (50mL) and TBME (50mL) were added. The mixture was filtered and the aqueous layer washed with TBME. The aqueous layer was then acidified with 1N HCl and the precipitated solid was collected and dried. Yield: 1.6 g, 82% (d) 3- {4-Chloro-3 - [[(4-fluoro-biphenyl-3-carbonyl) -amino] -phenyl} -acrylic acid methyl ester (51)

To acid (50) (66 mg, 0.30 mmol) in DCM (1.3 mL) was added oxalyl chloride (39 mg, 0.30 mmol), a catalytic amount of DMF (1 drop) and the reaction stirred at room temperature. environment for 1 hour. The solvent was concentrated under vacuum to afford acid chloride in situ. Acid chloride in DCM (1 mL) was added aniline (48) (64 mg, 0.30 mmol) in DCM (0.5 mL), then DIPEA (39 mg, 0.30 mmol) and the reaction mixture stirred at room temperature. room temperature at night. The solvent was concentrated under vacuum and the residue was purified using column chromatography eluting with 20% EtOAc in heptane to give the title compound.

Yield: 124 mg, 100%; LC-MS R t 1.94 min; HPLC purity:> 69%; MS (ES +) mlz 410 (M + H)

(e) 3- {4-Chloro-3 - [(4-fluoro-biphenyl-3-carbonyl) -amino] -phenyl} -acrylic acid (52)

Ester (51) (124 mg, 0.21) was hydrolyzed using Method C, except that MeOH (1.25 mL), THF and IM NaOH (1.25 mL) were used, and the reaction was stirred for 3 hours. The solvent was removed under a stream of nitrogen gas and the residue acidified with 1N HCl. The solid was filtered and dried to give the title compound. Yield: 91 mg, 76%; LC-MStr 2.28 min; HPLC purity: 94%; MS (ES +) mlz 396 (M + H); 1H NMR (400 MHz; DMSO): δ 6.60 (d, 1H), 7.45-7.75 (m, 7H), 7.80 ( d, 2H), 7.95 (m, 1H), 8.10 (d, 1H), 8.15 (s, 1H), 10.25 (s, 1H), 12.55 (br. s, 1H ) Example 11: 3- {3 - [(4-Fluoro-biphenyl-3-carboximidoyl) -amino] -phenyl} -acrylic acid (58)

<formula> formula see original document page 89 </formula>

(a) 4-Fluorobiphenyl-3-carbonitrile (54)

5-Bromo-2-fluorbenzonitrile (53) (500 mg, 2.54mmols) was coupled to phenylboronic acid (335 mg, 2.75mmols) with Cs2CO3 (1.63 g, 5.00 mmols) in toluene (4 mL) microwave at 140 ° C for 30 minutes. Water was added and the organics extracted several times with EtOAC, dried (MgSO 4), filtered and the solvent concentrated under vacuum. The crude product was purified by Flash Master Jones Chromatography using a 25 g silica cartridge and eluting with 10% EtOAc in heptane to yield the title compound. Yield: 375 mg, 76%; LC-MS R t 1.63 min; HPLC purity: 97%; MS (ES +) m / z undetectable (M + H)

(b) N- (3- [1,3] Dioxan-2-yl-phenyl) -4-fluoro-biphenyl-3-carboxamide (56)

To 3- (1,3-dioxan-2-yl) aniline (55) (336 mg, 1.87 mmol) in toluene (7.5 mL) cooled to 0 ° C was added a solution of 2M trimethylaluminum in heptane (1, 32 mL) dropwise and the resulting mixture was stirred at room temperature for 3.5 hours. Nitrile (54) (370 mg, 1.88 mmol) in toluene (7.5 mL) was added and the reaction heated to 70 ° C overnight. The reaction was then cooled, poured over a silica slurry in DCM / MeOH and more DCM / MeOH gushed over the organics. The filtrate was concentrated under vacuum and the residue purified by column chromatography using an EtOAc in heptane gradient (5-100%) to yield the title compound. Yield: 378 mg, 53%; LC-MS R t 1.32 min HPLC Purity: 71%; MS (ESt) mlz 377 (M + H)

