Compounds as soluble epoxide hydrolase inhibitors

Abstract

The present invention relates to a compound of formula (I): TIFF2024512553000021.tif29170 relates to soluble epoxide hydrolase (sEH) inhibitors, methods for obtaining same and their therapeutic indications.

Description

[Technical field]

[0001] The present invention relates to the field of human and veterinary medicine, and in particular to soluble epoxide hydrolase (sEH) inhibitors and their therapeutic indications. [Background technology]

[0002] Several classes of sEH inhibitors based on different chemical structures such as amides, thioamides, ureas, thioureas, carbamates, acylhydrazones, and chalcone oxides have been described in a total of over 100 patent publications (see, for example, the review "S. E. Gregory et al., 1999, 1999; ...

[0003] sEH inhibition has been associated with a variety of beneficial biological effects, which may have applications in a variety of therapeutic treatments (see, e.g., reviews 3 and 4 with 117 and 186 references, respectively).

[0004] More specifically, the references cited below describe the usefulness of sEH inhibition in the treatment of the following diseases: hypertension (Non-Patent Document 5), atherosclerosis (Non-Patent Document 6), pulmonary diseases such as chronic obstructive pulmonary disorder, asthma, sarcoidosis and cystic fibrosis (Non-Patent Document 7, Non-Patent Document 8, Non-Patent Document 9, Non-Patent Document 10), renal diseases such as acute kidney injury, diabetic nephrology, chronic kidney disease, renal damage due to hypertension and renal damage due to high-fat diet (Non-Patent Document 11, Non-Patent Document 12, Non-Patent Document 13, Non-Patent Document 14, Non-Patent Document 15, Non-Patent Document 16, Non-Patent Document 17, Non-Patent Document 18, Non-Patent Document 19, Non-Patent Document 20, Non-Patent Document 21, Non-Patent Document 22, Non-Patent Document 23, Non-Patent Document 24, Non-Patent Document 25, Non-Patent Document 26, Non-Patent Document 27, Non-Patent Document 28, Non-Patent Document 29, Non-Patent Document 30, Non-Patent Document 31, Non-Patent Document 32, Non-Patent Document 33, Non-Patent Document 34, Non-Patent Document 35, Non-Patent Document 36, Non-Patent Document 37, Non-Patent Document 38, Non-Patent Document 39, Non-Patent Document 40, Non-Patent Document 41, Non-Patent Document 42, Non-Patent Document 43, Non-Patent Document 44, Non- 5), stroke (Non-Patent Document 16, Non-Patent Document 17), pain (Non-Patent Document 18, Non-Patent Document 19), neuropathic pain (Non-Patent Document 18, Non-Patent Document 20, Non-Patent Document 21), inflammation (Non-Patent Document 19, Non-Patent Document 22), pancreatitis, particularly acute pancreatitis (Non-Patent Document 23), immune disorders (Patent Document 1), neurodevelopmental disorders, such as schizophrenia and autism spectrum disorders (Non-Patent Document 24), eye diseases (Patent Document 2, Non-Patent Document 25), particularly diabetic keratopathy (Non-Patent Document 26), exudative age-related macular degeneration (Non-Patent Document 27), and retinopathies (Non-Patent Document 28), such as retinal diseases of prematurity. and diabetic retinopathy, cancer (Non-Patent Document 29), obesity (Non-Patent Document 30) (including, for example, obesity-induced colonic inflammation (Non-Patent Document 31)), diabetes (Non-Patent Document 32), metabolic syndrome (Non-Patent Document 33), pre-eclampsia (Non-Patent Document 34), anorexia nervosa (Non-Patent Document 35), depression (Non-Patent Document 36), male sexual dysfunction (Non-Patent Document 37), e.g. erectile dysfunction (Non-Patent Document 38), wound healing (Non-Patent Document 39, Non-Patent Document 40), NSAID-induced ulcers (Non-Patent Document 41), emphysema (Non-Patent Document 7), scrapie (Non-Patent Document 42), Parkinson's Disease (Non-Patent Document 43, Non-Patent Document 44), arthritis (Non-Patent Document 45), arrhythmia (Non-Patent Document 46), cardiac fibrosis (Non-Patent Document 47), Alzheimer's disease (Non-Patent Document 4, Non-Patent Document 48), Raynaud's syndrome (Patent Document 3), Niemann-Pick disease type C (Non-Patent Document 49), cardiomyopathy (Non-Patent Document 50), vascular cognitive impairment (Non-Patent Document 51), mild cognitive impairment (Non-Patent Document 4), inflammatory bowel disease (Non-Patent Document 52, Non-Patent Document 53), liver cirrhosis (Non-Patent Document 54), non-alcoholic fatty liver disease (Non-Patent Document 55), non-alcoholic steatohepatitis (Non-Patent Document 56),Hepatic fibrosis (Non-Patent Document 57), osteoporosis (Non-Patent Document 58), chronic periodontitis (Non-Patent Document 59), sepsis (Non-Patent Document 60), seizure disorders, e.g. epilepsy (Non-Patent Document 61), dementia (Non-Patent Document 51), edema, e.g. cerebral edema (Non-Patent Document 62), attention deficit hyperactivity disorder (Patent Document 4), schizophrenia (Non-Patent Document 63), drug addiction (Patent Document 4), social anxiety disorder (Patent Document 4), colitis (Non-Patent Document 64), amyotrophic lateral sclerosis (Patent Document 5), chemotherapy-induced side effects (Non-Patent Document 65), Reference 65), laminitis (Non-Patent Document 66), inflammatory joint pain and synovitis (Non-Patent Document 67), endothelial dysfunction (Non-Patent Document 68), subarachnoid hemorrhage (Non-Patent Document 62) (including, for example, aneurysmal subarachnoid hemorrhage (Non-Patent Document 69)), traumatic brain injury (Non-Patent Document 70), cerebral ischemia (Non-Patent Document 71), diabetes-induced learning and memory impairment (Non-Patent Document 72), cytokine storm (Patent Document 6, Non-Patent Document 73), multiple sclerosis (Non-Patent Document 74), and idiopathic pulmonary fibrosis (Non-Patent Document 75).

[0005] Patent Document 7 describes polycyclic compounds as soluble epoxide hydrolase inhibitors.

[0006] Despite the high inhibitory activity of many reported sEH inhibitors, no sEH inhibitors have been on the market to date. Many sEH inhibitors, including those specifically described in Patent Document 7, have been found to lack sufficient metabolic stability (especially stability against hepatic CYP-mediated metabolism) to be useful as drugs.

[0007] In addition, inhibitors that can cross the blood-brain barrier (BBB) ​​are important for the treatment of nervous system diseases.

[0008] Therefore, there is a need to develop new sEH inhibitors that have both high inhibitory activity against soluble epoxide hydrolase and high metabolic stability, particularly against hepatic CYP-mediated metabolism as determined by a microsomal stability assay in human microsomes.

[0009] It is also advantageous that the compounds of the invention have high metabolic stability when tested in rat or mouse microsomes, since only those compounds with good microsomal stability in rats or mice are selected for further testing in humans. It is also advantageous that the compounds are able to cross the BBB. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] WO 00 / 23060 [Patent Document 2] International Publication No. 2007 / 009001 [Patent Document 3] International Publication No. 2003 / 002555 [Patent Document 4] International Publication No. 2017 / 120012 [Patent Document 5] International Publication No. 2016 / 133788 [Patent Document 6] International Publication No. 2020 / 146770 [Patent Document 7] International Publication No. 2019 / 243414 [Non-patent literature]

[0011] [Non-Patent Document 1] HC Shen, "Soluble epoxide hydrolase inhibitors: a patent review", Expert Opin Ther Patents 2010, vol. 20, pp. 941-956 [Non-Patent Document 2] C.-P. Sun et al. "Discovery of soluble epoxide hydrolase inhibitors from chemical synthesis and natural products", J Med Chem. 2021, vol 64, pp 184-215 [Non-licensed document 3] HC Shen and BD Hammock, "Discovery of inhibitors of soluble epoxide hydrolase: A target with multiple potential therapeutic indications", J Med Chem. 2012, vol. 55, pp. 1789-1808

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-licensed Document 17

Non-licensed Document 18

Non-licensed Document 19

Non-licensed Document 20

Non-licensed Document 21

Non-licensed Document 22

Non-licensed Document 23

Non-licensed Document 24

Non-licensed Document 25

Non-licensed Document 26

Non-licensed Document 27

Non-licensed Document 28

Non-licensed Document 29

Non-licensed Document 30

Non-licensed Document 31

Non-licensed Document 32

Non-licensed Document 33

Non-licensed Document 34

Non-licensed Document 35

Non-licensed Document 36

Non-licensed Document 37

Non-licensed Document 38

Non-licensed Document 39

Non-licensed Document 40

Non-licensed Document 41

Non-licensed Document 42

Non-licensed Document 43

Non-licensed Document 44

Non-licensed Document 45

Non-licensed Document 46

Non-licensed Document 47

Non-licensed Document 48

Non-licensed Document 49

Non-licensed literature 50

Non-licensed Document 51

Non-licensed Document 52

Non-licensed Document 53

Non-licensed Document 54

Non-licensed Document 55

Non-licensed Document 56

Non-licensed Document 57

Non-licensed Document 58

Non-licensed Document 59

Non-licensed Document 60

Non-licensed Document 61

Non-licensed Document 62

Non-licensed Document 63

Non-licensed Document 64

Non-licensed Document 65

Non-licensed Document 66

Non-licensed Document 67

Non-licensed Document 68

Non-licensed Document 69

Non-licensed Document 70

Non-licensed Document 71

[0012] The inventors have discovered new sEH inhibitors that have unexpectedly high inhibitory activity against soluble epoxide hydrolase, high metabolic stability, particularly against hepatic CYP-mediated metabolism as determined by a microsomal stability assay in human microsomes, and remarkable efficacy in seizure assays due to the ability of the compounds to cross the BBB, thus readily penetrating the CNS and protecting subjects from seizures.

[0013] Thus, in a first aspect, the present invention provides a compound of formula (I): [ka] (In the formula, G 1 represents a nitrogen atom or a -CH- group, G 1 When is a nitrogen atom group, R 1 teeth, a) a1) linear or branched C3-C6 acyl or C3-C6 cycloalkyl-C(=O), each of which is optionally substituted with one substituent selected from the group consisting of halogen atoms, cyano (C≡N), trifluoromethoxy (OCF3) and C1-C6 alkoxy; a2) trifluoroacetyl, 3,3,3-trifluoropropionyl, tetrahydropyrancarbonyl, oxetanecarbonyl or (tetrahydro-2H-thiopyran)carbonyl; and a3) heteroaryl groups having 5 to 14 members in the ring system and having 1 to 3 heteroatoms selected from the group consisting of N, O and S, each of which is a halogen atom, cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), carboxylic acid group (COOH), ester group (COOR), 4 ), C6-C optionally substituted by 1 to 4 substituents selected from the group consisting of amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. 14 -arylcarbonyl or C4-C 14 -a carbonyl-containing group selected from the group consisting of heteroarylcarbonyl; b) Halogen atoms, C1-C6 acyl, cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), fluorosulfonyl (SO2F), carboxylic acid group (COOH), ester group (COOR 4 ), amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxycarbonylmethyl, optionally substituted by 1 to 4 substituents selected from the group consisting of phenyl, c) Halogen atoms, nitro (NO2), cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), carboxylic acid group (COOH), ester group (COOR4 ), amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, linear or branched C1-C6 alkylsulfonyl optionally substituted with one or two substituents selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxycarbonylmethyl, C3-C6 cycloalkylsulfonyl and C6-C 10 arylsulfonyl; G 1 When is a -CH- group, R 1 may be unsubstituted or COOH, COOR 4 phenoxy optionally substituted by 1 to 4 groups selected from CONH, CN, fluorine, chloro, trifluoromethyl, cyclopropyl, and OH; R 2 is a halogen atom, R 3 is selected from the group consisting of hydrogen and methoxy; R 4 is a radical selected from C1-C6 alkyl and C3-C6 cycloalkyl, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

[0014] In a second aspect, the present invention relates to a pharmaceutical or veterinary composition comprising a therapeutically effective amount of a compound according to the first aspect of the invention, and preferably a suitable amount of a pharma- ceutically acceptable excipient.

[0015] In a third aspect, the present invention relates to a compound according to the first aspect of the invention and a composition according to the second aspect of the invention for use as a medicament.

[0016] In a fourth aspect, the present invention relates to compounds according to the first aspect of the invention and compositions according to the second aspect of the invention for use in the treatment or prevention of a disease or disorder amenable to amelioration by inhibition of soluble epoxide hydrolase in an animal, including a human.

[0017] In a fifth aspect, the present invention relates to the use of a compound of the first aspect of the invention in the manufacture of a medicament for the treatment or prevention of a disease or disorder amenable to amelioration by inhibition of soluble epoxide hydrolase in an animal, including a human.

