N- ((hetero) arylmethyl) -heteroaryl-carboxamide compounds as plasma kallikrein inhibitors

文档序号：1716992 发布日期：2019-12-17 浏览：34次中文

阅读说明：本技术 作为血浆激肽释放酶抑制剂的n-((杂)芳基甲基)-杂芳基-甲酰胺化合物 (N- ((hetero) arylmethyl) -heteroaryl-carboxamide compounds as plasma kallikrein inhibitors ) 是由丽贝卡·路易丝·戴维汉娜·乔伊·爱德华兹戴维·米歇尔·埃万斯西蒙·泰亚比·霍奇森于 2015-11-26 设计创作，主要内容包括：本发明提供式(I)的化合物；(I)包含这样的化合物的组合物；这样的化合物在治疗(例如在治疗或预防涉及血浆激肽释放酶活性的疾病或病症)中的用途；以及利用这样的化合物治疗患者的方法；其中R5、R6、R7、A、B、W、X、Y和Z如本文所定义。<Image he="639" wi="606" file="DDA0002175892660000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides compounds of formula (I); (I) compositions comprising such compounds; the use of such compounds in therapy (e.g. in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R5, R6, R7, A, B, W, X, Y and Z are as defined herein.)

1. A compound of the formula (I),

Wherein

B is phenyl substituted with 1 to 4 substituents selected from: alkyl radical^bAlkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃and CF₃；

Or B is selected from benzothienyl, benzofuranyl, benzomorpholinyl, and a 5 or 6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein the 5 or 6 membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothienyl, said benzofuranyl, said benzomorpholinyl, or said 5 or 6 membered heterocycle is substituted with 1 to 3 substituents selected from: alkyl radical^balkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃And CF₃；

W is C and X, Y and Z are independently selected from C, N, O and S such that the ring containing W, X, Y and Z is a five-membered aromatic heterocycle;

R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, -NR8R9, CN, -NR8COR9 and CF₃(ii) a Wherein at least one of R5 and R6 is present and is not H;

R7 is H;

A is selected from aryl and heteroaryl; wherein aryl is substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, - (CH)₂)_0-3-O-heteroaryl, aryl^b-O-aryl^b，-(CH₂)_1-3-aryl radical^b，-(CH₂)_1-3-heteroaryl, -COOR10, -CONR10R11, - (CH)₂)_0-3-NR10R11，OCF₃And CF₃(ii) a And heteroaryl is substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF₃Halo, CN, aryl, - (CH)₂)_1-3-aryl, - (CH)₂)_0-3-NR10R11, heteroaryl^b-COOR10, -CONR10R11 and CF₃；

R8 and R9 are independently selected from H and alkyl;

Alkyl is a radical having up to 10 carbon atoms (C)₁-C₁₀) Or a straight-chain saturated hydrocarbon of 3 to 10 carbon atoms (C)₃-C₁₀) Branched saturated hydrocarbons of (4); alkyl may be optionally substituted with 1 or 2 substituents independently selected from: (C)₁-C₆) Alkoxy, OH, CN, CF₃COOR10, CONR10R11, fluoro and NR10R 11;

Alkyl radical^bIs a straight-chain saturated hydrocarbon having up to 6 carbon atoms or 3 to 6 carbon atoms (C)_3-6) Branched saturated hydrocarbons of (4); alkyl radical^bmay be optionally substituted with 1 or 2 substituents independently selected from: (C)₁-C₆) Alkoxy, OH, CN, CF₃COOR10, CONR10R11 and fluoro;

Cycloalkyl is a monocyclic saturated hydrocarbon of 3 to 6 carbon atoms;

Alkoxy is 1 to 6 carbon atoms (C)₁-C₆) Or 3 to 6 carbon atoms (C)₃-C₆) Branched O-linked hydrocarbons of (a); alkoxy may be optionally substituted with 1 or 2 substituents independently selected from: OH, CN, CF₃CONR10R11, fluoro and NR10R 11;

Aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, - (CH)₂)_0-3-O-heteroaryl, aryl^b-O-aryl^b，-(CH₂)_1-3-aryl radical^b，-(CH₂)_1-3-heteroaryl, -COOR10, -CONR10R11, - (CH)₂)_0-3-NR10R11，OCF₃and CF₃；

Aryl radicals^bIs phenyl, biphenyl or naphthyl, which may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, halo, CN, -COOR10, -CONR10R11, CF₃And NR10R 11;

heteroaryl is a 5, 6, 9 or10 membered monocyclic or bicyclic aromatic ring, said aromaticThe ring contains, where possible, 1, 2, 3 or 4 ring members independently selected from N, NR8, S and O; heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF₃Halo, CN, aryl, - (CH)₂)_1-3-aryl, - (CH)₂)_0-3-NR10R11, heteroaryl^b-COOR10, -CONR10R11 and CF₃；

heteroaryl radical^bIs a 5, 6, 9 or10 membered monocyclic or bicyclic aromatic ring containing, where possible, 1, 2 or 3 ring members independently selected from N, NR8, S and O; wherein the heteroaryl group^bmay be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, halo, CN, aryl, - (CH)₂)_1-3-aryl, -COOR10, -CONR10R11, CF₃and NR10R 11;

r10 and R11 are independently selected from H, alkyl, aryl^band heteroaryl^bOr R10 and R11 together with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6-or 7-membered heterocyclic ring optionally containing a further heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono-or disubstituted by substituents selected from: oxo, alkyl, alkoxy, OH, halo and CF₃；

And pharmaceutically acceptable salts and solvates thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B is selected from phenyl substituted with 1 to 4 substituents selected from: alkyl radical^balkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃And CF₃(ii) a Or B is selected from benzothienyl, benzofuranyl and a 5 or 6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein the 5 or 6 membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothienyl, said benzofuranyl, or said 5 or 6 membered heterocycle is substituted with 1 to 3 substituents selected from: alkane (I) and its preparation methodbase of^balkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃And CF₃(ii) a Wherein the alkyl radical^balkoxy, R8 and R9 are as defined in claim 1.