(c) 4-Fluoro-N- (3-formyl-phenyl) -biphenyl-3-carboxamidine (57)

Acetal (56) (378 mg) in THF (2 mL) was added 1 N hydrochloric acid (2 mL) and the reaction mixture stirred at room temperature overnight, followed by heating to 50 ° C for a further 3 hours. hours The reaction mixture was cooled to 0 ° C and neutralized with saturated NaHCO 3 solution. The organics were extracted with EtOAC, dried (Mg-SO 4) and the solvent concentrated under vacuum to give the title compound. Yield: 307 mg, 96%; LC-MS R t 1.26 min; HPLC pure: 71%; MS (ES +) mlz 319 (M + H)

(d) 3- {3 - {(4-Fluoro-biphenyl-3-carboximidoyl) -amino] -phenyl} -acrylic acid (58)

Trimethyl phosphonoacetate (176 mg, 0.97 mmol) in THF (1.5 mL) was added dropwise (caution - vigorous reaction!) To sodium hydride (60% in oil) (58 mg, 1.46 mmol) under nitrogen atmosphere at 0 ° C. The reaction mixture was stirred for 15 minutes at 0 ° C and then aldehyde (57) (307mg, 0.97 mmol) in THF (1.50 mL) was added. After 3 hours, more sodium hydride (60% in oil) (1.5 eq) was added and the reaction mixture stirred at room temperature overnight. Saturated NaHCO 3 solution was added and washed with EtOAc. The aqueous layer was acidified to pH using 1.2M HCl and extracted with EtOAc. The aqueous layer was then neutralized to pH 7 and extracted into EtOAc. The organic layers were combined, dried (MgSO4) and the solvent concentrated in vacuo. The residue was purified by Flash Master Jones Chromatography using a 2 g silica cartridge and a gradient of EtOAc in heptane and MeOH in EtOAc to afford the title compound. Yield: 25 mg, 7%; LC-MStr 1.77 min; HPLC purity: 91%; MS (ES +) m / z 361 (M + H); 1H NMR (400 MHz; MeOH): δ 6.6 (d, 1H), 7.35-7.80 (m, 11H), 8.05 ( m, 1H), 8.15 (d, 1H)

Example 12: Biological Results

Human EP receptor binding capacity

Membranes were prepared from cells stably transfected with human EP receptor cDNA. Briefly, cells were cultured for confluence, scraped from culture flasks, and centrifuged (800 g, 8 minutes, 4 ° C).

The cells were washed twice in ice-cold homogenization buffer containing 10mM Tris-HCl, EDTA.2Na ImM, sucrose 250mM, PMSF ImM, 0.3mM indomethacin, pH 7.4, homogenized and re-centrifuged as before. The supernatant was stored on ice and the precipitates rehomogenized and rotated again. The supernatants were pooled and centrifuged at 40,000 g, 10 minutes at 4 ° C. The resulting membrane precipitates were stored at -80 ° C until use. For the assay, membranes expressing human EP4, EP3, EP2 or EPi receptors were incubated in Mil-lipore plates (MHVBN45) containing assay buffer, radiolabelled with [3HJPGE2 and concentrations of 0.1 to 10,000nM of the compounds. Incubations were performed at appropriate temperatures and for adequate times to reach equilibrium. Nonspecific binding was determined in the presence of 10μGE PGE2. Bound and free radiolabel was separated by vacuum collector filtration using appropriate wash buffers, and bound radiolabel was determined by scintillation counting. The constituents of each of the buffers are included in table 1 below.