[0018] In a sixth aspect, the present invention relates to a method of preventing or treating a disease or disorder amenable to amelioration by inhibition of soluble epoxide hydrolase by administering to a patient in need of such prevention or treatment a compound of the first aspect of the invention or a composition of the second aspect of the invention. [Brief description of the drawings]

[0019] [Figure 1] 1 shows histological images of amyloid plaques stained with Thioflavin-S from Example 15, showing representative β-amyloid plaque distribution in the hippocampus of WT-control, 5XFAD-control and 5XFAD-treated mice. As shown in FIG 1, a greater burden of plaques (white dots) is seen in most of the brain regions shown in the 5XFAD-control group compared to the WT-control and 5XFAD-treated mice. [Diagram 2] Figure 1 shows the percentage change in body weight at the end of the study described in Example 16 relative to t=0 hours. Effect of 12 consecutive doses of caerulein (50 μg / kg, IP) and treatment with the compound of Example 2 (single dose, 0.3 mg / kg or 0.1 mg / kg, IP) on body weight of C57BL / 6 male mice. Results are expressed as mean ± SEM (n=3-9). *p<0.05, **p<0.01, ****p<0.0001 vs. caerulein group (one-way ANOVA). [Diagram 3] FIG. 1 shows a representative H&E stained section of the pancreas from the in vivo efficacy study described in Example 16. Arrows indicate inflammatory cells and edema. Thick arrows indicate intracellular vacuoles. [Figure 4]Figure 1 shows histological scoring of pancreatic tissue from mice treated with vehicle (control), caerulein, and caerulein plus either 0.1 mg / kg or 0.3 mg / kg of the compound of Example 2. ***p<0.001 vs. control. #p<0.05 vs. caerulein. ###p<0.001 vs. caerulein. &p<0.05 as described in Example 16. [Figure 5a] FIG. 1 shows the viability of SH-SY5Y cells after exposure to the compound of Example 2 (100 μM) for 24 hours. [Figure 5b] FIG. 13 shows Ephx2 mRNA in AβO-treated primary microglia compared to non-activated microglia. [Figure 5c] Figure 2 shows that compound of Example 2 reduced pro-inflammation in primary microglia. mRNA levels of representative inflammatory markers from mouse primary microglia treated with AβOs followed by DMSO or compound of Example 2 using qPCR. [Figure 5d] Figure 1 shows mRNA levels of representative reactive astrocyte markers from human cortical astrocytes treated with DMSO or compound of Example 2 using qPCR. Amounts of cDNA were normalized using GAPDH (n=4 per group). Data are presented as mean±SEM. p values ​​were determined by one-way ANOVA. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 versus treatment with control, T / I / C or compound of Example 2. [Figure 5e] Figure 1 shows mRNA levels of representative reactive astrocyte markers from human cortical astrocytes treated with DMSO or compound of Example 2 using qPCR. Amounts of cDNA were normalized using GAPDH (n=4 per group). Data are presented as mean±SEM. p values ​​were determined by one-way ANOVA. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 versus treatment with control, T / I / C or compound of Example 2. [Figure 5f] FIG. 1 shows levels of C3 and p-p38 in reactive astrocytes treated with DMSO or 30 μM of the compound of Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] In a first aspect, the present invention provides a compound of formula (I): [ka] (In the formula, G 1 represents a nitrogen atom or a -CH- group, G 1 When is a nitrogen atom group, R 1 teeth, a) a1) linear or branched C3-C6 acyl or C3-C6 cycloalkyl-C(=O), each of which is optionally substituted with one substituent selected from the group consisting of halogen atoms, cyano (C≡N), trifluoromethoxy (OCF3) and C1-C6 alkoxy; a2) trifluoroacetyl, 3,3,3-trifluoropropionyl, tetrahydropyrancarbonyl, oxetanecarbonyl or (tetrahydro-2H-thiopyran)carbonyl; and a3) heteroaryl groups having 5 to 14 members in the ring system and having 1 to 3 heteroatoms selected from the group consisting of N, O and S, each of which is a halogen atom, cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), carboxylic acid group (COOH), ester group (COOR), 4 ), C6-C optionally substituted by 1 to 4 substituents selected from the group consisting of amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. 14 -arylcarbonyl or C4-C 14 -a carbonyl-containing group selected from the group consisting of heteroarylcarbonyl; b) Halogen atoms, C1-C6 acyl, cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), fluorosulfonyl (SO2F), carboxylic acid group (COOH), ester group (COOR 4 ), amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxycarbonylmethyl, optionally substituted by 1 to 4 substituents selected from the group consisting of phenyl, c) Halogen atoms, nitro (NO2), cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), carboxylic acid group (COOH), ester group (COOR 4 ), amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, linear or branched C1-C6 alkylsulfonyl optionally substituted with one or two substituents selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxycarbonylmethyl, C3-C6 cycloalkylsulfonyl and C6-C 10 arylsulfonyl; G 1 When is a -CH- group, R 1 may be unsubstituted or COOH, COOR 4 phenoxy optionally substituted by 1 to 4 groups selected from CONH, CN, fluorine, chlorine, trifluoromethyl, cyclopropyl, and OH; R 2 is a halogen atom, R 3 is selected from the group consisting of hydrogen and methoxy; R 4 is a radical selected from C1-C6 alkyl and C3-C6 cycloalkyl, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

[0021] In embodiments of the various aspects of the present invention, 1 is N.

[0022] In another embodiment of the various aspects of the invention, G 1 is N and R 1 are a1) linear or branched C3-C6 acyl or C3-C6 cycloalkyl-C(=O), each of which is optionally substituted with one substituent selected from the group consisting of halogen atoms, cyano (C≡N), trifluoromethoxy (OCF3) and C1-C6 alkoxy; a2) trifluoroacetyl, 3,3,3-trifluoropropionyl, tetrahydropyrancarbonyl, oxetanecarbonyl or (tetrahydro-2H-thiopyran)carbonyl; and a3) heteroaryl groups having 5 to 14 members in the ring system and having 1 to 3 heteroatoms selected from the group consisting of N, O and S, each of which is a halogen atom, cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), carboxylic acid group (COOH), ester group (COOR), 4 ), C6-C optionally substituted by 1 to 4 substituents selected from the group consisting of amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. 14 -arylcarbonyl or C4-C 14 -heteroarylcarbonyl. In certain embodiments, the arylcarbonyl is phenylcarbonyl and the heteroarylcarbonyl is pyridinecarbonyl or furancarbonyl.

[0023] In another embodiment of the various aspects of the invention, G 1 is N and R 1is a1) a linear or branched C3-C6 acyl or a C3-C6 cycloalkyl-C(=O), each of which is optionally substituted with one substituent selected from the group consisting of halogen atoms, cyano (C≡N), trifluoromethoxy (OCF3) and C1-C6 alkoxy; a2) trifluoroacetyl, 3,3,3-trifluoropropionyl, tetrahydropyrancarbonyl, oxetanecarbonyl or (tetrahydro-2H-thiopyran)carbonyl; and a3) the heteroaryl group has 5 to 14 members in the ring system; C6-C alkyl groups having 1 to 3 heteroatoms selected from the group consisting of N, O, and S, each of which is optionally substituted with 1 to 4 substituents selected from the group consisting of halogen atoms, cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), carboxylic acid group (COOH), amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. 14 -arylcarbonyl or C4-C 14 -heteroarylcarbonyl. In certain embodiments, the arylcarbonyl is phenylcarbonyl and the heteroarylcarbonyl is pyridinecarbonyl or furancarbonyl.

[0024] In another embodiment of the various aspects of the invention, G 1 is N and R 1 is selected from the group consisting of linear or branched C3-C6 acyl, C3-C6 cycloalkyl-C(=O) optionally substituted with an F atom or a cyano group, trifluoroacetyl, 3,3,3-trifluoropropionyl, tetrahydropyrancarbonyl, oxetanecarbonyl, (tetrahydro-2H-thiopyran)carbonyl, preferably 2-methylbutanoyl, cyclopropyl-C(=O) and tetrahydropyrancarbonyl.

[0025] In another embodiment of the various aspects of the invention, G 1 is N and R 1is a halogen atom, C1-C6 acyl, cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), fluorosulfonyl (SO2F), carboxylic acid group (COOH), ester group (COOR 4 ), amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxycarbonylmethyl.

[0026] In another embodiment of the various aspects of the invention, G 1 is N and R 1 is phenyl optionally substituted by 1 to 4 substituents selected from the group consisting of halogen atoms, C1 to C6 acyl, cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), fluorosulfonyl (SO2F), carboxylic acid group (COOH), amino (NH2), mono-C1 to C6 alkylamino, di-C1 to C6 alkylamino, hydroxyl, C1 to C6 alkoxy, C1 to C6 alkyl, C3 to C6 cycloalkyl, and C1 to C6 alkoxycarbonylmethyl.

[0027] In another embodiment of the various aspects of the invention, G 1 is N and R 1 are halogen atoms, nitro (NO2), cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), carboxylic acid group (COOH), ester group (COOR 4), amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl and C1-C6 alkoxycarbonylmethyl, preferably linear or branched C1-C6 alkylsulfonyl, C3-C6 cycloalkylsulfonyl and C6-C6 cycloalkylsulfonyl, which may be optionally substituted by one or two substituents selected from the group consisting of C1-C6 alkylsulfonyl and C3-C6 cycloalkylsulfonyl. 10 The sulfonyl-containing group is selected from the group consisting of arylsulfonyl.

[0028] In another embodiment of the various aspects of the invention, G 1 is N and R 1 is a straight-chain or branched C1-C6 alkylsulfonyl, C3-C6 cycloalkylsulfonyl and C6-C alkylsulfonyl optionally substituted by one or two substituents selected from the group consisting of halogen atoms, nitro (NO2), cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), a carboxylic acid group (COOH), amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl and C1-C6 alkoxycarbonylmethyl, preferably C1-C6 alkylsulfonyl and C3-C6 cycloalkylsulfonyl. 10 The sulfonyl-containing group is selected from the group consisting of arylsulfonyl.

[0029] In another embodiment of the various aspects of the invention, G 1 is a -CH- group, R 1 may be unsubstituted or COOH, COOR 4 , CONH2, CN, phenoxy optionally substituted by one or two groups selected from fluorine, chlorine, trifluoromethyl, cyclopropyl and OH.

[0030] In another embodiment of the various aspects of the invention, G 1is a -CH- group, R 1 is phenoxy which may be unsubstituted or substituted by one or two groups selected from COOH, CONH2, CN, fluorine, chlorine, trifluoromethyl, cyclopropyl and OH.

[0031] G 1 is a -CH- group, and R 1 is an optionally substituted phenoxy group as defined above; R 5 COOH, COOR 4 , CONH, CN, fluorine, chlorine, trifluoromethyl, cyclopropyl, and OH (preferably R 5 is selected from the group consisting of COOH, CONH2, CN, fluorine, chlorine, trifluoromethyl, cyclopropyl and OH), and when n has a value from 0 to 4, the compound of formula (Ia) exists in the cis and trans configurations as shown below, both of which are encompassed by the present invention. In a preferred embodiment, the compound of formula (I) is in the trans configuration (Ia trans). [ka]

[0032] In embodiments of the various aspects of the invention, R 2 is a chlorine or fluorine atom, preferably G 1 is a fluorine atom when is a nitrogen atom, and G 1 When is CH, it is a chlorine atom.

[0033] In embodiments of the various aspects of the invention, R 3 Both are hydrogen atoms.

[0034] In certain embodiments of the various aspects of the invention, the compound is i. 4-[((1r,4r)-4-(3-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)cyclohexyl)oxy]benzoic acid, ii. 4-[((1r,4r)-4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)cyclohexyl)oxy]benzoic acid, iii. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea; iv. 1-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea, v. 1-(9-fluoro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea, vi. 1-(9-chloro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea, vii. 1-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(cyclopropanecarbonyl)piperidin-4-yl)urea, viii. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(cyclopropanecarbonyl)piperidin-4-yl)urea, ix. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)urea, x. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)urea, xi. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(isopropylsulfonyl)piperidin-4-yl)urea, xii. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-propionylpiperidin-4-yl)urea, xiii. 4-(4-(3-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidin-1-yl)benzoic acid, xiv. 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidin-1-yl)benzoic acid, xv. methyl 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annullen-7-yl)ureido)piperidine-1-carbonyl)benzoate, and xvi. 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidine-1-carbonyl)benzoic acid.

[0035] Some of the compounds of the invention are metabolized to different compounds according to the invention as well, the latter having improved microsomal stability.

[0036] In certain embodiments of the third, fourth, fifth and sixth aspects of the invention, diseases or disorders amenable to amelioration by inhibition of soluble epoxide hydrolase include pulmonary diseases such as hypertension, atherosclerosis, chronic obstructive pulmonary disorder, asthma, sarcoidosis and cystic fibrosis, renal diseases such as acute kidney injury, diabetic kidney disease, chronic kidney disease, kidney damage due to hypertension and kidney damage due to high fat diet, stroke, pain, neuropathic pain, inflammation, pancreatitis, particularly acute pancreatitis, immune disorders, neurodevelopmental disorders such as schizophrenia and autism spectrum disorders, eye diseases, particularly diabetic keratopathy, exudative age-related macular degeneration and retinopathies such as retinopathy of prematurity and diabetic retinopathy, cancer, obesity including obesity-induced colon inflammation, diabetes, metabolic syndrome, pre-eclampsia, anorexia nervosa, depression, male sexual dysfunction such as erectile dysfunction, The therapeutic agent is selected from the group consisting of wound healing, NSAID-induced ulcers, emphysema, scrapie, Parkinson's disease, arthritis, arrhythmias, cardiac fibrosis, Alzheimer's disease, Raynaud's syndrome, Niemann-Pick disease type C, cardiomyopathy, vascular cognitive impairment, mild cognitive impairment, inflammatory bowel disease, liver cirrhosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver fibrosis, osteoporosis, chronic periodontitis, sepsis, seizure disorders such as epilepsy, dementia, edema such as cerebral edema, attention deficit hyperactivity disorder, schizophrenia, drug addiction, social anxiety disorder, colitis, amyotrophic lateral sclerosis, chemotherapy-induced side effects, laminitis, inflammatory joint pain and synovitis, endothelial dysfunction, subarachnoid hemorrhage including aneurysmal subarachnoid hemorrhage, traumatic brain injury, cerebral ischemia, diabetes-induced learning and memory impairment, cytokine storm, multiple sclerosis, and idiopathic pulmonary fibrosis.