3. the compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B is selected from phenyl, thienyl, benzothienyl and pyridyl, each of which is substituted with 1 to 3 substituents selected from: alkyl radical^bAlkoxy, halo, CN, COOR8, CONR8R9, OCF₃And CF₃(ii) a Wherein the alkyl radical^bAlkoxy, R8 and R9 are as defined in claim 1.

4. the compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B is selected from phenyl and pyridyl, each of which is substituted with 1 to 3 substituents selected from: alkyl radical^balkoxy, CF₃And halo; wherein the alkyl radical^band alkoxy is as defined in claim 1.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C and X, Y and Z are independently selected from C and N such that the ring containing W, X, Y and Z is a five-membered aromatic heterocycle.

6. the compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C, X is N and Y and Z are selected from C and N.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 and R6 are independently absent or independently selected from H, CH₂OCH₃cycloalkyl, -NR8R9, -NR8COR9, CN and CF₃(ii) a Wherein cycloalkyl, R8 and R9 are as defined in claim 1; and wherein at least one of R5 and R6 is present and is not H.

8. according to claim 1 or 2A compound or pharmaceutically acceptable salt or solvate thereof, wherein R5 is CH₂OCH₃。

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein a is- (CH) or₂)_1-3-heteroaryl or- (CH)₂)_1-3-NR10R11 and optionally substituted with 1 or 2 additional substituents independently selected from alkyl, halo and CF₃phenyl substituted with the substituent of (1); wherein alkyl, heteroaryl, R10 and R11 are as defined in claim 1.

10. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein a is heteroaryl^bor-NR 10R11 and optionally substituted with 1 or 2 additional substituents independently selected from alkyl, halo and CF₃Pyridyl substituted with the substituent(s) of (a); wherein alkyl, heteroaryl^br10 and R11 are as defined in claim 1.

11. a compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R10 and R11 together with the nitrogen atom to which they are attached form a carbon-containing 5-or 6-membered heterocyclic ring optionally containing a further N atom, which may be saturated or unsaturated with 1 or 2 double bonds, and optionally mono-or di-substituted by a substituent selected from oxo, methyl, Cl and F.

12. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein a is selected from:

13. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein a is selected from:

14. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein a is selected from:

15. A compound according to claim 1, selected from the following:

3-amino-1- [4- (2-oxo-2H-pyridin-1-ylmethyl) -benzyl ] -1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-5-methoxyphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (4-chloro-2, 6-difluorophenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- { [ 3-chloro-2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-4-methylphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (3-fluoro-4-methoxypyridin-2-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (5-chloro-1-benzothien-3-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

3-cyclopropyl-N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (2-fluoro-3, 6-dimethoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3- (dimethylamino) -N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-5-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-4-methylphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [2- (difluoromethyl) phenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [2- (difluoromethyl) -3-methoxyphenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3-amino-N- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3-acetamido-N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (3-chloro-2, 6-difluorophenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (5-chloro-2-cyanophenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (6-cyano-2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [ 5-methoxy-2- (trifluoromethyl) phenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [2- (difluoromethyl) -6-fluorophenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- { [2- (difluoromethyl) -5-methoxyphenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- { [2- (difluoromethyl) -6-fluoro-3-methoxyphenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-carbamoyl-6-fluorophenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-carbamoyl-5-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- { [3- (difluoromethoxy) -2-fluorophenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [2- (difluoromethoxy) -6-fluorophenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2, 5-difluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-6-methylphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (6-chloro-2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3-amino-N- [ (2-fluoro-3-hydroxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (3-ethyl-2-fluorophenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3- (methoxymethyl) -N- [ (3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (4-methyl-2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (5-fluoro-2-oxopyridin-1-yl) methyl ] phenyl } methyl) -3- (methoxymethyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -2-methyl-1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) imidazole-4-carboxamide;

n- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) -2- (trifluoromethyl) imidazole-4-carboxamide;

3-amino-N- [ (7-chloro-4-methyl-2, 3-dihydro-1, 4-benzoOxazin-2-yl) methyl]-1- ({4- [ (2-oxopyridin-1-yl) methyl]Phenyl } methyl) pyrazole-4-carboxamide;

3-amino-N- [ (7-chloro-3, 4-dihydro-2H-1, 4-benzoOxazin-2-yl) methyl]-1- ({4- [ (2-oxopyridin-1-yl) methyl]Phenyl } methyl) pyrazole-4-carboxamides

and pharmaceutically acceptable salts and solvates thereof.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

17. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated.

18. Use according to claim 17, wherein the disease or condition involving plasma kallikrein activity is selected from the following: impaired visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and post-surgical bleeding.

19. The use according to claim 17, wherein the disease or condition involving plasma kallikrein activity is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

20. the use according to claim 17, wherein the disease or condition in which plasma kallikrein activity is implicated is diabetic macular edema.

21. The use according to claim 17, wherein the disease or condition in which plasma kallikrein activity is implicated is hereditary angioedema.

22. the use according to claim 17, wherein the disease or condition involving plasma kallikrein activity is inflammation.