The affinity or pKf of each receptor was calculated from the concentration that causes 50% of the displacement (IC50) using the Cheng-Prusoff equation:

<formula> formula see original document page 92 </formula>

This approach follows what was established by Kenakin in Pharmacologic of drug receptor interaction; Ra-ven Press, New York, 2nd Edition.Table 1

<table> table see original document page 93 </column> </row> <table>

Determination of agonist activity in recombinant human Ep2 prostanoid receptors and antagonist activity in EP4 prostanoid receptors.

HEK-293 cell clones stably transfected with human EP2 or EP4 prostanoid receptors were cultured at 37 ° C in a 5% CO 2 incubator in poly-L-lysine coated 96-well plates at a density of 50,000 cells / well. The culture medium was minimal essential culture medium (MEM) supplemented with 10% fetal bovine serum, 100 U / mL penicillime, 100 ng / mL streptomycin, 2.5 µg / mL fungizone, 2mM glutamine. Cells were cultured for confluence (3-4 days) prior to use. The culture medium was removed, and the confluent cells washed three times in MEM. 175 μL of assay buffer (MEM without supplements + IBMX ImM) were incubated with cell cells for 60 minutes. The cells were then stimulated by the addition of 25 μΙ; of PGE2 or agonists prepared in assay buffer. In antagonist studies, cells were preincubated with the compounds for 30 minutes prior to PGE2-mediated stimulation.

The plates were incubated for 15 minutes at 37 ° C before the end of the reaction by the addition of 25 μL of 1M HCl. Plaque was then frozen at -20 ° C overnight prior to determining cAMP concentration.

Stimulated cAMP levels were determined by radioligand displacement binding. In summary, the plates were rapidly thawed in a water bath, and samples neutralized by the addition of 25 μL of 1M NaOH. 30μL were transferred to pre-coated Millipore plates with 0.5% Polyethylenimine (PEI). Samples were diluted by the addition of 90 μΐι cAMP determination buffer (tris50mM, 5mM EDA, pH 7.0). A cAMP standard curve (10 -10M to 10-5M) was constructed. 15 μΐ of 2nM [3H] cAMP (final concentration) and 15 μL of 3'5'-cAMP protein kinase (8 μg / per final concentration well) prepared in cAMP determination buffer containing 0.1% BSA were added to each well.

The plates were incubated on ice for 2 hours before the bound and free radiolabel were separated by vacuum filtration using the Millipo-re vacuum collector, employing ice water as the termination buffer. was removed from the Millipo-re plates, and the filtrates left to dry overnight. 50μΐϋ of Microscint O (Packar Bioscience) was added to each well, and the plate counted using the Micro-BetaTrilux topcount 3H program.

CAMP accumulation was determined from the standard curve, and values calculated in pmols of cAMP / well. Antagonist affinities (pA2 values) were determined by assuming a unit slope and the Gaddam-Schild equation, where pA2 = Iog [concentration ratio-1] -Iog (antagonist). EC50, denoting the concentration of agonist required to produce 50% of the agonist response.

Table 2

<table> table see original document page 95 </column> </row> <table>

Claims (54)