[0037] In another particular embodiment of the third, fourth, fifth and sixth aspects of the invention, the disease or disorder amenable to amelioration by inhibition of soluble epoxide hydrolase is selected from the group consisting of pulmonary diseases such as hypertension, atherosclerosis, chronic obstructive pulmonary disorder, asthma, sarcoidosis and cystic fibrosis, renal diseases such as acute kidney injury, diabetic kidney disease, chronic kidney disease, kidney damage due to hypertension and kidney damage due to high fat diet, stroke, pain, neuropathic pain, inflammation, pancreatitis, particularly acute pancreatitis, immune disorders, neurodevelopmental disorders such as schizophrenia and autism spectrum disorders, eye diseases, particularly diabetic keratopathy, exudative age-related macular degeneration and retinopathies such as retinopathy of prematurity and diabetic retinopathy, cancer, obesity including obesity-induced colon inflammation, diabetes, metabolic syndrome, pre-eclampsia, anorexia nervosa, depression, male disorders such as erectile dysfunction and the like. sexual dysfunction, wound healing, NSAID-induced ulcers, emphysema, scrapie, Parkinson's disease, arthritis, arrhythmias, cardiac fibrosis, Alzheimer's disease, Raynaud's syndrome, Niemann-Pick disease type C, cardiomyopathy, vascular cognitive impairment, mild cognitive impairment, inflammatory bowel disease, cirrhosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hepatic fibrosis, osteoporosis, chronic periodontitis, sepsis, seizure disorders such as epilepsy, dementia, edema such as cerebral edema, attention deficit hyperactivity disorder, schizophrenia, drug addiction, social anxiety disorder, colitis, amyotrophic lateral sclerosis, chemotherapy-induced side effects, laminitis, inflammatory joint pain and synovitis, endothelial dysfunction, subarachnoid hemorrhage including aneurysmal subarachnoid hemorrhage, traumatic brain injury, cerebral ischemia, diabetes-induced learning and memory impairment, and cytokine storm.

[0038] According to another aspect of the present invention, compounds of formula (I) may be prepared by reacting an amine of formula (II), preferably in the form of a salt such as the hydrochloride, with an isocyanate of formula (III) in the presence of a base such as triethylamine in an inert solvent such as dichloromethane (DCM). [ka]

[0039] According to another aspect of the invention, the compound of formula (I) can also be prepared in a first step by converting an amine of formula (II), preferably in the form of a salt, to an isocyanate of formula (IV) by reacting with an (NH2→NCO) converting agent, such as triphosgene, in an inert solvent, such as DCM. In a second step, an amine of formula (V) is reacted with an isocyanate of formula (IV) to obtain a compound of formula (I). The coupling reaction may be carried out without a catalyst, and the reaction is conveniently carried out at room temperature in the presence of an organic solvent, typically DCM, tetrahydrofuran (THF) or N,N-dimethylformamide (DMF). In the structure shown below for the compound of formula (I), R 1 is H, which is a compound of formula (XII), in the reaction of an amine of formula (V) with an isocyanate of formula (IV), R 1 The group is preferably an amine protecting group such as a tert-butoxycarbonyl group (Boc), which is deprotected after the coupling reaction by conventional means, for example by treatment with an acid (e.g., HCl) in an organic solvent (e.g., DCM) to form R 1 The amine (I), i.e. the compound of formula (XII), in which R is H, is obtained. This compound (XII) having an unsubstituted piperidinyl rest is then converted to a substituent R as defined in the claims using the procedures described below for compound (Ic), i.e. using RCOH, EDCI, DMAP or HOBt, EtOAc, or using RCOCl and Et3N in DCM. 1 The resulting piperidinyl residue is converted to a

[0040] The amine of formula (II) is a substituent R 2 and R 3 Depending on the nature of the amines, various different reactions can be used to obtain the amines of formula (II), some of which have been disclosed in the art (see, for example, Bioorg Med Chem. 2014, 22, 2678; Bioorg Med Chem. 2015, 23, 290 and US Pat. No. 5,399,633). [ka]

[0041] R 2 When is bromine or fluorine, the amines of formula (IIb) and formula (IIc) can be prepared according to the reaction scheme shown below: [ka]

[0042] Alternatively, the amine (IIc) can be obtained starting from compound (VII) according to the following scheme: [ka]

[0043] The deprotection step of the chloroacetamide to give the final amine (IIc) can be carried out by refluxing compound (VIII) in ethanol in the presence of thiourea and acetic acid overnight.

[0044] R 2 When is chlorine, the amine of formula (IId) can be prepared according to the reaction scheme shown below: [ka]

[0045] The deprotection step of the chloroacetamide to give the final amine (IId) can be carried out by refluxing compound (IX) in ethanol in the presence of thiourea and acetic acid overnight.

[0046] The intermediate compounds of formula (VI) and formula (VII) can be prepared according to the reaction scheme shown below: [ka]

[0047] The deprotection step of the chloroacetamide to give the compound of formula (VI) can be carried out by refluxing compound (VII) in ethanol in the presence of thiourea and acetic acid overnight.

[0048] Diketone (X) is R 3 =H (Liebigs Ann Chem. 1973; 1839-1850) and R 3 When =OCH3 (Patent Document 7), it is a known compound.

[0049] Finally, it is worth mentioning that G 1 When is a nitrogen group, the compounds of the present invention can also be prepared according to the method described above from a precursor of formula (XII) as shown below, in which the unsubstituted piperidinyl residue is not substituted by the substituent R as defined in the claims. 1 is converted to a piperidinyl residue having the formula:

[0050] The reaction of compound (XII) to give compound (Id) is carried out with K2CO3 and anhydrous DMSO by heating. The reaction of compound (XII) to give compound (Ic) is carried out as shown (RCOH, EDCI, DMAP or HOBt, EtOAc) or with RCOCl and Et3N in DCM. The reaction of compound (XII) to give compound (Ib) is carried out with RSO2Cl and Et3N in DCM. [ka] Here, R 6 is a halogen atom, C1-C6 acyl, cyano (C≡N), trifluoromethyl (CF3), trifluoromethoxy (OCF3), pentafluorosulfanyl (SF5), sulfonyl (SO3H), fluorosulfonyl (SO2F), carboxylic acid group (COOH), ester group (COOR 4), amino (NH2), mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 alkoxycarbonylmethyl, where n has a value of 0 to 4.

[0051] As used herein, the term halogen atom refers to an atom selected from the group consisting of chlorine, fluorine, bromine and iodine atoms, preferably fluorine, chlorine or bromine atoms. The term halo has the same meaning when used as a prefix.

[0052] As used herein, the term alkyl refers to a straight or branched chain hydrocarbon radical having 1 to 6 carbon atoms (C n H 2n+1 ). Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl, isopentyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl and 3-methylpentyl. In a preferred embodiment, the alkyl group has 1 to 3 carbon atoms (C1-C3 alkyl).

[0053] As used herein, the term aryl generally refers to C6-C aryl groups such as phenyl, naphthyl, and anthranyl. 14 It refers to a monocyclic or polycyclic aryl radical. The aryl group may be unsubstituted or substituted with one to four substituents.

[0054] As used herein, the term heteroaryl typically refers to a 5- to 14-membered ring system containing at least one aromatic heterocycle and containing at least one heteroatom selected from O, S, and N, typically 1, 2, or 3 heteroatoms. The heteroaryl group may contain a single ring or two or more fused rings, at least one ring containing a heteroatom. The heteroaryl group may be unsubstituted or substituted with one to four substituents.

[0055] As used herein, the term cycloalkyl includes hydrocarbon cyclic groups having 3 to 6 carbon atoms. Such cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0056] As used herein, the term alkoxy refers to a straight or branched alkyl group linked to an oxygen atom (C n H 2n+1 It is used to refer to radicals that contain the radical —O—). Preferred alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy and t-butoxy.

[0057] As used herein, the term cycloalkoxy is used to refer to a radical containing a cycloalkyl group linked to an oxygen atom.

[0058] As used herein, the term acyl is used to refer to the group formed by a straight or branched alkyl bonded to a carbonyl group. When the carbon number of acyl is specified, it is understood to indicate the total number of carbons including the carbonyl group (i.e., C3-acyl is propanoyl). Preferred acyl radicals include propanoyl, butanoyl, 2-methylbutanoyl, pentanoyl and hexanoyl.

[0059] As used herein, the term sulfonyl is used to refer to the group -SO2-.

[0060] As used herein, the term aryl is used to refer to an aromatic hydrocarbon group such as phenyl or anthranyl.

[0061] As used herein, the term pharma- ceutically acceptable salt refers to any salt that can result (directly or indirectly) in the compounds described herein after administration to a patient. For example, pharma- ceutically acceptable salts of the compounds provided herein are synthesized from parent compounds that contain a basic or acidic moiety by conventional chemical methods. In general, such salts are prepared, for example, by reacting these compounds in free acid or free base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of both. In general, non-aqueous media such as ether, ethyl acetate, ethanol, 2-propanol or acetonitrile are preferred. Examples of acid addition salts include mineral acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts, such as acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts such as sodium salts, potassium salts, calcium salts and ammonium salts, as well as organic alkali salts such as ethylenediamine salts, ethanolamine salts, N,N-dialkyleneethanolamine salts, triethanolamine salts and basic amino acid salts.

[0062] As used herein, the term stereoisomers refers to molecules that have the same molecular formula and sequence of bonded atoms (structure), but differ in the three-dimensional orientation of the atoms in space.

[0063] Throughout the specification and claims, the word "comprise" and variations of this word are not intended to exclude other technical features, additives, ingredients, or steps. Furthermore, the word "comprise" encompasses the case of "consisting of." Additional objects, advantages, and features of the present invention will become apparent to those skilled in the art upon examination of the specification or may be learned by practice of the present invention. The following examples are offered by way of illustration and are not intended to limit the present invention. Moreover, the present invention encompasses all possible combinations of specific and preferred embodiments described herein.

[0064] Abbreviation: The following abbreviations have been used throughout this application: anh.: anhydrous AcOH: acetic acid AcCl: acetyl chloride AD: Alzheimer's disease AIBN: Azobisisobutyronitrile ANOVA: Analysis of variance ATR: Attenuated total reflection Bis / Tris: 2-bis(2-hydroxyethyl)amino-2-(hydroxymethyl)-1,3-propanediol BSA: bovine serum albumin Bu3SnD: Tributyl(deuterio)stannane Calcd: Calculated value CMNPC: Cyano(6-methoxynaphthalen-2-yl)methyl 2-(3-phenyloxiran-2-yl)methyl carbonate CYP: Cytochrome P450 d: doublet DAST: Diethylaminosulfur trifluoride Dec: Decomposition DCM: dichloromethane DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide dq: Quartet of Doublets dt: triplet of doublet EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI: electrospray ionization Et2O: Diethyl ether Et3N: Triethylamine EtOAc: ethyl acetate EtOH: Ethanol FAD: Familial Alzheimer's Disease FT-IR: Fourier transform infrared spectroscopy GAPDH: glyceraldehyde 3-phosphate dehydrogenase GFAP: glial fibrillary acidic protein HOBt: Hydroxybenzotriazole h: time H&E staining: Hematoxylin and eosin staining Hz: Hertz HRMS: High resolution mass spectrometry IR: Infrared LC-MSD-TOF: Liquid chromatography / electrospray ionization mass spectrometry m:Multiplet MeOH: Methanol mp: melting point n-Bu: n-Butyl NADP: Nicotinamide adenine dinucleotide phosphate NMR: nuclear magnetic resonance NSAIDs: Nonsteroidal anti-inflammatory drugs p-TSA: p-toluenesulfonic acid PBS: Phosphate-buffered saline PHOME: Cyano(6-methoxynaphthalen-2-yl)methyl 2-(3-phenyloxiran-2-yl)acetate PS1: presenilin-1 PVDF: Polyvinylidene difluoride s: singlet sEH: soluble epoxide hydrolase t: triplet TBS: Tris-buffered saline THF: tetrahydrofuran TPPU: N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl]urea TREM2: Triggering Receptor Expressed On Myeloid Cells 2 t-TUCB: 4-[[trans-4-[[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]amino]cyclohexyl]oxy]benzoic acid SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis UPLC / MS: Ultra-high performance liquid chromatography-mass spectrometry UV: Ultraviolet WT: wild type EXAMPLES

[0065] Analysis method Melting points were determined in open capillary tubes using a MFB 595010 M Gallenkamp melting point apparatus. Infrared (IR) spectra were measured on either a Perkin-Elmer Spectrum RX I spectrophotometer (using attenuated total reflectance) or a Nicolet Avatar 320 FT-IR spectrophotometer. Absorption values ​​are expressed in wavenumbers (cm -1 ) and only significant absorption bands are shown. Elemental analyses were performed at the Microanalysis Service of IIQAB (CSIC, Barcelona, ​​Spain) using a Carlo Erba model 1106 analyzer. Preparative normal phase chromatography was performed using prepacked RediSep Rf silica gel cartridges on a CombiFlash Rf 150 (Teledyne Isco). Thin layer chromatography was performed using silica gel 60 F254 (Merck, ref. 1.05554 or Sigma-Aldrich, ref. 60805) on aluminum backed sheets and spots were visualized with UV light, 1% KMnO4 in water and / or iodine. High resolution mass spectrometry (HRMS) was performed using an Agilent Technologies LC / MSD TOF spectrometer. Analytical grade solvents were used for crystallization and synthetic pure solvents were used for reactions, extractions and column chromatography.