Background

the heterocyclic derivatives of the present invention are inhibitors of plasma kallikrein and have a number of therapeutic applications, in particular in the treatment of retinal vascular permeability (retinal vascular permeability) associated with diabetic retinopathy and diabetic macular edema.

plasma Kallikrein, a trypsin-like serine protease that can release kinins from kininogens (see K.D. Bhoola et al, "Kallikrein-kinetin Cascade", Encyclopedia of respiratory Medicine, p 483-493; J.W.Bryant et al, "Human plasma Kallikrein-kinetin system: physical and Biological parameters (Human plasma Kallikrein-kininosystem: physiological and biochemical parameters)," Cardiovascular and hematological chemistry agents in pharmaceutical chemistry ", Med.234-250, 2009; K.D. Bhoola et al, Biological v., Pharmacologal, 1992, 44, and J.44. C.J.S. read and study of peptides from the Journal system: Biological peptides, see results of kininogenases measurement of kininogens in Biological systems, 33, 665-677). Although the role of plasma kallikrein in the coagulation cascade does not involve release of bradykinin or enzymatic cleavage, it is an essential member of the cascade. Plasma prekallikrein is encoded by a single gene and synthesized in the liver. It is secreted by hepatocytes as an inactive plasma prekallikrein which circulates in plasma as a heterodimeric complex bound to high molecular weight kininogen, which is activated to produce active plasma kallikrein. Kinins are potent mediators of inflammation that act through G-protein coupled receptors, and antagonists of kinins (such as bradykinin antagonists) have been previously investigated as potential therapeutic agents for the treatment of a variety of conditions (f. marceau and d. regoli, Nature rev., Drug Discovery, 2004, 3, 845-852).

Plasma kallikrein is thought to play a role in a variety of inflammatory disorders. The main inhibitor of plasma kallikrein is the serine protease inhibitor protein C1 esterase inhibitor (serpin C1 esterase inhibitor). Patients with genetic defects in C1 esterase inhibitors develop Hereditary Angioedema (HAE), which leads to intermittent swelling of the face, hands, throat, gastrointestinal tract and genitalia. The vesicles formed during acute episodes contain high levels of plasma kallikrein, which cleaves high molecular weight kininogen to release bradykinin, resulting in increased vascular permeability. Treatment with large protein plasma kallikrein inhibitors has been shown to be effective in treating HAE by preventing the release of bradykinin which causes increased vascular permeability (a. lehmann "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of genetic angioedema and the prevention of blood loss in on-pump cardiac surgery)" Expert opin. biol. ther.8, p 1187-99).

The plasma kallikrein-kinin system is abnormally abundant in patients with late diabetic macular edema. It has recently been disclosed that Plasma kallikrein contributes to retinal vascular dysfunction in diabetic rats (a. clermont et al "Plasma kallikrein mechanisms involved in retinal vascular dysfunction and indulges involved in retinal thickening in Diabetes)" Diabetes, 2011, 60, p 1590-98. In addition, administration of the plasma kallikrein inhibitor ASP-440 reduced retinal vascular permeability and retinal blood flow abnormalities in diabetic rats. Therefore, plasma kallikrein inhibitors should have utility as therapeutic agents to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

Other complications of diabetes, such as cerebral hemorrhage, nephropathy, cardiomyopathy, and neuropathy, all of which are associated with plasma kallikrein, can also be considered targets for plasma kallikrein inhibitors.

synthetic and small molecule plasma kallikrein Inhibitors have been described previously, for example by Garrett et al ("Peptide inhibitor", J.peptide Res.52, p62-71(1998)), T.Griesbacher et al ("invent of tissue. kallikrein but for tissue protein secretion peptides in the Development of symptoms mediated by endogenous kinins in rat acute pancreatitis", see "tissue kallikrein instead of plasma kallikrein", see "Peptide Inhibitors" ("Peptide Inhibitors", "protein Inhibitors", "protein", "Peptide Inhibitors", "protein Inhibitors", "protein Inhibitors",.

to date, no small molecule synthetic plasma kallikrein inhibitor has been approved for medical use. The molecules described in the known art have limitations such as poor selectivity in relation to related enzymes like KLK1, thrombin and other serine proteases, as well as poor oral availability. Large protein plasma kallikrein inhibitors risk anaphylactic reactions as reported for escalatide (Ecallantide). Thus, there remains a need for compounds that selectively inhibit plasma kallikrein, do not induce allergic reactions, and are orally available. Furthermore, the vast majority of molecules in the known art are characterized by a high degree of polarity and ionizable guanidine or amidine functionality. It is well known that such functionality may be limited to intestinal permeability and therefore oral availability. For example, Tamie J. Chilcote and Sukanto Sinha ("ASP-634: An Oral drug candidate for Diabetic macular edema)," ARVO 5.6.2012-5.9.2012, Fort Lauderdale, Florida, Presentation2240) have reported that ASP-440 (a benzamidine) has poor Oral availability. It is further reported that absorption can be improved by generating a prodrug such as ASP-634. However, it is known that prodrugs may have several disadvantages, such as poor chemical stability and potential toxicity from inert carriers or unexpected metabolites. In another report, indoleamides, as compounds that may overcome the problems associated with drugs with poor or inadequate ADME-tox and physicochemical properties, are claimed, but no inhibition of plasma kallikrein is given or claimed (griffien et al, "Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases", WO2010, 142801).

BioCryst Pharmaceuticals inc. has reported the discovery Of An orally available Plasma Kallikrein Inhibitor BCX4161 ("BCX 4161, An Oral Kallikrein Inhibitor: Safety and pharmacokinetic Results Of Phase 1 studies In Healthy Volunteers" BCX4161, An Oral Kallikrein Inhibitor, Journal Of Allergy and Clinical Immunology, Volume 133, Issue 2, Supplement, February 2014, page AB39 and "a Simple, Sensitive and Selective fluorescence assay to Monitor the Activity Of a Kallikrein Inhibitor BCX4161, Plasma selectivity and inhibition Of Plasma Activity 40", Simple fluorescence inhibition Of Plasma Kallikrein In inhibition, Plasma 4161, Plasma 19, inhibition Of Plasma Activity, Plasma 19, Plasma 201432, etc. However, human doses are relatively large and are currently tested in proof of concept studies at doses of 400mg three times a day.