1. A compound, characterized in that it is formula (III): <formula> formula see original document page 96 </formula> or a chemically protected salt, solvate and form, wherein R5 is an optionally substituted group of arylC5-C2O or alkyl C4-C20; L 'is a single bond, -0- or -C (= 0) -; A is selected from the group consisting of: <formula> formula see original document page 96 </formula> where XeY are selected from the group consisting of: 0 eCR3; S and CR3; NH and CR3; NH and N; OeN; SeN; N and S; and N and O, and where the dotted lines indicate an appropriate nolocal double bond; and where Q is either N or CH; R 3 is selected from H, F, Cl and optionally substituted groups of C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl; R 4 is selected of H, F, Cl and optionally substituted groups of C1-4 alkyl, C1-4 alkoxy, C5-7 aryl and C5-7 aryl-C1-4 alkyl; R6 is selected from H, F, Cl and optionally groups. substituted C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl; D is selected from: <formula> formula see original document page 97 </formula> B is selected from the group consisting of: where Rp6 is selected from fluorine and chlorine, where one of Rp3 and Rp4 is -Cm alkylene-R2 and the other of Rp3 and Rp4 is H, m and η may be Ooul, at + n = lou2; Additionally when Rp3 is -Cm alkylene-R2, m may also be 2 or 3, and m + η = 1, 2, 3 or 4, and when R2 is tetrazol-5-yl, m + η may be 0; or where one of Rp3 and Rp4 is -O-CH2-R2, and the other of Rp3 and Rp4 is Η, η is 0. Rn is H or optionally substituted C1-4 alkyl; R 2 is: (i) -CO 2 H; (ii) -CONH 2; (iii) -CH 2 -OH; or (iv) tetrazol-5-yl. A compound according to claim 1, characterized in that R 5 is a C 6 aryl group. A compound according to claim 2, characterized in that R 5 is phenyl. 4. A compound according to any one of claims 1 to 3, characterized by the fact that L 'is a simple bond. 5. A compound according to any of claims 1 to 4, characterized in that A is A compound according to claim 5, characterized in that R3 and R4 are H. 7. A compound according to any preceding claim, characterized by the fact that D is <formula> formula see original document page 99 </formula> A compound according to claim 7, characterized in that Rn is H. 9. A compound according to any one of claims 1 to 8, characterized in that B is <formula> formula see original document page 99 </formula> A compound according to any preceding claim, characterized in that R 2 is carboxy. A compound according to any preceding claim, characterized in that Rp4 is H and Rp3 is -CH = CH-R2. 12. Compound according to any of the preceding claims, CHARACTERIZED by the fact that η is 0. 13. Compound, characterized in that it is formula (I): <formula> formula see original document page 100 </formula> or a chemically protected salt, solvate and form, wherein R5 is an optionally substituted group of arylC5-C2O or alkyl C4-C20; L is -0- or -C (= 0) -; A is selected from the group consisting of: <formula> formula see original document page 100 </formula> where XeY are selected from the group consisting of: te at: 0 and CR3; S and CR3; NH and CR3; NH and N; 0 and N; S and Ν; N eS; and N and 0, and where the dotted lines indicate a double bond at the appropriate location; and where Q is N or CH; R 3 is selected from H, F, Cl and optionally substituted groups of C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 1-7 alkyl-C 1-4 alkyl; R 4 is selected from H. F, Cl and optionally substituted groups. substituted C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl R 6 is selected from H, F, Cl and optionally substituted groups of C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5 aryl -7-C1-4 alkyl; D is selected from: <formula> formula see original document page 101 </formula> B is selected from the group consisting of: <formula> formula see original document page 101 </formula> where R is selected from H and C1-4 alkyl; <formula> formula see original document page 101 </formula> where one of R and R is -Cm alkylene-R and the other dee Rp4 is H, m and may be Ooul, in + η = 1 or 2; Additionally when Rp3 is -Cm alkylene-R2, m may also be 2 or 3, and m + η = 1, 2, 3 or 4, and when R2 is tetrazol-- 5-yl, m + η may be 0; and where B is selected from the group that <formula> formula see original document page 102 </formula> consists of: <formula> formula see original document page 102 </formula> m + η may be 0, or where one of Rp3 and Rp4 is -O-CH2-R2, and the other of Rp3e R is Η, η is 0, Rn is H or optionally substituted C1-4 alkyl, R2 is: (i) -CO2 H (ii) -CONH2; ) -CH 2 -OH; or (iv) tetrazol-5-yl. A compound according to claim 13, characterized in that R 5 is an aryl group Ce. A compound according to claim 14, characterized in that R 5 is phenyl. 