[0066] Reference Example 1: 2,3-Dimethoxy-7-methylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulen-11-one A suspension of NaH (1.31 g, 60% in hexane, 32.7 mmol) in anhydrous DMSO (67 mL) was heated to 75 °C for 1.5 h. After the reaction was cooled to room temperature, a solution of methyltriphenylphosphonium iodide (8.24 g, 20.4 mmol) in anhydrous DMSO (47 mL) was added dropwise. After stirring at room temperature for 15 min, a solution of 2,3-dimethoxy-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione (4.47 g, 16.3 mmol) in anhydrous DMSO (52 mL) was added dropwise. The mixture was heated at 75 °C overnight, cooled to room temperature, and poured into water (340 mL). The aqueous layer was extracted with hexane (4 x 350 mL). The combined organic fractions were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, hexane / ethyl acetate mixture) gave 2,3-dimethoxy-7-methylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulen-11-one as a pale yellow solid (1.05 g, 24% yield). mp 162°C-165°C. IR(ATR): 3076, 2927, 2827, 1685, 1600, 1513, 1463, 1413, 1349, 1258, 1167, 1097, 1027, 1006, 877, 810 cm -1 HRMS: [C 17 H 20 O3+H] + Calculated value: 273.1485, actual value: 273.1486.

[0067] Reference Example 2: 2-Chloro-N-(9-hydroxy-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide To a solution of 2,3-dimethoxy-7-methylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulen-11-one (1.05 g, 3.83 mmol) in DCM (7.5 mL) was added chloroacetonitrile (0.291 g, 3.83 mmol). The mixture was cooled to 0° C. and concentrated H2SO4 (0.57 g, 5.74 mmol) was added dropwise (T<10° C.). The mixture was stirred at room temperature overnight. To the sticky residue was added water (10 mL) and DCM (12 mL). The mixture was stirred vigorously and the aqueous layer was extracted with DCM (3×15 mL). The organic fractions were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Column chromatography (SiO2, DCM / methanol mixtures) afforded 2-chloro-N-(9-hydroxy-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide as a beige solid (0.46 g, 39% yield). mp 182°C-185°C. IR(ATR): 3060, 2923, 1660, 1603, 1562, 1505, 1445, 1410, 1359, 1248, 1150, 1081, 1033, 1014, 865, 729 cm -1 HRMS: [C 19 H 24 ClNO4+H] + Calculated value: 364.1321, actual value: 364.1326.

[0068] Reference Example 3: 2-Chloro-N-(9-chloro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide A mixture of 2-chloro-N-(9-hydroxy-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (0.46 g, 1.26 mmol) and thionyl chloride (16 mL) was stirred at reflux for 1 h. The reaction was stirred at room temperature overnight. The crude reaction was coevaporated with toluene in vacuo. Column chromatography afforded 2-chloro-N-(9-chloro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide as a white off solid (200 mg, 42% yield). mp 201°C-205°C. IR(ATR):3306, 3071, 2933, 2855, 1667, 1606, 1518, 1468, 1445, 1416, 1377 , 1359, 1335, 1251, 1229, 1189, 1163, 1088, 1023, 976, 944, 864, 814, 733cm -1 HRMS: [C 19 H 23 Cl2NO3-H] - Calculated value: 382.0982, actual value: 382.0993.

[0069] Reference Example 4: 2-Chloro-N-(9-fluoro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide A solution of DAST (1.11 mL, 1 M, 1.11 mmol) was added dropwise to a mixture of 2-chloro-N-(9-hydroxy-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (270 mg, 0.74 mmol) in anhydrous DCM (8 mL) at −30° C. The reaction was stirred at room temperature overnight. Water (10 mL) was added and basified to pH 11 with 5N NaOH. The aqueous layer was extracted with DCM (4 × 10 mL) and the organic fractions were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 2-chloro-N-(9-fluoro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide as a pale yellow solid (220 mg, 81% yield), mp 197 °C-200 °C. IR(ATR):3287, 3081, 2935, 2857, 1668, 1606, 1557, 1519, 1466, 1417, 1359, 1346 , 1314, 1291, 1255, 1238, 1193, 1166, 1089, 1025, 1000, 932, 875, 790, 736, 657cm -1 HRMS: [C 19 H 23 ClFNO3+H] + Calculated value: 368.1423, actual value: 368.1423.

[0070] Reference Example 5: 9-Chloro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride Thiourea (45 mg, 0.59 mmol) and glacial acetic acid (0.41 mL) were added to a suspension of 2-chloro-N-(9-chloro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (0.19 g, 0.49 mmol) in absolute ethanol (11 mL). The mixture was stirred at reflux overnight. The resulting suspension was brought to room temperature and the ethanol was removed under reduced pressure. Water (7 mL) was added to the resulting residue and the pH was adjusted to 11-12 with 5N NaOH. The aqueous layer was extracted with DCM (4 × 7 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 9-chloro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulene-7-amine. Its hydrochloride salt was obtained by adding excess dioxane / HCl to a solution of the amine in DCM followed by filtration of the precipitate (136 mg, 80% yield). mp > 250 °C. IR (ATR): 2903, 2844, 1603, 1514, 1356, 1308, 1252, 1171, 1107, 1064, 1013, 938, 866, 812 cm -1 HRMS: [C 17 H 22 ClNO2+H] + Calculated value: 308.1412, actual value: 308.1415.

[0071] Reference Example 6: 9-Fluoro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride 2-Chloro-N-(9-fluoro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (0.22 g, 0.60 mmol) was used to obtain 9-fluoro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (108 mg, 55% yield) according to the procedure described in Reference Example 5. mp>250°C. IR(ATR):2934, 2853, 2555, 2055, 1605, 1518, 1459, 1366, 1318, 1254, 1172, 1150, 1088, 1004, 863, 801, 734cm -1 HRMS: [C 17 H 22 FNO2+H] + Calculated value: 292.1707, actual value: 292.1714.

[0072] Reference Example 7: tert-Butyl 4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annullen-7-yl)ureido)piperidine-1-carboxylate To a solution of 9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (800 mg, 2.81 mmol) in DCM (17 mL) and saturated aqueous NaHCO3 (10 mL) was added triphosgene (309 mg, 1.04 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 1 mL-2 mL of a solution of the isocyanate in DCM. To this solution was added tert-butyl 4-aminopiperidine-1-carboxylate (564 mg, 2.81 mmol). The mixture was stirred at room temperature overnight and the solvent was evaporated. Column chromatography (SiO2, DCM / methanol mixtures) afforded tert-butyl 4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidine-1-carboxylate as a yellowish solid (768 mg, 58% yield). HRMS-ESI - m / z[MH] - [C 26 H 36 ClN3O3-H] - Calculated value: 472.2372, actual value: 472.2365.

[0073] Reference Example 8: 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(piperidin-4-yl)urea To a solution of 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-isobutyrylpiperidin-4-yl)urea (530 mg, 1.12 mmol) in DCM (4 mL) was added 4N HCl in dioxane (3 mL). The mixture was stirred at room temperature overnight. The solvent was then evaporated and the residue was dissolved in DCM (10 mL) and washed with 2N NaOH (2×5 mL). The organics were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(piperidin-4-yl)urea as a yellowish solid (390 mg, 99% yield). HRMS-ESI + m / z[M+H] + [C 21 H 28 ClNO + H] + Calculated value: 374.19, actual value: 374.05.

[0074] Comparative Example 1: 1-(1-acetylpiperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea The compound was prepared as described in Example 38 of WO 02 / 04396.

[0075] Comparative Example 2: 1-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea The compound was prepared as described in Example 67 of WO 02 / 04396.

[0076] Comparative Example 3: 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(cyclopropanecarbonyl)piperidin-4-yl)urea To a solution of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (112.5 mg, 0.43 mmol) in DCM (6 mL) was added saturated aqueous NaHCO3 (5 mL) and triphosgene (93.8 mg, 0.16 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 2-3 mL of a solution of the isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl)(cyclopropyl)methanone (72 mg, 0.43 mmol). After stirring the mixture at room temperature overnight, the solvent was evaporated. Column chromatography (SiO2, DCM / methanol mixture) afforded 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(cyclopropanecarbonyl)piperidin-4-yl)urea as a white solid (60 mg, 33% yield). mp 115°C-120°C. IR(ATR): 3341, 2899, 1633, 1607, 1549, 1448, 1311, 1222, 1128, 1064, 1027, 979, 756 cm -1 HRMS: [C 26 H 35 N3O2+H] + Calculated value: 422.2802, measured value: 422.2808. C 26 H 35 Calculated for N3O2·0.4H2O: C 72.83 H 8.42, N 9.80. Found: C 73.08, H 8.23, N 9.53.

[0077] Comparative Example 4: 1-(9-methyl-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(2,3,4-trifluorophenyl)urea The compound was prepared as described in Example 58 of WO 2005 / 023391, except that 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride was used as the starting material.

[0078] Comparative Example 5: 1-(1-benzylpiperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea The compound was prepared as described in Example 48 of WO 2005 / 023991, except that 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride was used as the starting material.

[0079] Comparative Example 6: 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-propionylpiperidin-4-yl)urea The compound was prepared as described in Example 63 of WO 02 / 04396.

[0080] Comparative Example 7: 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea The compound was prepared as described in Example 65 of WO 02 / 04396.

[0081] Comparative Example 8: 1-(1-acetylpiperidin-4-yl)-3-(2-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea The compound was prepared as described in Example 68 of WO 02 / 04396.

[0082] Comparative Example 9: 1-(1-acetylpiperidin-4-yl)-3-(1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea The compound was prepared as described in Example 70 of WO 02 / 04396.

[0083] Comparative Example 10: 1-(1-acetylpiperidin-4-yl)-3-(2-methoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea The compound was prepared as described in Example 69 of WO 02 / 04396.

[0084] Comparative Example 11: 1-[1-(isopropylsulfonyl)piperidin-4-yl]-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea The compound was prepared as described in Example 47 of WO 2005 / 023391, except that 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride was used as the starting material.

[0085] Comparative Example 12: 1-(1-(4-acetylphenyl)piperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea The compound was prepared as described in Example 64 of WO 02 / 04396.

[0086] Example 1: 4-[((1r,4r)-4-(3-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)cyclohexyl)oxy]benzoic acid To a solution of 9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (180 mg, 0.67 mmol) in DCM (3 mL) and saturated aqueous NaHCO3 (2 mL) was added triphosgene (74 mg, 0.25 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic phase was washed with brine (3 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 1 mL-2 mL of a solution of the isocyanate in DCM. To this solution was added DMF (4 mL), 4-[((1r,4r)-4-aminocyclohexyl)oxy]benzoic acid hydrochloride (182 mg, 0.67 mmol) and Et3N (136 mg, 1.34 mmol). The mixture was stirred at room temperature overnight and then the solvent was evaporated. The residue was dissolved in DCM (5 mL) and washed with 2N HCl (3 mL). The organic phase was dried over anh.Na2SO4, filtered and evaporated under vacuum to give 4-[((1r,4r)-4-(3-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)cyclohexyl)oxy]benzoic acid (240 mg, 72% yield) as a yellow residue. An analytical sample was obtained by crystallization from a hot ethyl acetate / pentane mixture. mp 253°C-254°C. IR(ATR): 3325, 2929, 2859, 1682, 1629, 1606, 1558, 1511, 1424, 1359, 1317, 1282, 1251, 1221, 1165, 1104, 1090, 1003, 938, 851, 772, 697, 642cm -1 HRMS: [C 29 H 33 FN2O4-H] - Calculated value: 491.2352, actual value: 491.2334.

[0087] Example 2: 4-[((1r,4r)-4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)cyclohexyl)oxy]benzoic acid To a solution of 9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (180 mg, 0.63 mmol) in DCM (3 mL) and saturated aqueous NaHCO3 (2 mL) was added triphosgene (69 mg, 0.23 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic phase was washed with brine (3 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 1 mL-2 mL of a solution of the isocyanate in DCM. To this solution was added DMF (4 mL), 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoic acid hydrochloride (171 mg, 0.63 mmol) and Et3N (127 mg, 1.26 mmol). The mixture was stirred at room temperature overnight and then the solvent was evaporated. The residue was dissolved in DCM (5 mL) and washed with 2N HCl (3 mL). The organic phase was dried over anh.Na2SO4, filtered and evaporated under vacuum to give benzoic acid 4-[((1r,4r)-4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)cyclohexyl)oxy]benzoic acid (217 mg, 67% yield) as a yellow residue. An analytical sample was obtained by crystallization from a hot ethyl acetate / pentane mixture. mp 201°C-202°C. IR(ATR):3355, 3299, 2932, 2856, 1697, 1682, 1631, 1605, 1555, 1498, 1469, 1452, 1428, 1406, 1373, 1357, 1 322, 1301, 1253, 1163, 1100, 1077, 1041, 1027, 1013, 977, 946, 905, 844, 804, 772, 753, 695, 643, 634, 608cm -1 HRMS: [C 29 H 33 ClNO4-H] - Calculated value: 507.2056, actual value: 507.2057.

[0088] Example 3: 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea To a solution of 9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (130 mg, 0.46 mmol) in DCM (4 mL) and saturated aqueous NaHCO3 (3 mL) was added triphosgene (50 mg, 0.17 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic phase was washed with brine (3 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 1 mL-2 mL of a solution of the isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (97 mg, 0.46 mmol). The mixture was stirred at room temperature overnight and the solvent was evaporated. Column chromatography (SiO2, DCM / methanol mixtures) afforded 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea as a yellowish solid (90 mg, 41% yield). An analytical sample was obtained by washing the product with ethyl acetate to give a white solid. mp 214°C-215°C. IR(ATR):2924, 2851, 1675, 1610, 1546, 1493, 1451, 1361, 1319, 1296, 1282, 1246, 1 225, 1208, 1120, 1084, 1017, 991, 946, 908, 874, 810, 755, 730, 696, 644, 619, 564cm -1 HRMS: [C 27 H 36 ClN3O3+H] + Calculated value: 486.2518, measured value: 486.2522. C 27 H 36Calculated for ClN3O3: C 66.72, H 7.47, N 8.65. Found: C 66.92, H 7.40, N 8.43.