There have been few reports of plasma kallikrein inhibitors that are not characterized by guanidine or amidine functionality. An example is Brandl et al ("N- ((6-amino-pyridin-3-yl) methyl) -hexanoyl-amides inhibitors of plasma kallikrein" WO2012/017020), which describes compounds characterized by amino-pyridine functionality. The oral efficacy was verified in the rat model at higher doses of 30mg/kg and 100mg/kg, but no pharmacokinetic profile was reported. Therefore, it is not yet known whether such compounds will provide sufficient oral availability or efficacy for clinical progress. Other examples are Brandl et al ("Aminopyradine derivatives as plasmatic enzyme inhibitors" WO2013/111107) and Flohr et al ("5-memberanderoerylcarboxamide derivatives as plasmatic enzyme inhibitors" WO 2013/111108). However, none of these documents reports any in vivo data and therefore it is not yet known whether such compounds would provide sufficient oral availability or efficacy for clinical progress. Another example is Allen et al "Benzylamine derivatives" WO 2014/108679.

Accordingly, there is a need to develop new plasma kallikrein inhibitors that are useful in the treatment of various disorders, in particular for reducing retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. Preferred compounds will have good pharmacokinetic properties and are particularly useful for drugs for oral delivery.

summary of The Invention

The present invention relates to a series of heterocyclic derivatives as inhibitors of plasma kallikrein. These compounds show good selectivity for plasma kallikrein and are potentially useful in the treatment of impaired visual acuity (impaired visual acuity), diabetic retinopathy (diabetic retinopathy), macular edema (macular edema), hereditary angioedema (hereditary angioedema), diabetes mellitus (diabetes), pancreatitis (pancreatic inflammation), cerebral hemorrhage (ventricular haematography), nephropathy (nephropathy), cardiomyopathy (cardiomyopathy), neuropathy (neuropathy), inflammatory bowel disease (inflammatory bowel disease), arthritis (arthritis), inflammation (inflammation), septic shock (cardiac shock), hypotension (hypertension), cancer, adult respiratory distress syndrome (acute respiratory syndrome), disseminated vascular disease (surgery), cardiopulmonary bypass (cardiopulmonary bypass). The invention also relates to pharmaceutical compositions of said inhibitors, the use of said compositions as therapeutic agents and methods of treatment using these compositions.

in a first aspect, the present invention provides a compound of formula I

Wherein

B is phenyl substituted with 1 to 4 substituents selected from: alkyl radical^bAlkoxy, OH, halo (halogen, halo), CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃And CF₃；

or B is selected from benzothienyl, benzofuranyl, benzomorpholinyl, and a 5 or 6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein the 5 or 6 membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothienyl, said benzofuranyl, said benzomorpholinyl, or said 5 or 6 membered heterocycle is substituted with 1 to 3 substituents selected from: alkyl radical^bAlkoxy, OH, oxo (oxo), halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃And CF₃；

w is C and X, Y and Z are independently selected from C, N, O and S such that the ring containing W, X, Y and Z is a five-membered aromatic heterocycle;

R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, alkoxy, halo, OH, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9 and CF 6₃(ii) a Wherein at least one of R5 and R6 is present and is not H;

R7 is H;

A is selected from aryl and heteroaryl; wherein aryl is substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, - (CH)₂)_0-3-O-heteroaryl, aryl^b-O-aryl^b，-(CH₂)_1-3-aryl radical^b，-(CH₂)_1-3-heteroaryl, -COOR10, -CONR10R11, - (CH)₂)_0-3-NR10R11，OCF₃And CF₃(ii) a And heteroaryl is substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF₃halo, CN, aryl, - (CH)₂)_1-3-aryl, - (CH)₂)_0-3-NR10R11, heteroaryl^b-COOR10, -CONR10R11 and CF₃；

R8 and R9 are independently selected from H and alkyl;

Alkyl is a radical having up to 10 carbon atoms (C)₁-C₁₀) Or a straight-chain saturated hydrocarbon (group) or a hydrocarbon having 3 to 10 carbon atoms (C)₃-C₁₀) Branched saturated hydrocarbons (groups); alkyl may be optionally substituted with 1 or 2 substituents independently selected from: (C)₁-C₆) Alkoxy, OH, CN, CF₃COOR10, CONR10R11, fluoro and NR10R 11;

alkyl radical^bIs a straight-chain saturated hydrocarbon (radical) having up to 6 carbon atoms or 3 to 6 carbon atoms (C)_3-6) Branched saturated hydrocarbons (groups); alkyl radical^bMay be optionally substituted with 1 or 2 substituents independently selected from: (C)₁-C₆) Alkoxy, OH, CN, CF₃COOR10, CONR10R11 and fluoro;

Cycloalkyl is a monocyclic saturated hydrocarbon (group) of 3 to 6 carbon atoms;

Alkoxy is 1 to 6 carbon atoms (C)₁-C₆) Or a linear O-linked hydrocarbon (group) of 3 to 6 carbon atoms (C)₃-C₆) Branched O-linked hydrocarbons (groups); alkoxy may be optionally substituted with 1 or 2 substituents independently selected from: OH, CN, CF₃COOR10, CONR10R11, fluoro and NR10R 11;

aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, - (CH)₂)_0-3-O-heteroaryl, aryl^b-O-aryl^b，-(CH₂)_1-3-aryl radical^b，-(CH₂)_1-3-heteroaryl, -COOR10, -CONR10R11, - (CH)₂)_0-3-NR10R11，OCF₃And CF₃；

Aryl radicals^bis phenyl, biphenyl or naphthyl, which may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, halo, CN, -COOR10, -CONR10R11, CF₃And NR10R 11;