16. A compound according to any one of claims 13 to 15, characterized by the fact that A is A compound according to claim 16, characterized in that R3 and R4 are H. 18. A compound according to any one of claims 13 to 17, characterized in that D is <formula> formula see original document page 103 </formula> A compound according to claim 18, characterized in that Rn is H. 20. A compound according to any one of claims 13 to 19, characterized in that B is: <formula> formula see original document page 103 </formula> 21. A compound according to any one of claims 13 to 20, characterized in that R2 is carboxy. A compound according to any one of claims 13 to 21, characterized in that Rp4 is He and Rp3 is -CH = CH-R2. 23. Composed according to any of claims 13 to 22, characterized by the fact that η is 0. 24. Compound, characterized in that it is formula (II): <formula> formula see original document page 103 </formula> or a chemically protected salt, solvate and form, wherein R5 is an optionally substituted group of arylC5-C2O or alkyl C4-C20; L 'is a single bond, -O- or -C (= 0) -; A is selected from the group consisting of: <formula> formula see original document page 104 </formula> where X and Y are selected from the group consisting of: 0 and CR3; S and CR3; NH and CR3; NH and N; 0 and N; S and Ν; N eS; and N and 0, and where the dotted lines indicate a double bond at the appropriate location; and where Q is either N or CH; R 3 is selected from H, F, Cl and optionally substituted groups of C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl; is selected from H, F, Cl and optionally substituted groups of C 1-4 alkyl, C 1-4 alkoxy, C 5-7 aryl and C 5-7 aryl-C 1-4 alkyl; R 6 is selected from H, F, Cl and groups optionally substituted C1-4 alkyl, C1-4 alkoxy, C5-7 aryl and C5-7-aryl C1-4 alkyl; D is selected from: <formula> formula see original document page 105 </formula> B is selected from the group consisting of: <formula> formula see original document page 105 </formula> where Rn 'is selected from H and C1-4 alkyl, where one of Rp3 and Rp4 is -Cm alkylene-R2 and the other ofRp3 and Rp4 is H, me η can be Ooul, at + n = lou2; Additionally when Rp3 is -Cm alkylene-R2, m may also be 2 or 3, at + η = 1, 2, 3 or 4, and when R2 is tetrazol-- 5-yl, m + η may be 0 ; and where B is selected from the group consisting of: m + η may be 0, or where one of Rp3 and Rp4 is -O-CH2-R2, and the other of Rp3e Rp4 is Η, η is 0; Rn is H or optionally substituted C1-4 alkyl R2 is: (i) -CO2 H; (ii) -CONH2; (iii) -CH2-OH; or (iv) tetrazol-5-yl. A compound according to claim 24, characterized in that R 5 is a C 6 aryl group. A compound according to claim 25, characterized in that R 5 is phenyl. 27. A compound according to any one of claims 24 to 26, characterized by the fact that L 'is a simple bond. 28. A compound according to any one of claims 24 to 27, characterized by the fact that A is A compound according to claim 28, characterized in that R3 and R4 are H. 30. A compound according to any one of claims 24 to 29, characterized by the fact that D is selected from: <formula> formula see original document page 107 </formula> 31. A compound according to any one of claims 24 to 30, characterized by the fact that B is 32. A compound according to any one of claims 24 to 31, characterized in that R2 is carboxy. 33. A compound according to any one of claims 24 to 32, characterized in that Rp4 is He and Rp3 is -CH = CH-R2. 34. A compound according to any of claims 24 to 33, characterized by the fact that η is 0. 