[0089] Example 4: 1-(9-Fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea To a solution of 9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (150 mg, 0.56 mmol) in DCM (4.5 mL) was added saturated aqueous NaHCO3 (3.5 mL) and triphosgene (61.5 mg, 0.21 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic layer was washed with brine (3.5 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 1 mL-2 mL of a solution of the isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (119 mg, 0.56 mmol). The mixture was stirred at room temperature overnight and the solvent was evaporated. Column chromatography (SiO2, DCM / methanol mixture) afforded 1-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea as a yellowish solid (75 mg, 28% yield). mp 210°C-213°C. IR(ATR): 3351, 2926, 2850, 1609, 1549, 1444, 1358, 1306, 1210, 1124, 1089, 1005, 983, 867, 759 cm -1 HRMS: [C 27 H 36 Calculated value for FN3O3+H: 470.2813, Found value: 470.2815. 27 H 36Calculated for FN3O3·0.2CH2Cl2: C 67.14, H 7.54, N 8.64. Found: C 67.47, H 7.57, N 8.29.

[0090] Example 5: 1-(9-fluoro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea To a solution of 9-fluoro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (100 mg, 0.31 mmol) in DCM (3 mL) was added saturated aqueous NaHCO3 (2.5 mL) and triphosgene (33.5 mg, 0.11 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic layer was washed with brine (3 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 1 mL-2 mL of a solution of the isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (64.8 mg, 0.31 mmol). After stirring the mixture at room temperature overnight, the solvent was evaporated. Column chromatography (SiO2, DCM / methanol mixtures) afforded 1-(9-fluoro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea as a yellowish solid (35 mg, 22% yield). mp 230°C-233°C. IR(ATR): 3351, 2938, 2853, 1679, 1596, 1546, 1515, 1468, 1445, 1264, 1214, 1161, 1126, 1091, 1020, 1010, 988, 874, 801, 585 cm -1 HRMS: [C 29 H 40 FN3O5+H] + Calculated value: 530.3025, measured value: 530.3017. C29 H 40 Calculated for FN3O5·0.5H2O: C 64.66, H 7.67, N 7.80. Found: C 64.57, H 7.52, N 7.51.

[0091] Example 6: 1-(9-chloro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea To a solution of 9-chloro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (92 mg, 0.27 mmol) in DCM (4 mL) was added saturated aqueous NaHCO3 (3 mL) and triphosgene (29 mg, 0.10 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic layer was washed with brine (3 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 2-3 mL of a solution of the isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (57 mg, 0.27 mmol). The mixture was stirred at room temperature overnight and the solvent was evaporated. Column chromatography (SiO2, DCM / methanol mixture) afforded 1-(9-chloro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea as a white solid (39 mg, 27% yield). mp 147°C-150°C. IR(ATR): 3358, 2928, 2847, 1612, 1546, 1516, 1443, 1285, 1250, 1214, 1161, 1087, 1123, 1019, 983, 942, 869, 816 cm -1 HRMS [C 29 H 40 ClN3O5+H] + Calculated value: 546.2729, actual value: 546.2727.

[0092] Example 7: 1-(9-Fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(cyclopropanecarbonyl)piperidin-4-yl)urea To a solution of 9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (150 mg, 0.56 mmol) in DCM (4.5 mL) was added saturated aqueous NaHCO3 (3.5 mL) and triphosgene (61.5 mg, 0.21 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic layer was washed with brine (3.5 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 1 mL-2 mL of a solution of the isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl)(cyclopropyl)methanone (94.2 mg, 0.56 mmol). After stirring the mixture at room temperature overnight, the solvent was evaporated. Column chromatography (SiO2, DCM / methanol mixture) afforded 1-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(cyclopropanecarbonyl)piperidin-4-yl)urea as a white solid (60 mg, 25% yield). mp 187°C-191°C. IR(ATR): 3320, 2934, 1630, 1568, 1450, 1358, 1317, 1221, 1125, 865, 767, 734, 569 cm -1 HRMS [C 25 H 32 FN3O2+H] + Calculated value: 426.2551, measured value: 426.2556. C 25 H 32 Calculated for FN3O2·0.1CH2Cl2: C 69.46 H 7.48, N 9.68. Found: C 69.64, H 7.52, N 9.45.

[0093] Example 8: 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(cyclopropanecarbonyl)piperidin-4-yl)urea To a solution of 9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (130 mg, 0.46 mmol) in DCM (4 mL) and saturated aqueous NaHCO3 (3 mL) was added triphosgene (50 mg, 0.17 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic phase was washed with brine (3 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 1 mL-2 mL of a solution of the isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl)(cyclopropyl)methanone (77 mg, 0.46 mmol). The mixture was stirred at room temperature overnight and the solvent was evaporated. Column chromatography (SiO2, DCM / methanol mixtures) afforded 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(cyclopropanecarbonyl)piperidin-4-yl)urea as a white solid (70 mg, 35% yield). mp 119°C-120°C. IR(ATR):3367, 3330, 2926, 2853, 1682, 1654, 1605, 1565, 1550, 1481, 1452, 1374, 1357, 1319, 1299, 1264, 1224, 1128, 1088, 1036, 1013, 993, 967, 948, 925, 911, 870, 799, 755, 735, 700, 632, 604, 564cm -1 HRMS: [C 25 H 32 ClNO2+H] + Calculated value: 442.2256, measured value: 442.2262. C 25 H 32 Calculated for ClN3O2·0.75H2O: C 66.05, H 7.41, N 9.24. Found: C 66.21, H 7.31, N 9.00.

[0094] Example 9: 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)urea To a solution of 9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (130 mg, 0.46 mmol) in DCM (4 mL) and saturated aqueous NaHCO3 (3 mL) was added triphosgene (50 mg, 0.17 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic phase was washed with brine (3 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 1 mL-2 mL of a solution of the isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl)(1-fluorocyclopropyl)methanone hydrochloride (101 mg, 0.46 mmol) and Et3N (92 mg, 0.91 mmol). The mixture was stirred at room temperature overnight and the mixture was washed with water (10 mL). The organic phase was dried over anh.Na2SO4, filtered and evaporated under vacuum to give an orange gum (140 mg). Column chromatography (SiO2, DCM / methanol mixtures) gave 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)urea as a yellowish solid (20 mg, 10% yield). An analytical sample was obtained by crystallization from hot ethyl acetate / pentane mixture. mp 120°C-121°C. IR(ATR):3340, 2921, 2856, 1730, 1632, 1553, 1493, 1453, 1439, 1356, 1327, 1299, 1274 , 1244, 1204, 1122, 1088, 1047, 1025, 993, 970, 947, 907, 801, 760, 729, 697, 680, 643cm -1 HRMS: [C 25 H 31 ClFN3O2+H] +Calculated value: 460.2162, actual value: 460.2165.

[0095] Example 10: 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)urea To a solution of 9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (130 mg, 0.46 mmol) in DCM (4 mL) and saturated aqueous NaHCO3 (3 mL) was added triphosgene (50 mg, 0.17 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic phase was washed with brine (3 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 1 mL-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)-2,2,2-trifluoroethan-1-one hydrochloride (106 mg, 0.46 mmol) and Et3N (92 mg, 0.91 mmol). The mixture was stirred at room temperature overnight and the mixture was washed with water (15 mL). The organic phase was dried over anh.Na2SO4, filtered and evaporated under vacuum to give an orange gum (196 mg). Column chromatography (SiO2, DCM / methanol mixtures) gave 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)urea as a yellowish solid (55 mg, 26% yield). An analytical sample was obtained by crystallization from hot ethyl acetate / pentane mixture. mp 188°C-189°C. IR(ATR):3348, 2926, 2859, 1689, 1634, 1556, 1495, 1466, 1454, 1357, 1298, 1266, 120 3, 1179, 1137, 1091, 1044, 1009, 992, 971, 946, 897, 802, 757, 698, 660, 623, 599, 556cm -1 HRMS: [C 23 H27 ClF3N3O2-H] - Calculated value: 468.1671, measured value: 468.1671. C 23 H 27 Calculated for ClF3N3O2·0.75CH3OH: C 57.75, H 6.12, N 8.51. Found: C 58.04, H 5.82, N 8.20.

[0096] Example 11: 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(isopropylsulfonyl)piperidin-4-yl)urea To a solution of 9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (268 mg, 0.94 mmol) in DCM (8 mL) and saturated aqueous NaHCO3 (5 mL) was added triphosgene (103 mg, 0.35 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 1-2 mL of a solution of the isocyanate in DCM. To a solution of 1-(isopropylsulfonyl)piperidin-4-amine (194 mg, 0.94 mmol) in anh.THF (8 mL) was added dropwise over 20 min at −78° C. under argon atmosphere a solution of n-butyllithium (2.5 M in hexanes, 0.49 mL, 1.22 mmol). After addition, the mixture was tempered to 0° C. using an ice bath. This solution was carefully added to a solution of isocyanate from the previous step cooled to 0° C. under argon atmosphere. The reaction mixture was stirred overnight at room temperature. Methanol (2 mL) was then added to quench any unreacted n-butyllithium. The solvent was evaporated under vacuum to give a yellow residue (690 mg). Column chromatography (SiO2, DCM / methanol mixture) gave a white solid. Crystallization from hot DCM:pentane gave 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(isopropylsulfonyl)piperidin-4-yl)urea as a yellowish solid (75 mg, 17% yield). An analytical sample was obtained by crystallization from hot ethyl acetate / pentane mixture. mp 223°C-224°C. IR (NaCl disk): 3407, 3370, 2926, 2856, 1672, 1538, 1494, 1451, 1353, 1304, 1296, 1223, 1209, 1177, 1130, 1090, 1045, 972, 949, 903, 885, 841, 805, 767, 735, 668, 623 cm -1 HRMS: [C 24 H 34 ClN3O3S+H] +Calculated value: 480.2082, measured value: 480.2084. C 24 H 34 Calculated for ClN3O3S·0.05 ethyl acetate: C 60.00, H 7.16, N 8.67. Found: C 60.38, H 7.08, N 8.27.

[0097] Example 12: 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-propionylpiperidin-4-yl)urea To a solution of 9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (150 mg, 0.53 mmol) in DCM (4 mL) and saturated aqueous NaHCO3 (3 mL) was added triphosgene (56 mg, 0.19 mmol). After stirring the biphasic mixture at room temperature for 30 min, the two phases were separated and the organic phase was washed with brine (3 mL), dried over anh.Na2SO4, filtered and evaporated under vacuum to give 1 mL-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)propan-1-one (83 mg, 0.53 mmol). The mixture was stirred at room temperature overnight and the solvent was evaporated. Column chromatography (SiO2, DCM / methanol mixtures) afforded 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-propionylpiperidin-4-yl)urea as an orange solid. An analytical sample was obtained by crystallization from hot ethyl acetate / pentane mixtures to give a yellowish solid (79 mg, 35% yield). mp 155°C-156°C. IR(ATR):3359, 2924, 2852, 1681, 1652, 1637, 1612, 1565, 1447, 1373, 1356, 132 2, 1297, 1263, 1221, 1134, 1075, 1045, 1022, 967, 946, 908, 804, 755, 618, 559cm -1 HRMS: [C 24 H 32 ClNO2+H]+ Calculated value: 430.2256, measured value: 430.2253. C 24 H 32 Calculated for ClN3O2·0.75H2O: C 65.00, H 7.61, N 9.47. Found: C 65.27, H 7.51, N 9.15.

[0098] Example 13: 4-(4-(3-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidin-1-yl)benzoic acid A suspension of 9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine (150 mg, 0.65 mmol) in DCM (1 mL) was added to a stirred biphasic mixture of DCM (5 mL), saturated NaHCO3 (5 mL) and triphosgene (70 mg, 0.24 mmol). The mixture was then stirred at room temperature for 30 min. The phases were separated and the organic layer was dried over anh.Na2SO4, filtered and concentrated in vacuo. A suspension of 4-(4-aminopiperidin-1-yl)benzoic acid dihydrochloride (229 mg, 0.78 mmol) in DCM (3 mL) was added followed by triethylamine (216 μL, 157 mg, 1.56 mmol) and the mixture was stirred at RT overnight. Water (10 mL) was added and the layers were separated. The aqueous layer was extracted again with 9 / 1 EtOAc / MeOH (15 mL x 2). All organic layers were combined, dried over anh.Na2SO4, filtered and the solvent was concentrated in vacuum. The resulting crude was purified by silica gel column chromatography (using a mixture of 0% to 6% MeOH in DCM as eluent). The fractions containing the desired product were collected and concentrated in vacuum to give 4-(4-(3-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidin-1-yl)benzoic acid as a beige solid (13 mg, 4% yield). mp 267°C-268°C. IR(ATR): 3334, 2928, 2851, 1675, 1602, 1555, 1520, 1306, 1224, 1183, 1120, 1098, 1045, 1010, 867, 771, 752, 719, 618, 570cm -1 HRMS: [C 28 H 32 FN3O3+H] + Calculated value: 478.2500, actual value: 478.2523.