Heteroaryl is a 5, 6, 9 or10 membered monocyclic or bicyclic aromatic ring containing, where possible, 1, 2, 3 or 4 ring members independently selected from N, NR8, S and O; heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF₃Halo, CN, aryl, - (CH)₂)_1-3-aryl, - (CH)₂)_0-3-NR10R11, heteroaryl^b-COOR10, -CONR10R11 and CF₃；

Heteroaryl radical^bIs a 5, 6, 9 or10 membered monocyclic or bicyclic aromatic ring containing, where possible, 1, 2 or 3 ring members independently selected from N, NR8, S and O; wherein the heteroaryl group^bmay be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, halo, CN, aryl, - (CH)₂)_1-3-aryl, -COOR10, -CONR10R11, CF₃and NR10R 11;

R10 and R11 are independently selected from H, alkyl, aryl^bAnd heteroaryl^bOr R10 and R11 together with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6-or 7-membered heterocyclic ring optionally containing a further heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono-or disubstituted by substituents selected from: oxo, alkyl, alkoxy, OH, halo and CF₃；

And tautomers, isomers, stereoisomers (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), pharmaceutically acceptable salts, and solvates thereof.

in another aspect, the present invention provides a prodrug of a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides an N-oxide of a compound of formula (I) as defined herein, or a prodrug or pharmaceutically acceptable salt thereof.

it will be understood that certain compounds of the present invention may exist in solvated (e.g. hydrated) as well as unsolvated forms. It is to be understood that the invention encompasses all such solvated forms.

In a further aspect, there is also provided a compound of formula (I), wherein:

b is selected from the group consisting of phenyl, thienyl, benzothienyl, and pyridyl, each of which is substituted with 1 to 3 substituents selected from the group consisting of: alkyl radical^bAlkoxy, halo, CN, COOR8, CONR8R9, OCF₃and CF₃(ii) a Wherein the alkyl radical^balkoxy, R8 and R9 are as defined above;

W is C and X, Y and Z are independently selected from C and N such that the ring containing W, X, Y and Z is a five-membered aromatic heterocycle;

r5 and R6 are independently absent or independently selected from H, CH₂OCH₃cycloalkyl, -NR8R9, -NR8COR9 and CF₃(ii) a Wherein at least one of R5 and R6 is present and is not H;

R7 is H;

a is selected from:

Wherein alkyl, cycloalkyl, alkoxy, R8 and R9 are as defined above;

And tautomers, isomers, stereoisomers (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), pharmaceutically acceptable salts, and solvates thereof.

In a further aspect, there is also provided a compound of formula (I), wherein:

B is selected from phenyl and pyridyl, each of which is substituted by 1 to 3 substituentsSubstituents selected from the following: methyl, ethyl, methoxy, ethoxy, CF₃CN and F;

W is C, X is N and Y and Z are selected from C and N;

R7 is H and R5 and R6 are independently absent or independently selected from H, CH₂OCH₃Cyclopropyl, NH₂And CF₃(ii) a Wherein at least one of R5 and R6 is present and is not H;

A is selected from:

And tautomers, isomers, stereoisomers (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), pharmaceutically acceptable salts, and solvates thereof.

the aspects of the invention described above may also include the following features:

b is phenyl substituted with 1 to 4 substituents selected from: alkyl radical^balkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃And CF₃(ii) a Or B is selected from benzothienyl, benzofuranyl, benzomorpholinyl, and a 5 or 6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein the 5 or 6 membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothienyl, said benzofuranyl, said benzomorpholinyl, or said 5 or 6 membered heterocycle is substituted with 1 to 3 substituents selected from: alkyl radical^balkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃And CF₃；

B is phenyl substituted with 1 to 4 substituents selected from: alkyl radical^bAlkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃And CF₃(ii) a Or B is selected from benzothienyl, benzofuranyl and a 5 or 6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein the 5-or 6-membered heterocyclic ring may be aromatic or non-aromaticAromatic; and wherein said benzothienyl, said benzofuranyl, or said 5 or 6 membered heterocycle is substituted with a substituent selected from 1 to 3: alkyl radical^bAlkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃And CF₃(ii) a Wherein the alkyl radical^bAlkoxy, R8 and R9 are as defined above.

B is selected from phenyl, pyridyl, pyrimidinone, pyrimidine, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, isothiazolylAzolyl group,Oxazolyl, thienyl, benzothienyl and furyl, each of which is substituted, where possible, with 1 to 3 substituents selected from: alkyl radical^balkoxy, OH, oxo, halo, CN, COOR8, CONR8R9, OCF₃And CF₃(ii) a Wherein the alkyl radical^bAlkoxy, R8 and R9 are as defined above.

B is selected from phenyl, pyridyl, pyrimidone, thiazolyl, pyrazolyl, isooxazolyl, thienyl, benzothienyl and furyl, each of which is substituted, where possible, with 1 to 3 substituents selected from: alkyl radical^bAlkoxy, OH, oxo, halo, CN, COOR8, CONR8R9, OCF₃And CF₃(ii) a Wherein the alkyl radical^bAlkoxy, R8 and R9 are as defined above.

B is selected from phenyl, thienyl, benzothienyl and pyridyl, each of which is substituted with 1 to 3 substituents selected from: alkyl radical^balkoxy, halo, CN, COOR8, CONR8R9, OCF₃And CF₃(ii) a Wherein the alkyl radical^balkoxy, R8 and R9 are as defined above.

B is selected from phenyl and pyridyl, which areEach substituted with 1 to 3 substituents selected from: alkyl radical^bAlkoxy, CN, CF₃and halo; wherein the alkyl radical^bAnd alkoxy is as defined above.

B is selected from phenyl and pyridyl, each of which is substituted with 1 to 3 substituents selected from: alkyl radical^bAlkoxy, CF₃And halo; wherein the alkyl radical^bAnd alkoxy is as defined above.