35. A compound, characterized in that it is formula (IV): <formula> formula see original document page 107 </formula> or a chemically protected salt, solvate and form, wherein: A 'is: <formula> formula see original wherein T is selected from O and S, R represents one or more optional substituents selected from F, Cl and optionally substituted groups of C1-4 alkyl, C1-4 alkoxy, C5-7 aryl and C 5-7 aryl-C 1-4 alkyl; and R represents one or more optional substituents selected from F, Cl and optionally substituted groups from C1-4 alkyl, C1-4 alkoxy, C5-7 aryl and C5-7 aryl-C1-4 alkyl; D is selected from: <formula> formula see original document page 109 </formula> selected from the group consisting of: <formula> formula see original document page 109 </formula> where Rn 'is selected from H and C1-4 alkyl, where Rp6 is selected from fluorine and chlorine; where one of Rp3 and Rp4 is -Cm alkylene-R2 and the other of Rp3 and Rp4 is H, m and η may be Ooul, at + η = 1 or 2; Additionally when Rp3 is -Cm alkylene-R2, m may also be 2 or 3, and m + η = 1, 2, 3 or 4, and when R2 is tetrazol-5-yl, m + η may be 0; and where B is selected from the group consisting of: m + η may be 0, or where one of Rp3 and Rp4 is -O-CH2-R2, and the other of Rp3e Rp4 is Hf η is 0, Rn is H or optionally substituted C1-4 alkyl R2 is: (i) -CO2 H; (ii) -CONH2; (iii) -CH2-OH; or (iv) tetrazol-5-yl. A compound according to claim 35, characterized in that T is 0. A compound according to claim 35 or 36, characterized in that A 'is unsubstituted. 38. A compound according to any one of claims 35 to 37, characterized in that D is <formula> formula see original document page 111 </formula> A compound according to claim 38, characterized in that Rn is H. 40. A compound according to any one of claims 35 to 39, characterized by the fact that B is: <formula> formula see original document page 111 </formula> 41. A compound according to any one of claims 35 to 40, characterized in that R2 is carboxy. 42. A compound according to any one of claims 35 to 41, characterized in that Rp4 is He and Rp3 is -CH = CH-R2. 43. A compound according to any one of claims 35 to 42, characterized by the fact that η is 0. 44. A compound, characterized in that it is formula (V): <formula> formula see original document page 111 </formula> or a chemically protected salt, solvate and form wherein: R5 is an optionally substituted group of arylC5-20 or C4-20 alkyl; Lr is a single bond, -O- or -C (= 0) -; B is selected from the group consisting of: <formula> formula see original document page 112 </formula> where Rn 'is selected from H and C1-4 alkyl, where Rp6 is selected from fluorine and chlorine, where one of Rp3 and Rp4 is -Cm alkylene-R2 and the other of Rp3 and Rp4 is H, m and η may be Ooul, at + n = lou2; and additionally when Rp3 is -Cm alkylene-R2, m may also be 2 or 3, at + η = 1, 2, 3 or 4, and when R2 is tetrazol-5-yl, m + η may be 0 and where B is selected from the group consisting of: <formula> formula see original document page 112 </formula> m + η may also be equal to 0; or where one of Rp3 and Rt "1 is -O-CH2- R 1, and the other of R 1, R 1 is, η is 0, R 11 is H or optionally substituted C 1-4 alkyl, R 2 is: (i) -CO 2 H, (ii) -CONH 2; (iv) tetrazol-5-yl. A compound according to claim 44, characterized in that R 5 is a C 6 aryl group. A compound according to claim 45, characterized in that R 5 is phenyl. 47. A compound according to any one of claims 44 to 46, characterized by the fact that L 'is a simple bond. 48. A compound according to any one of claims 44 to 47, characterized by the fact that B is: 49. A compound according to any one of claims 44 to 48, characterized in that R2 is carboxy. 50. A compound according to any one of claims 4 to 49, characterized in that Rp4 is He and Rp3 is -CH = CH-R2. 51. A compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, characterized in that it is for use in a therapeutic method. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. Use of a compound as defined in any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, characterized in that it is in the preparation of a medicament for the treatment of an agonically relieved condition of a EP2 receptor. Use according to claim 53, characterized in that the condition relieved by an EP2 receptor agonism is selected from: dysmenorrhea, premature birth, glaucoma, ocular hypertension, immune disorders, inflammatory disorders, osteoporosis, asthma. , chronic obstructive pulmonary disease, allergy, bone disease, fracture repair, male sexual dysfunction, female sexual dysfunction, infertility, periodontal disease, ulceragastric, kidney disease and psoriasis.