[0099] Example 14: 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidin-1-yl)benzoic acid 9-Chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine (110 mg, 0.39 mmol) was added to a stirred biphasic mixture of DCM (2.5 mL), saturated NaHCO3 (2.5 mL) and triphosgene (80 mg, 0.27 mmol). The mixture was then stirred at room temperature for 30 min. DCM (10 mL) and water (10 mL) were added and the phases were separated. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. A suspension of this crude material in DCM (3 mL) was added to a suspension of 4-(4-aminopiperidin-1-yl)benzoic acid dihydrochloride (148 mg, 0.50 mmol) and triethylamine (210 μL, 153 mg, 1.51 mmol) in DMSO (3 mL) and the mixture was stirred at RT overnight. Water (10 mL) and ethyl acetate (10 mL) were added followed by 2M HCl until pH was 3. The layers were separated. The aqueous layer was extracted again with EtOAc (15 mL×2). All organic layers were combined, dried over anhydrous Na2SO4, filtered and the solvent was concentrated in vacuum. The resulting crude material was purified by silica gel column chromatography (using a mixture of 0%→2% MeOH in DCM as eluent). Fractions containing the desired product were collected and concentrated in vacuo to give 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidin-1-yl)benzoic acid as a brown solid (77 mg, 40% yield). mp 226°C-227°C. IR(ATR): 2922, 2851, 1672, 1601, 1553, 1518, 1385, 1357, 1221, 1184, 1120, 1089, 1039, 802, 759, 698, 607, 553 cm -1 HRMS: [C 28 H 32 ClN3O3-H] - Calculated value: 492.2059, actual value: 492.2057.

[0100] Example 15: Methyl 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annullen-7-yl)ureido)piperidine-1-carbonyl)benzoate 1-(9-Chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(piperidin-4-yl)urea (260 mg, 0.73 mmol) was dissolved in DCM (25 mL) and EDCI·HCl (211 mg, 1.1 mmol), DMAP (134 mg, 1.1 mmol) and 4-(methoxycarbonyl)benzoic acid (198 mg, 1.1 mmol) were added. The mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 1N HCl (3 mL). The phases were separated and the aqueous layer was extracted with DCM (4×10 mL). The organics were then washed with 2N NaOH (2×10 mL), dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give a white solid. Column chromatography (SiO2, DCM / methanol mixture) gave 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annullen-7-yl)ureido)piperidine-1-carbonyl)benzoate as a white solid (190 mg, 48% yield). mp 128°C-129°C. IR(ATR): 3354, 2927, 1722, 1606, 1547, 1434, 1357, 1273, 1226, 1147, 1108, 1019, 990, 967, 938, 891, 861, 823, 802, 758, 725, 699 cm -1 HRMS-ESI + m / z[M+H] + [C 30 H 34 ClN3O4+H] + Calculated value: 536.2311, actual value: 536.2313.

[0101] Example 16: 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidine-1-carbonyl)benzoic acid 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidine-1-carbonyl)benzoate (70 mg, 0.13 mmol) was dissolved in ACN (1.75 mL) and LiOH (9.3 mg, 0.39 mmol) was added followed by water (0.7 mL). The mixture was stirred at room temperature overnight. Then, Amberlite-H + to acidic pH, filtered and the solvent evaporated under vacuum to give 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annullen-7-yl)ureido)piperidine-1-carbonyl)benzoic acid as a white solid (60 mg, 88% yield). mp 200°C~dec. IR(ATR): 3361, 2927, 1722, 1607, 1551, 1440, 1357, 1274, 1229, 1108, 1047, 1019, 990, 967, 938, 862, 802, 758, 697 cm -1 HRMS-ESI - m / z[MH] - [C 29 H 32 ClNO4-H] - Calculated value: 520.2009, actual value: 520.1999.

[0102] Example 17: a) In vitro determination of sEH inhibitory activity The following fluorescent assay was used to measure sEH inhibitory activity (IC) with the substrates and control compound (t-TUCB) shown below. 50 ) was decided.

[0103] Substrate: Cyano(6-methoxynaphthalen-2-yl)methyl 2-(3-phenyloxiran-2-yl)methyl carbonate (CMNPC); Morrisseau, C.; Hammock, BD Measurement of soluble epoxide hydrolase (sEH) activity. Curr. Protoc. Toxicol. 2007, Chapter 4, Unit 4.23.

[0104] t-TUCB: 4-[[trans-4-[[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]amino]cyclohexyl]oxy]benzoic acid

[0105] protocol: A fluorescent assay was used with purified recombinant human or mouse sEH protein. The enzyme was incubated with 0.1 mg / mL BSA and 1% DMSO in 100 mM sodium phosphate buffer (200 μL, pH 7.4) containing the inhibitor ([I] 最終 =0.4nM~100000nM) at 30°C for 5 minutes. Then, the substrate (CMNPC) was added ([S] 最終 = 5 μM). The fluorescent 6-methoxynaphthaldehyde product (λ ex = 330 nm, λ em Activity was assessed by measuring the appearance of IC50 (=465 nm) once every 30 seconds for 10 minutes at 30°C on a SpectraMax M2 (Molecular Devices). Results were obtained by regression analysis from the linear region of the curve. All measurements were performed in triplicate and the average values ​​are reported. The classical sEH inhibitor t-TUCB was measured in parallel and the resulting IC50 50 was confirmed by reported literature values ​​to verify the experimental results.

[0106] b) In vitro determination of microsomal stability The human recombinant microsomes used were purchased from Tebu-Xenotech. Compounds were incubated with microsomes at 37°C in 50 mM phosphate buffer (pH=7.4) containing 3 mM MgCl2, 1 mM NADP, 10 mM glucose-6-phosphate and 1 U / mL glucose-6-phosphate dehydrogenase. Samples (75 μL) were removed from each well at 0, 10, 20, 40 and 60 min and transferred to a plate at 4°C, and 75 μL acetonitrile and 30 μL 0.5% formic acid in water were added to improve chromatographic conditions. The plate was centrifuged (46000g, 30 min) and the supernatant was removed and analyzed in a UPLC-MS / MS (Xevo-TQD, Waters) using a BEH C18 column and an isocratic gradient of 0.1% formic acid in water: 0.1% formic acid acetonitrile (60:40). The metabolic stability of the compounds was calculated from the log of remaining compound at each time point studied.

[0107] [Table 1]

[0108] Example 18: Activity against mouse models of Alzheimer's disease statistical analysis Data are expressed as mean ± standard error of the mean (SEM) from at least each group of samples for behavioral tests and four to six samples for molecular analyses. Data analysis was performed using GraphPad Prism ver.8. statistical software. For statistical analysis of treatment groups and 5XFAD-Ct, one-way ANOVA was applied, followed by two-tailed Dunnett's test, and between control groups, Student's t-test. Statistical significance was considered when p-value was less than 0.05.

[0109] Mouse model 5XFAD (tg6799) is an early-onset mouse transgenic model that overexpresses mutant human APP (695) carrying the Swedish (K670N, M671L), Florida (I716V) and London (V717I) familial Alzheimer's disease (FAD) mutations together with human PS1 carrying two FAD mutations (M146L and L286V). The Tg6799 strain used is the original hybrid B6SJL background, which is used as a control for healthy animals. The mouse Thy1 promoter regulates both transgenes and drives overexpression in the brain. 5XFAD mice are a useful model of Aβ-42-induced neurodegeneration in neurons that recapitulates key features of AD amyloid pathology, with increased amyloid brain content and amyloid plaque formation and tau hyperphosphorylation (J Neurosci. 2006, 26(40), 10129-10140).

[0110] treatment Animals were treated with vehicle (control) or the compound of Example 2 in drinking water for 4 weeks. Test compounds were dissolved in 1.8% hydroxypropyl-β-cyclodextrin, and the concentration in water was calculated according to the weekly consumption of animals to reach the correct daily dose. Drinking liquid was replaced with freshly prepared liquid every week. The amount of water that animals drank was monitored weekly by cage, and drug concentration was adjusted once a week to reach the correct dose. After 4 weeks of treatment maintenance, mice were studied in behavioral tests.

[0111] Behavioral testing An in vivo model to assess the efficacy of test compounds in learning and memory disorders (Novel Object Recognition Test; NORT) Mice were placed in a 90°, 2-arm, black maze with a length of 25 cm, a height of 20 cm, and a width of 5 cm. The walls could be lifted to facilitate cleaning. The light intensity in the center of the field was 30 lux. The objects to be identified were made of plastic and were selected so as not to scare the mice, avoiding objects with parts that could be bitten.

[0112] Before testing, the mice were individually habituated to the apparatus for 10 min over three days. On the fourth day, the animals were given a 10 min acquisition trial (trial 1) in which they were placed in the maze with two identical novel objects (A+A or B+B) at the end of each arm. Two hours later, a 10 min retention trial (trial 2) was given. In this second trial, objects A and B were placed in the maze and the mouse's behavior was recorded by a camera. The time the mouse explored the new object (TN) and the time the mouse explored the old object (TO) were measured. The discrimination index (DI) was defined as (TN-TO) / (TN+TO). To avoid object preference bias, objects A and B were counterbalanced so that half of the animals in each experimental group first saw object A and then object B, and the other half first saw object B and then object A. After each test, the maze and objects were wiped with 70° ethanol to remove olfactory cues. The learning and memory paradigm is based on spontaneous exploratory activity of rodents and does not involve rule learning or reinforcement. The object recognition paradigm has been shown to be particularly sensitive to aging and cholinergic dysfunction (Neurosci. Lett. 1994, vol. 170, pp 117-120; Pharmacol. Biochem. Behav. 1996, vol. 35 53, pp. 277-283). This model has been adapted to mice and validated with drugs (Front. Biosci. (Schol. Ed.) 2015, vol. 7, pp 10-29).

[0113] Evaluation of the neuroprotective properties of the compound of Example 2 (5 mg / kg) in the 5XFAD model by NORT showed that memory deficits were reduced in the treated group compared to the control group, and the 5XFAD treated group regained the DI level of the wild type (Wt) control group. Thus, the compound of Example 2 (5 mg / kg) can improve cognitive performance in a mouse model of Alzheimer's disease. The results are shown in Tables 2 and 3.

[0114] Table 2 shows the DI values ​​of 2-hour NORT in 6-month-old wild-type (Wt-Ct) and 5XFAD (5XFAD-Ct) control and 5XFAD male mice treated with the compound of Example 2 (5 mg / kg). The treatment period was 4 weeks. Data are the observed mean ± standard error of the mean (SEM). ### p<0.01 compared with the Wt-Ct group. *** p<0.001 compared with the 5XFAD-Ct group.

[0115] [Table 2]

[0116] Table 3 shows the DI values ​​of 24-hour NORT in 6-month-old control wild-type (Wt-Ct) and 5XFAD (5XFAD-Ct) male mice and 5XFAD treated with the compound of Example 2 (5 mg / kg). The treatment period was 4 weeks. Data are the observed mean ± standard error of the mean (SEM) (n=10-12 for each group). #### p<0.0001 compared with the Wt-Ct group. * p<0.05 compared with the 5XFAD-Ct group.

[0117] [Table 3]

[0118] Brain tissue dissection After NORT, animals were sacrificed and either whole hippocampi were dissected or brain sections were obtained from control and treated mice using a cryostat. Tissues were stored at -80°C until used for Western blot analysis or thioflavin staining experiments.

[0119] Western Blot: Tau pathology and neuroinflammation For Western blotting (WB), an aliquot of 15 μg hippocampal protein was used. Protein samples were separated by SDS-PAGE (8%–12%) and transferred to PVDF membranes (Millipore). The membranes were then blocked in 5% nonfat milk in 0.1% Tween 20 TBS (TBS-T) for 1 h at room temperature, followed by incubation overnight at 4°C with primary antibodies (p-tau (Ser404) (Invitrogen; 1:1000), total tau (Invitrogen; 1000), GFAP (Millipore; 1:2500), and TREM2 (Invitrogen; 1:1000) and GAPDH (Abcam; 1:5000)).

[0120] The membrane was then washed and incubated with secondary antibody for 1 h at room temperature. Immunoreactive proteins were observed with a chemiluminescence-based detection kit according to the manufacturer's protocol (ECL Kit; Millipore), and digital images were acquired using a ChemiDoc XRS+ System (BioRad). Semiquantitative analysis was performed using ImageLab software (BioRad), and the results were expressed in arbitrary units (AU), considering the control protein level as 100%. Protein loading was routinely monitored for immunodetection of GADPH. The results are shown in Tables 4 and 6 below.

[0121] Treatment of 5XFAD mice with the compound of Example 2 reduced the rate of hyperphosphorylation of tau protein, which was significantly increased in 5XFAD mice compared to WT animals.

[0122] Table 4 shows the protein level values ​​of hyperphosphorylated tau at serine 404 in hippocampal tissue of 6-month-old wild-type (Wt-Ct) and 5XFAD (5XFAD-Ct) control and 5XFAD male mice treated with the compound of Example 2 (5mg / kg). The treatment period was 4 weeks. The protein levels of p-tau (Ser404) and total tau were determined by Western blotting, and the ratio of p-tau / total tau was calculated. ## p<0.01 compared to 5Wt-Ct. **p<0.01 compared to 5XFAD-Ct.

[0123] [Table 4]

[0124] Due to the involvement of neuroinflammation in AD pathology and the reduction of inflammatory mediators after sEH inhibition, several gliotic markers were evaluated (GFAP and TREM2), both of which showed a significant reduction in protein levels after treatment with the compound of Example 2.

[0125] Table 5 shows the values ​​of GFAP and TREM2 protein levels assessed by WB in hippocampal tissues of 6-month-old wild-type control (Wt-Ct) and 5XFAD (5XFAD-Ct) male mice and 5XFAD treated with the compound of Example 2 (5 mg / kg). The treatment period was 4 weeks. ## p<0.01 compared with Wt-Ct. * p<0.05 compared to 5XFAD-Ct.