B is selected from phenyl and pyridyl, each of which is substituted with 1 to 3 substituents selected from: methyl, ethyl, methoxy, ethoxy, CF₃CN and F.

b is selected from phenyl and pyridyl, each of which is substituted with 1 to 3 substituents selected from: methyl, ethyl, methoxy, ethoxy, CF₃，Cl，CHF₂And F.

B is selected from phenyl substituted with 1 to 3 substituents selected from: methyl, ethyl, methoxy, ethoxy, CN, CF₃，Cl，CHF₂and F.

B is selected from phenyl substituted with 1 to 3 substituents selected from: methyl, ethyl, methoxy, ethoxy, CF₃，Cl，CHF₂And F.

w is C and X, Y and Z are independently selected from C and N such that the ring containing W, X, Y and Z is a five-membered aromatic heterocycle.

w is C and X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is selected from pyrrole, pyrazole, imidazole, and 1, 2, 3-triazole.

w is C and X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is selected from pyrazole and imidazole.

w is C.

X is N.

W is C, X is N and Y and Z are selected from C and N.

w is C, X is N, Y is N and Z is C.

W is C, X is N, Y is C and Z is N.

R5 and R6 independentlyIs absent or is independently selected from H, alkyl, cycloalkyl, alkoxy, halo, OH, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9, and CF₃(ii) a Wherein at least one of R5 and R6 is present and is not H; wherein alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, R8 and R9 are as defined above.

R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, -NR8R9, CN, -NR8COR9 and CF₃(ii) a Wherein at least one of R5 and R6 is present and is not H; wherein alkyl, cycloalkyl, R8 and R9 are as defined above.

r5 and R6 are independently absent or independently selected from H, CH₂OCH₃Cycloalkyl, CN, -NR8R9, -NR8COR9 and CF₃(ii) a Wherein at least one of R5 and R6 is present and is not H; wherein cycloalkyl, R8 and R9 are as defined above.

R5 and R6 are independently absent or independently selected from H, cycloalkyl, CN, -NR8R9, -NR8COR9 and CF₃(ii) a Wherein at least one of R5 and R6 is present and is not H; wherein cycloalkyl, R8 and R9 are as defined above.

R5 and R6 are independently absent or independently selected from H, CH₂OCH₃Cycloalkyl, CN, NR8R9 and CF₃(ii) a Wherein R8 and R9 are H and cycloalkyl is as defined above; and wherein at least one of R5 and R6 is present and is not H.

r7 is H.

R7 is H and R5 and R6 are independently absent or independently selected from H, CH₂OCH₃Cyclopropyl, CN, NH₂And CF₃(ii) a Wherein at least one of R5 and R6 is present and is not H.

r7 is H and R5 and R6 are independently absent or independently selected from H, CH₂OCH₃cyclopropyl, NH₂CN and CF₃(ii) a Wherein at least one of R5 and R6 is present and notIs H.

r7 is H and R5 and R6 are independently absent or independently selected from H, CH₂OCH₃Cyclopropyl, NH₂And CF₃(ii) a Wherein at least one of R5 and R6 is present and is not H.

R7 is H, R6 is absent and R5 is selected from CH₂OCH₃Cyclopropyl, NH₂and CF₃。

R7 is H, R6 is absent and R5 is CH₂OCH₃。

W is C, X is N, Y and Z are selected from C and N, R7 is H and R5 and R6 are independently absent or independently selected from H, CH₂OCH₃Cycloalkyl, NR8R9 and CF₃(ii) a Wherein R8 and R9 are H and cycloalkyl is as defined above.

w is C, X is N, Y is N, Z is C, R7 is H, R6 is absent and R5 is selected from CH₂OCH₃cyclopropyl, NH₂And CF₃。

A is selected from aryl and heteroaryl, each of which is substituted as described above.

A is phenyl, pyridyl, thienyl or quinolinyl, each of which is substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, halo, CN, aryl^b，-(CH₂)_1-3-aryl radical^b，-(CH₂)_1-3-heteroaryl, - (CH)₂)_0-3-NR10R11 and CF₃(ii) a Wherein alkyl, alkoxy, heteroaryl, aryl^br10 and R11 are as defined above.

a is phenyl or pyridyl, each of which is substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, halo, - (CH)₂)_1-3-aryl radical^b，-(CH₂)_1-3-heteroaryl, CF₃and- (CH)₂)_0-3-NR10R 11; wherein alkyl, alkoxy, heteroaryl, aryl^bR10 and R11 are as defined above.

a is 1, 2 or 3 independently selected fromPyridyl substituted with the substituent(s) in (1): alkyl, halo, heteroaryl^b，CF₃and-NR 10R 11; wherein alkyl, heteroaryl^br10 and R11 are as defined above.

a is heteroaryl^bor-NR 10R11 and optionally substituted with 1 or 2 additional substituents independently selected from alkyl, halo and CF₃(ii) a Wherein alkyl, heteroaryl^br10 and R11 are as defined above.

A is phenyl substituted with 1, 2 or 3 substituents independently selected from: alkyl, halo, - (CH)₂)_1-3-heteroaryl, CF₃And- (CH)₂)_1-3-NR10R 11; wherein alkyl, heteroaryl, R10 and R11 are as defined above.

A is- (CH)₂)_1-3-heteroaryl or- (CH)₂)_1-3-NR10R11 and optionally substituted with 1 or 2 additional substituents independently selected from alkyl, halo and CF₃Phenyl substituted with the substituent of (1); wherein alkyl, heteroaryl, R10 and R11 are as defined above.

A is selected from:

a is:

R8 and R9 are independently selected from H and alkyl; wherein alkyl is as defined above.

R8 and R9 are independently selected from H and methyl, ethyl, n-propyl and isopropyl.

R8 and R9 are independently selected from H and methyl.