[0126] [Table 5]

[0127] Thioflavin S staining Brain slices were thawed at room temperature and then rehydrated with PBS solution for 5 min. Then, brain slices were incubated with 0.3% Thioflavin S (Sigma-Aldrich) for 20 min at room temperature in the dark. They were then subjected to a series of 3 min washes, namely 80% ethanol (2 × 15 washes), 90% ethanol (1 wash) and 3 washes with PBS. Finally, slides were mounted with Fluoromount-G™ mounting medium (EMS), dried overnight at room temperature in the dark and stored at 4 °C. Image acquisition was performed with an epifluorescence microscope (BX51; Olympus, Germany). For quantification of plaques, similar and comparable histological areas were selected, focusing on adjacent positions of the hippocampus and the entire cortical field (Table 6 and Figure 1).

[0128] Table 6 shows the histological image values ​​of amyloid plaques stained with Thioflavin-S in 6-month-old wild-type (Wt-Ct) and 5XFAD (5XFAD-Ct) control and 5XFAD male mice treated with the compound of Example 2 (5mg / kg). The treatment period was 4 weeks. Data are the observed mean ± standard error of the mean (SEM) (n=4 for each group). #### p<0.001 compared to Wt-Ct. *** p<0.001 compared to 5XFAD-Ct.

[0129] [Table 6]

[0130] Example 19: Activity in a mouse model of acute pancreatitis Acute pancreatitis (AP) is a potentially life-threatening gastrointestinal disease whose incidence has been increasing over the past decades. The onset of the disease is thought to be triggered by intraacinar cell activation of digestive enzymes, resulting in interstitial edema, inflammation and acinar cell death, often leading to a systemic inflammatory response. The efficacy of the new compound of Example 2 at 0.1 mg / kg and 0.3 mg / kg was evaluated in a caerulein-induced AP mouse model. The experimental procedure for the in vivo efficacy study followed a previously published protocol (Non-Patent Document 23).

[0131] First, the health of the animals was analyzed by monitoring the change in body weight along the experimental procedure. After the dietary replacement (with the last caerulein injection), the control animals gained some weight, and as expected, no weight gain was observed in the animals that received caerulein only. In contrast, the animals treated with the compound of Example 2 at both doses (0.3 mg / kg and 0.1 mg / kg) showed an increase in body weight, but only the group treated with 0.3 mg / kg reached statistical significance (p<0.01 vs. caerulein group) (Figure 2).

[0132] Finally, pancreatic histological analysis was evaluated to determine whether treatment with the compound of Example 2 reduced the severity of caerulein-induced pancreatitis. Pathological changes were studied in H&E stained pancreatic sections (Figure 3). As expected, the caerulein control group showed strong pancreatic damage representative of AP, including edema, necrosis, and infiltration of inflammatory cells. In contrast, treatment with both doses of the compound of Example 2 ameliorated the effects induced by caerulein. At the higher dose (0.3 mg / kg), pancreatic damage, edema, and neutrophil infiltration were more efficiently reversed (Figures 3 and 4).

[0133] Experimental section: In vivo efficacy study. Forty-one male C57BL / 6 mice (8 weeks old; approximately 24 g) were provided by Envigo (Barcelona, ​​Spain) (reference number 16512). During the experimental procedure, the animals were identified with a permanent marker (tail code number). Upon arrival, the animals were housed in groups of 8 or 9 animals / cage in polysulfone holding cages (480 × 265 × 210 mm, surface area 940 cm) with wire tops and wood chip bedding. 2). Animals were kept in an environmentally controlled room (ventilated, with a temperature of 22 ± 2 °C and humidity of 35% to 65%) with a 12-h light / dark cycle. An acclimation period of 7 days was allowed from the date of arrival to the start of the procedure. During this period, animals were observed to ensure their general health. Maintenance diet was provided by Harlan Interfauna Iberica SL (2018 Harlan Teklad Global Diets). The animals were allowed to consume the maintenance diet ad libitum, but were fasted overnight before the first caerulein injection and the diet was replaced after the last caerulein injection. Tap water was provided by CASSA (Servei d'Aiguees de Sabadell) and was available ad libitum. Animals were maintained in accordance with the European Directive for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes (86 / 609 / EU), Decree 214 / 1997 of July 30th (Ministry of Agriculture, Forestry and Fisheries, Generalitat de Catalunya, Spain) and Royal Decree 53 / 2013 of February 1st (Spain). All experimental procedures were approved by the Ethical Committee on human and animal experimentation (CEEAH) of the Autonomous University of Barcelona (UAB) (Procedure number: 4107) and by the Animal Experimentation Committee of the Generalitat de Catalunya (DAAM: 10146). Test articles were dissolved in the vehicle 10% 2-hydroxypropyl-β-cyclodextrin (CAS 128446-35-5) (Sigma-Aldrich (Reference number 332607)). Vehicle was prepared the day before and stored at 4°C. Pancreatitis induction: Mice (n=41) were weighed, identified by individual numbers at the base of the tail, and fasted overnight. Caerulein (caerulein group and caerulein + compound of Example 2 group) (50 μg / kg, prepared in 0.9% NaCl) or vehicle (0.9% NaCl) (control group) were intraperitoneally injected (V=5 mL / kg) 12 times consecutively at 1 hour intervals (h=0-11). Food was replaced after the last injection.A satellite experiment was designed, with animals (n=3) divided into a control group, a caerulein group and a caerulein + compound of Example 2 treatment group. Pancreatitis was induced by seven injections of caerulein (or vehicle in the control group) at 1 hour intervals (h=0-6). Treatment: 14 hours after the first caerulein injection, the test article was administered intraperitoneally in a single injection to the group of compound of Example 2 (0.3 mg / kg) and the group of compound of Example 2 (0.1 mg / kg). Animals in the control and caerulein groups received vehicle treatment (10% 2-hydroxypropyl-β-cyclodextrin) (V=10 mL / kg). Two hours after the first caerulein injection, additional groups were treated: the group of compound of Example 2 (0.3 mg / kg), the control group and the group of caerulein (10% 2-hydroxypropyl-β-cyclodextrin). Study termination: 24 hours after the first caerulein injection, animals were weighed and anesthetized with isoflurane. Blood was collected from the vena cava into Eppendorfs containing K2-EDTA and centrifuged at 10000 rpm for 5 min for plasma collection. Plasma was stored at -80°C until analysis. Mice were sacrificed by cervical dislocation and pancreases were dissected and weighed. Pancreases from three animals were frozen in liquid N2 and stored at -80°C until analysis. Pancreases from five mice were sectioned, one part was placed in 10% formalin and sent to Anapath (Granada, Spain) for histological analysis, and the other part was immediately placed in RNase-free Eppendorfs, frozen in N2, and stored at -80°C for gene expression assays.

[0134] Histological analysis. Pancreatic samples were treated with increasing strength alcohol, two xylol baths and embedded in paraffin. They were subsequently sectioned using a microtome and processed for staining. For deparaffinization of the samples, two xylene baths (10 min) and three decreasing solutions of alcohol (100%, 90% and 70%) were used (5 min), followed by staining with hematoxylin (5 min) and eosin (5 min). For the dehydration process after staining with eosin, increasing solutions of alcohol (70%, 96% and 100%) and xylene were used again. Finally, the samples were mounted with DPX.

[0135] Histological scoring of pancreatic sections was performed to grade the degree of atrophy of the pancreatic parenchyma, cellular vacuolar degeneration, edema, hemorrhage, mononuclear inflammatory cells, polymorphonuclear inflammatory cells, and necrosis. Scores were assigned as follows: 0 (no change): no lesions were observed or the observed changes were within normal limits; 1 (minimal): minor changes but above the limits considered normal; 2 (mild): lesions were discernible but of moderate severity; 3 (moderate): significant damage, but still with potential for increased severity; 4 (very severe): lesions were very severe and occupied the majority of the tissue analyzed. Lesions were evaluated in the most affected lobule of the entire pancreas. Atrophy was graded based on the percentage of atrophic tissue as follows: 0: no atrophy; 1: 0%-25% atrophic parenchyma; 2: 25%-50%; 3: 50%-75% and 4: 75%-100%.

[0136] Example 20: Seizure Assay Animals and treatments Age-matched male CD1 mice weighing 35-40 g were treated by gavage with vehicle (control or test compound TPPU, compound of Example 2) at a dose of 5 mg / kg. Test compounds were dissolved in 20% hydroxypropyl-β-cyclodextrin and concentrations were calculated according to the animal's weight to reach the correct dose. Animals were housed in a standard animal facility with a 12-hour light-dark cycle and free access to water and food.

[0137] Behavioral testing To investigate the ability of compounds to cross the blood-brain barrier (BBB), a standard acute study was used involving administration of the convulsant drug pentylenetetrazole (PTZ) (Inceoglu et al, PLoS ONE, 2013, 8(12), e80922; WO 2015 / 148954). In the study, 85 mg / kg PTZ was administered by subcutaneous route and the time to first clonic seizure occurrence, mean clonic seizure, tonic seizure latency and mortality were monitored for 30 minutes. 5 mg / kg vehicle or compound was administered by gavage 1 hour prior to the convulsant drug.

[0138] result Table 7 shows the effect of compounds on various seizure behavior parameters in the PTZ test.

[0139] [Table 7]

[0140] Compound of Example 2 was found to protect mice from convulsions and associated lethality, indicating that the compounds claimed herein can cross the BBB. The PTZ assay is believed to be highly applicable from mice to humans. In this seizure assay, which is entirely dependent on the compound's ability to cross the BBB, compound of Example 2 showed significant efficacy, suggesting that this compound easily penetrates the CNS and protects mice from seizures (Table 7).

[0141] Treatment with 5 mg / kg TPPU and the compound of Example 2 delays the onset of PTZ-induced tonic seizures compared to the control group (vehicle). Note that animals that did not show tonic seizures within 30 minutes were excluded from this table. The compound of Example 2 produced better results than TPPU.

[0142] Example 21: Inflammation and reactive transformation in primary glial cells method Treatment of microglia with AβOs To verify the inhibitory effect of sEH, 3 × 10 cells isolated from the brains of CD1 mice were used. 5 Microglia were seeded in microglia medium in 12-well culture plates. Cells were incubated in serum-free conditions for 24 h and pretreated with sEH inhibitor (compound of Example 2) for 30 min, followed by AβO (1 μM, β-Amyloid(1-42), Ultra Pure, HFIP A-1163-1, rPeptide) or PBS for 4 h.

[0143] Treatment of astrocytes with T / I / C To verify the inhibitory effect of sEH, we used 10 sEH isolated from the brains of CD1 mice. 6 Astrocytes (Sciencell #M1800) or primary human astrocytes (Sciencell #1800) were seeded in 6-well culture plates in astrocyte medium (Sciencell #1831 or #1801). Cells were incubated in serum-free conditions for 24 h and pretreated with sEH inhibitors (compound of Example 2, 10 μM or 30 μM) for 30 min followed by recombinant T / I / C:Il-1α (3 ng / ml, Peprotech), TNFα (30 ng / ml, R&D), C1q (400 ng / ml, R&D) or PBS for 24 h.

[0144] Quantitative real-time PCR (qPCR) Total RNA was isolated from microglia or astrocytes using the Quick-RNA kit (Zymo Research, Inc., Irvine, CA, USA). The concentration of total RNA was measured using a UV-Vis spectrophotometer (NanoDrop8000, Thermo Fisher Scientific Inc., Wilmington, DE, USA) and reverse transcribed using a High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Carlsbad, CA, USA). Gene expression was quantified by Fast SYBR Green real-time PCR on a Quantstudio 5 system (Applied Biosystems). Primer sequences are listed below (Table 8). Data were analyzed according to the comparative Ct method. Glyceraldehyde 3-phosphate dehydrogenase (Gapdh) was used to normalize the amount of cDNA in each sample.

[0145] [Table 8]

[0146] Western blotting Proteins were extracted from microglia or astrocytes with RIPA buffer (Thermo Fisher Scientific Inc.). Extracted proteins were separated by SDS / PAGE and then transferred to nitrocellulose membranes (Bio-Rad, Hercules, CA, USA). Membranes were blocked in 3% BSA for 1 h at RT and incubated with primary antibodies against EPHX2 (Abcam ab155280), C3 (Abcam, ab200999) and GAPDH (Santa Cruz Biotechnology, Inc sc-32233) overnight at 4°C, followed by incubation with highly adsorbed secondary antibodies Alexa Fluor Plus 800 or 680 (Life Technologies) for 1 h at RT. Membranes were visualized with Odyssey (LI-COR Biosciences, NE, USA).

[0147] Cell viability assay SHSY5Y cells were cultured in a 96-well plate (5 × 10 4 The cells were cultured with 100 μl of sEH inhibitor (compound of Example 2) or PBS for 24 hours, followed by treatment with sEH inhibitor (compound of Example 2) or PBS for 24 hours and equilibrated to room temperature for 30 minutes. 50 μl of Cell titer Glo reagent was added to each well and incubated for 10 minutes. Luminescence of each sample was measured (n=3) in a plate reader (Bio-Tek) with parameters of 1 minute delay and 0.5 seconds / well read time.

[0148] result The compound of Example 2 (100 μM) did not show any neurotoxicity in SH-SY5Y cells over 24 hours. To verify the inhibitory effect of the compound of Example 2 on AβO (Aβ1-42)-induced microglial activation, mouse primary microglia isolated from CD1 brain tissue were pretreated with the compound of Example 2, followed by Aβ1-42 (2 μM), and assessed by qPCR. AβO significantly induced the mRNA of inflammatory cytokines, including Il-6 and Il-1b, which was blocked by the compound of Example 2.

[0149] We next investigated whether inhibition of reactive astrocyte conversion by the compound of Example 2 is neuroprotective. Recently, it has been shown that microglial activation leads to the conversion of normal astrocytes to reactive astrocytes via the secretion of TNF-α, IL-1α and C1q (T / I / C) in various neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. As shown in Figure 5, human primary astrocytes were treated with T / I / C for 24 hours in the presence or absence of the compound of Example 2. The compound of Example 2 blocked the induction of mRNA for Nos and Cox2, which are potent inflammatory mediators. More importantly, the mRNA levels of Cxcl10 and C3, which are representative markers of reactive astrocytes, were significantly reduced by treatment with the compound of Example 2. Consistent with the inhibitory effect of the compound of Example 2 on mRNA, the protein levels of C3 and phosphor-p38 were reduced in T / I / C-induced reactive astrocytes treated with the compound of Example 2. Therefore, it can be concluded that the compound of Example 2 inhibited inflammation and reactive transformation in primary glial cells.