R10 and R11 are independently selected from H, alkyl, aryl^band heteroaryl^bOr R10 and R11 together with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6-or 7-membered heterocyclic ring optionally containing a further heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono-or disubstituted by substituents selected from: oxo, alkyl, alkoxy, OH, halo and CF₃(ii) a Wherein the alkyl, alkoxy, aryl^band heteroaryl^bis as defined above.

R10 and R11 are independently selected from H and alkyl or R10 and R11 form together with the nitrogen atom to which they are attached a carbon-containing 5 or 6 membered heterocyclic ring optionally containing a further N atom, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono-or disubstituted by substituents selected from: oxo, alkyl, alkoxy, OH, Cl, F and CF₃(ii) a Wherein alkyl and alkoxy are as defined above.

r10 and R11 are independently selected from H and alkyl or R10 and R11 form together with the nitrogen atom to which they are attached a 5 or 6 membered carbon containing heterocyclic ring optionally containing a further N atom which may be saturated or unsaturated with 1 or 2 double bonds and optionally mono or disubstituted with substituents selected from: oxo, methyl, Cl and F; wherein alkyl is as defined above.

R10 and R11, together with the nitrogen atom to which they are attached, form a 5-or 6-membered carbon-containing heterocyclic ring, optionally containing a further N atom, which may be saturated or unsaturated with 1 or 2 double bonds, and optionally mono-or disubstituted by substituents selected from: oxo, methyl, Cl and F.

R10 and R11, together with the nitrogen atom to which they are attached, form a 6-membered carbon-containing heterocyclic ring, optionally containing a further N atom, which may be saturated or unsaturated with 1 or 2 double bonds, and which may optionally be substituted by oxo.

R10 and R11 form, together with the nitrogen atom to which they are attached, a carbon-containing 5-or 6-membered saturated heterocyclic ring.

r10 and R11 are independently selected from H and alkyl^b(ii) a Wherein the alkyl radical^bIs as defined above.

The present invention also includes, but is not limited to, the compounds listed below:

N- (3, 5-dimethoxybenzyl) -3- (methoxymethyl) -1- (4- ((2-oxopyridin-1 (2H) -yl) methyl) benzyl) -1H-pyrazole-4-carboxamide;

3-amino-1- [4- (2-oxo-2H-pyridin-1-ylmethyl) -benzyl ] -1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzamide;

1- (7-chloro-quinolin-3-ylmethyl) -3-methoxymethyl-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (3-methoxyphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (3-ethoxyphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -N- { [3- (trifluoromethoxy) phenyl ] methyl } -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (4-methylphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-5-methoxyphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

n- [ (2, 4-dimethoxyphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2, 6-difluoro-4-methoxyphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

n- { [ 4-methoxy-2- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2, 6-difluorophenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2-chloro-6-fluorophenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

n- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (4-chloro-2, 6-difluorophenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (4-chloro-2-fluorophenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

n- [ (3-chloro-2, 6-difluorophenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (3-chloro-2-fluorophenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

n- [ (5-chloro-2-fluorophenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- { [ 3-chloro-2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2, 6-dichlorophenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- { [ 5-chloro-2- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2, 4-dimethylphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2, 6-dimethylphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) -N- [ (2, 4, 6-trimethylphenyl) methyl ] pyrazole-4-carboxamide;

n- [ (3-fluoro-2-methylphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-4-methylphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (3-fluoropyridin-2-yl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (4-chloropyridin-2-yl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) -N- { [4- (trifluoromethyl) pyridin-3-yl ] methyl } pyrazole-4-carboxamide;

3- (methoxymethyl) -N- [ (6-methylpyridin-3-yl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (4-fluoro-5-methoxypyridin-3-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (4-acetamidopyridin-3-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [ 4-fluoro-2- (trifluoromethyl) pyridin-3-yl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) -N- { [2- (trifluoromethyl) pyridin-3-yl ] methyl } pyrazole-4-carboxamide;

3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) -N- { [4- (trifluoromethyl) pyridin-3-yl ] methyl } pyrazole-4-carboxamide;

N- [ (4-fluoropyridin-3-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3- (methoxymethyl) -N- [ (6-methylpyridin-3-yl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3- (methoxymethyl) -N- [ (6-methoxypyridin-2-yl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (3-fluoro-4-methoxypyridin-2-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (3-fluoro-6-methoxypyridin-2-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (3-chlorothien-2-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (3-chloro-5-methylthiophen-2-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (5-chloro-1-benzothien-3-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (5-chloro-1-benzothien-3-yl) methyl ] -3- (methoxymethyl) -1- { [6- (pyrrolidin-1-yl) pyridin-3-yl ] methyl } pyrazole-4-carboxamide;

N- [ (5-chloro-1-benzothien-3-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-carbamoylphenyl) methyl ] -3-cyclopropyl-1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (3-carbamoylphenyl) methyl ] -3-cyclopropyl-1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (4-carbamoylphenyl) methyl ] -3-cyclopropyl-1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

3-cyclopropyl-N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-3, 6-dimethoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methylamino) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3- (ethylamino) -N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (isopropylamino) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3-amino-1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) -N- { [4- (trifluoromethoxy) phenyl ] methyl } pyrazole-4-carboxamide;

3- (dimethylamino) -N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3-amino-N- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -3- (methylamino) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluorophenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) -N- { [2- (trifluoromethyl) phenyl ] methyl } pyrazole-4-carboxamide;

n- [ (2-fluoro-5-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-4-methylphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (3-chloro-5-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [2- (difluoromethyl) phenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [2- (difluoromethyl) -3-methoxyphenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3-amino-N- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3-acetamido-N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (N-methylacetamido) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (3-chloro-2, 6-difluorophenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-3-methoxy-4-methylphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (2-cyano-5-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (5-chloro-2-cyanophenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (6-cyano-2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [ 3-methoxy-2- (trifluoromethyl) phenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [ 5-methoxy-2- (trifluoromethyl) phenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- { [2- (difluoromethyl) -6-fluorophenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [2- (difluoromethyl) -5-methoxyphenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [6- (difluoromethyl) -2-fluoro-3-methoxyphenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- { [2- (difluoromethyl) -6-fluoro-3-methoxyphenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (2-chloro-5-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-carbamoyl-6-fluorophenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-carbamoyl-5-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

2- ({ [3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazol-4-yl ] carboxamido } methyl) benzoic acid

n- { [ 2-fluoro-6- (1, 2, 3, 4-tetrazol-1-yl) phenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- { [ 2-fluoro-5- (1, 2, 3, 4-tetrazol-1-yl) phenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- { [3- (difluoromethoxy) -2-fluorophenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- { [3- (difluoromethoxy) phenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [2- (difluoromethoxy) -6-fluorophenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [2- (difluoromethyl) -6-fluoro-4-methylphenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2, 5-difluorophenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (3-fluoro-5-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2, 5-difluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-6-methylphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (5-chloro-2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (6-chloro-2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [ 2-fluoro-3-methoxy-6- (trifluoromethyl) phenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [ 2-fluoro-4-methyl-6- (trifluoromethyl) phenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- { [ 4-chloro-2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3-cyano-N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (2-fluoro-3-hydroxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3-amino-N- [ (2-fluoro-3-hydroxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

Methyl 2- ({ [3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazol-4-yl ] carboxamido } methyl) benzoate

N- [ (3-ethyl-2-fluorophenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3- (methoxymethyl) -N- [ (3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyrazin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (4-fluoro-2-oxopyridin-1-yl) methyl ] phenyl } methyl) -3- (methoxymethyl) pyrazole-4-carboxamide;

n- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (4-methyl-2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

1- ({4- [ (5-fluoro-2-oxopyridin-1-yl) methyl ] phenyl } methyl) -N- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) pyrazole-4-carboxamide;

N- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (5-fluoro-2-oxopyridin-1-yl) methyl ] phenyl } methyl) -3- (methoxymethyl) pyrazole-4-carboxamide;

N- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (4-ethoxy-2-oxopyridin-1-yl) methyl ] phenyl } methyl) -3- (methoxymethyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (5-methoxy-4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (methoxymethyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- { [5- (2-oxopyridin-1-yl) thiophen-3-yl ] methyl } pyrazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({5- [ (2-oxopyridin-1-yl) methyl ] thiophen-3-yl } methyl) pyrazole-4-carboxamide;

3-amino-N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

3-methoxymethyl-1- [4- (4-methyl-pyrazol-1-ylmethyl) -benzyl ] -1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzamide;

3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzamide;

1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-fluoro-6-oxopyridin-1-yl) methyl ] phenyl } methyl) -3- (methoxymethyl) pyrazole-4-carboxamide;

1- ({4- [ (2-chloro-6-oxopyridin-1-yl) methyl ] phenyl } methyl) -N- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) pyrazole-4-carboxamide;

n- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({2- [ (methylamino) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (2, 6-difluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- { [2- (methylamino) pyridin-4-yl ] methyl } pyrazole-4-carboxamide;

n- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- { [2- (2, 2, 2-trifluoroethyl) phenyl ] methyl } pyrazole-4-carboxamide;

n- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- { [2- (trifluoromethoxy) phenyl ] methyl } pyrazole-4-carboxamide;

n- [ (2-fluoro-3-methoxyphenyl) methyl ] -2-methyl-1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) imidazole-4-carboxamide;

2-amino-N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) imidazole-4-carboxamide;

2-cyclopropyl-N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) imidazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) -2- (trifluoromethyl) imidazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -2- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) imidazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- { [6- (pyrrolidin-1-yl) pyridin-3-yl ] methyl } -3- (trifluoromethyl) pyrazole-4-carboxamide;

3-amino-N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- { [6- (pyrrolidin-1-yl) pyridin-3-yl ] methyl } pyrazole-4-carboxamide;

N- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- { [6- (pyrrolidin-1-yl) pyridin-3-yl ] methyl } pyrazole-4-carboxamide;

3-methoxymethyl-1- (6-pyrrolidin-1-yl-pyridin-3-ylmethyl) -1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzamide;

1- (6-pyrrolidin-1-yl-pyridin-3-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzamide;

3-amino-N- [ (7-chloro-4-methyl-2, 3-dihydro-1, 4-benzoOxazin-2-yl) methyl]-1- ({4- [ (2-oxopyridin-1-yl) methyl]Phenyl } methyl) pyrazole-4-carboxamide;

3-amino-N- [ (7-chloro-3, 4-dihydro-2H-1, 4-benzooxazin-2-yl) methyl]-1- ({4- [ (2-oxopyridin-1-yl) methyl]Phenyl } methyl) pyrazole-4-carboxamides

And pharmaceutically acceptable salts and solvates thereof.

The present invention also includes, but is not limited to, the compounds listed below:

3-amino-1- [4- (2-oxo-2H-pyridin-1-ylmethyl) -benzyl ] -1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzamide;

n- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-5-methoxyphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

n- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (4-chloro-2, 6-difluorophenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

n- { [ 3-chloro-2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

N- [ (2-fluoro-4-methylphenyl) methyl ] -1- ({4- [ (4-methylpyrazol-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

n- [ (3-fluoro-4-methoxypyridin-2-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- [ (5-chloro-1-benzothien-3-yl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

N- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl } -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide;

3-cyclopropyl-N- [ (2-fluoro-3-methoxyphenyl) methyl ] -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;

n- [ (2-fluoro-3-methoxyphenyl) methyl ] -3- (methoxymethyl) -1- ({4- [ (2-oxopyridin-1-yl) methyl ] phenyl } methyl) pyrazole-4-carboxamide;