[0150] List of References Non-Patent Documents Cited in This Specification 1. Abstracts of Papers, 241st ACS National Meeting & Exposition, Anaheim, CA, United States, March 27-31, 2011 (2011), MEDI-92 2. ACS Chem Biol. 2018 Jan 19; 13:45-52 3. Alcoholism. 2018, 42, 1970 4. Am J Physiol Renal Physiol. 2013 Jan 15;304(2):F168-76 5. Am J Physiol Renal Physiol. 2014 Oct 15;307(8):F971-80 6. Am J Physiol Gastrointest Liver Physiol. 2019, 316, G527-G538 7. Am J Respir Cell Mol Biol. 2012 May;46(5):614-22 8. Am J Respir Crit Care Med. 2014 Oct 15;190(8):848-50 9. Anticancer Res. 2013 Dec;33(12):5261-5271 10. Aust J Chem. 1983; 36:2465-2472 11. Bioorg Med Chem. 2014, 22, 2678 12. Bioorg Med Chem. 2015, 23, 290 13. Bioorg Med Chem Lett. 2014 Jan 15;24(2):565-70 14. BioRxiv. 2019 March 8, doi: 10.1101 / 571984 15. Cancer Metastasis Rev 2020, 39:337 16. Cardiovasc Ther. 2011 Apr;29(2):99-111 17. Clinics Res Hepatol Gastroenterol. 2018, 42, 118-125 18. Curr. Protoc. Toxicol. 2007, Chapter 4, Unit 4.23 19. Diabetes. 2018 Jun;67(6):1162-1172 20. Dig Dis Sci. 2012 Oct;57(10):2580-91 21. Drug Discov Today. 2015 Nov;20(11):1382-90 22. Drug Metab Dispos. 2015 May;43(5):788-802 23. Equine Vet J. 2017 May;49(3):345-351 24. Exp Diabetes Res. 2012:758614 25. Exp Mol Med., 2021, 53(5):864-874 26. Expert Opin Ther Patents. 2010, vol. 20, pp. 941-956 27. Experimental Molecular Medicine. 2018, 50:149 28. FASEB J. 2015 Mar;29(3):1092-101 29. FASEB J.March 2008 22 (Meeting Abstract Supplement) 479.17 30. Free Rad Biol Med. 2012, 53, 160 31. Frontiers Pharmacol. 2019, 9:1551 32. Frontiers Pharmacol. 2019, 10:95 33. Biomed. & Pharmacother. 2019, 115: 108897 34. Inflamm Allergy Drug Targets. 2012 Apr;11(2):143-58 35. Int J Cardiol. 2012 Mar 8;155(2):181-7 36. Int J Mol Sci., 2021, 22(9):4650 37. J Agric Food Chem. 2011 Apr 13;59(7):2816-24 38. J Biol Chem. 2014 Dec 26;289(52):35826-38 39. J Cardiovasc Pharmacol. 2008 Oct;52(4):314-23 40. J Neurosci Res. 2017 Dec;95(12):2483-2492 41. J Pharmacol Exp Ther. 2016 Jun;357(3):529-36 42. J Pharmacol Exp Ther. 2017 Jun;361(3):408-416 43. J Surg Res. 2013 Jun 15;182(2):362-7 44. J Vet Pharmacol Ther. 2018 Apr;41(2):230-238 45. J Med Chem. 2012, vol. 55, pp. 1789-1808 46. J Med Chem. 2021, vol 64, pp. 184-215 47. J Neurosurg Anesthesiol. 2015 Jul; 27(3):222-240 48. Liebigs Ann Chem. 1973; 1839-1850 49. Life Sci. 2013 Jun 21;92(23):1145-50 50. Med Hypotheses, 2017 Oct;108:81-5 51. Mol Neurobiol. 2015 Aug;52(1):187-95 52. Mol Pharmacol. 2015 Aug;88(2):281-90 53. Nature. 2017 Dec 14;552(7684):248-252 54. Neurotherapeutics Jun; 2020, 17:1825-1835 55. Nutr Metab Cardiovasc Dis. 2012 Jul;22(7):598-604 56. Oncotarget. 2017 Sep 21;8(61):103236-60 57. Pharmacol Ther. 2017 Dec;180:62-76 58. Phytother Res. 2016 Jul;30(7):1119-27 59. PLoS One. 2013 Dec 11;8(12):e80922 60. PLoS One. 2014 May 13;9(5):e97529 61. PLoS One. 2014 Oct 13, 9(10):e110162 62. PLoS One. 2019 Apr 19, 14(4):e0215033 63. Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9772-7 64. Proc Natl Acad Sci U S A. 2011 May 31;108(22):9038-43 65. Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):9082-7 66. Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):E1944-52 67. Proc Natl Acad Sci U S A. 2018 May 15;115(20):5283-5288 68. Proc Natl Acad Sci U S A. 2018, 115:E5815-E5823 69. Proc Natl Acad Sci U S A. 2019, 116:5154-5159 70. Proc Natl Acad Sci U S A. 2019, 116:7083-7088 71. Prog Lipid Res. 2014 Jan;53:108-23 72. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:30-7 73. Prostaglandins Other Lipid Mediat. 2017 Jul;131:67-74 74. Prostaglandins Other Lipid Mediat. 2018 May;136:84-89 75. Recent Pat Cardiovasc Drug Discov. 2006 Jan;1(1):67-72. 76. Resp Res. 2018, 19:236 77. Scientific Reports. 2018, 8:5279 78. Stroke. 2015 Jul;46(7):1916-22 79. Tetrahedron Lett. 1987, 28, 1585-1588. 80. Toxicol Appl Pharmacol. 2015 Jul 15;286(2):102-11 81. Toxicology. 2017 Aug 15;389:31-41 82. J Neurosci. 2006, 26(40), 10129-10140 83. Neurosci. Lett. 1994, vol. 170, pp 117-120 84. Pharmacol. Biochem. Behav., 1996, vol. 35 53, pp. 277- 283 85. Front. Biosci. (Schol. Ed.) 2015, vol. 7, pp 10-29 Patent documents cited herein 86. International Publication No. 2000 / 23060 87. International Publication No. 2007 / 009001 88. International Publication No. 2003 / 002555 89. International Publication No. 2015 / 148954 90. International Publication No. 2017 / 120012 91. International Publication No. 2016 / 133788 92. International Publication No. 2019 / 243414 93. International Publication No. 2020 / 146770

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, G １ represents a nitrogen atom or a -CH- group, G １ is a nitrogen atom group, R １ teeth, a) a1) All of the above are halogen atoms, cyano (C≡N), trifluoromethoxy (OCF ３ ) and C １ ~C ６ A linear or branched C optionally substituted with one substituent selected from the group consisting of alkoxy. ３ ~C ６ Acyl or C ３ ~C ６ Cycloalkyl-C(=O), a2) trifluoroacetyl, 3,3,3-trifluoropropionyl, tetrahydropyrancarbonyl, oxetanecarbonyl or (tetrahydro-2H-thiopyran)carbonyl, and a3) heteroaryl groups having 5 to 14 members in the ring system and having 1 to 3 heteroatoms selected from the group consisting of N, O and S, all of which are halogen atoms, cyano (C≡N), trifluoromethyl (CF ３ ), trifluoromethoxy (OCF ３ ), pentafluorosulfanyl (SF ５ ), sulfonyl (SO ３ H), carboxylic acid group (COOH), ester group (COOR ４ ), amino (NH ２ ), mono-C １ ~C ６ Alkylamino, di-C １ ~C ６ Alkylamino, Hydroxyl, C １ ~C ６ Alkoxy and C １ ~C ６ C optionally substituted with 1 to 4 substituents selected from the group consisting of alkyl ６ ~C １４ -arylcarbonyl or C ４ ~C １４ - a carbonyl-containing group selected from the group consisting of heteroarylcarbonyl; b) a halogen atom, C １ ~C ６ Acyl, cyano (C≡N), trifluoromethyl (CF ３ ), trifluoromethoxy (OCF ３ ), pentafluorosulfanyl (SF ５ ), sulfonyl (SO ３ H), fluorosulfonyl (SO ２ F), carboxylic acid group (COOH), ester group (COOR ４ ), amino (NH ２ ), mono-C １ ~C ６ Alkylamino, di-C １ ~C ６ Alkylamino, Hydroxyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and C １ ~C ６ phenyl, optionally substituted with 1 to 4 substituents selected from the group consisting of alkoxycarbonylmethyl, and c) halogen atom, nitro (NO ２ ), cyano (C≡N), trifluoromethyl (CF ３ ), trifluoromethoxy (OCF ３ ), pentafluorosulfanyl (SF ５ ), sulfonyl (SO ３ H), carboxylic acid group (COOH), ester group (COOR ４ ), amino (NH ２ ), mono-C １ ~C ６ Alkylamino, di-C １ ~C ６ Alkylamino, Hydroxyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl and C １ ~C ６ A straight or branched C optionally substituted with one or two substituents selected from the group consisting of alkoxycarbonylmethyl １ ~C ６ Alkylsulfonyl, C ３ ~C ６ Cycloalkylsulfonyl and C ６ ~C １０ arylsulfonyl; G １ When is a -CH- group, R １ may be unsubstituted or may be COOH, COOR ４ , C.O.N.H. ２ phenoxy optionally substituted by 1 to 4 groups selected from CN, fluorine, chloro, trifluoromethyl, cyclopropyl and OH; R ２ is a halogen atom, R ３ is selected from the group consisting of hydrogen and methoxy; R ４ is C １ ~C ６ Alkyl and C ３ ~C ６ cycloalkyl), or a stereoisomer or pharma- ceutically acceptable salt thereof.

2. G １ The compound of claim 1 , wherein is N.

3. R １ However, a1) all of them are halogen atoms, cyano (C≡N), trifluoromethoxy (OCF ３ ) and C １ ~C ６ A linear or branched C optionally substituted with one substituent selected from the group consisting of alkoxy. ３ ~C ６ Acyl, C ３ ~C ６ Cycloalkyl-C(=O), a2) trifluoroacetyl, 3,3,3-trifluoropropionyl, tetrahydropyrancarbonyl, oxetanecarbonyl or (tetrahydro-2H-thiopyran)carbonyl, and a3) heteroaryl groups having 5 to 14 members in the ring system and having 1 to 3 heteroatoms selected from the group consisting of N, O and S, all of which are halogen atoms, cyano (C≡N), trifluoromethyl (CF ３ ), trifluoromethoxy (OCF ３ ), pentafluorosulfanyl (SF ５ ), sulfonyl (SO ３ H), carboxylic acid group (COOH), ester group (COOR ４ ), amino (NH ２ ), mono-C １ ~C ６ Alkylamino, di-C １ ~C ６ Alkylamino, Hydroxyl, C １ ~C ６ Alkoxy and C １ ~C ６ C optionally substituted with 1 to 4 substituents selected from the group consisting of alkyl ６ ~C １４ -arylcarbonyl or C ４ ~C １４ -heteroarylcarbonyl.

4. R １ is a straight-chain or branched C optionally substituted with an F atom or a cyano group, trifluoroacetyl, 3,3,3-trifluoropropionyl, tetrahydropyrancarbonyl, oxetanecarbonyl, and (tetrahydro-2H-thiopyran)carbonyl; ３ ~C ６ Acyl, C ３ ~C ６ 4. The compound of claim 3, selected from the group consisting of cycloalkyl-C(=O).

5. R １ is a halogen atom, C １ ~C ６ Acyl, cyano (C≡N), trifluoromethyl (CF ３ ), trifluoromethoxy (OCF ３ ), pentafluorosulfanyl (SF ５ ), sulfonyl (SO ３ H), fluorosulfonyl (SO ２ F), carboxylic acid group (COOH), ester group (COOR ４ ), amino (NH ２ ), mono-C １ ~C ６ Alkylamino, di-C １ ~C ６ Alkylamino, Hydroxyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and C １ ~C ６ The compound of claim 2, which is phenyl optionally substituted with one to four substituents selected from the group consisting of alkoxycarbonylmethyl.

6. R １ However, halogen atoms, nitro (NO ２ ), cyano (C≡N), trifluoromethyl (CF ３ ), trifluoromethoxy (OCF ３ ), pentafluorosulfanyl (SF ５ ), sulfonyl (SO ３ H), carboxylic acid group (COOH), ester group (COOR ４ ), amino (NH ２ ), mono-C １ ~C ６ Alkylamino, di-C １ ~C ６ Alkylamino, Hydroxyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl and C １ ~C ６ A straight-chain or branched C optionally substituted with one or two substituents selected from the group consisting of alkoxycarbonylmethyl １ ~C ６ Alkylsulfonyl, C ３ ~C ６ Cycloalkylsulfonyl and C ６ ~C １０ 3. The compound of claim 2, wherein the sulfonyl-containing group is selected from the group consisting of arylsulfonyl.

7. G １ is a -CH- group, and R １ may be unsubstituted or COOH, COOR ４ , C.O.N.H. ２ , phenoxy optionally substituted by one or two groups selected from CN, fluorine, chloro, trifluoromethyl, cyclopropyl and OH.

8. R ２ The compound according to any one of claims 1 to 7, wherein is a chlorine or fluorine atom.

9. R ３ The compound according to any one of claims 1 to 7, wherein both are hydrogen atoms.

10. i. 4-[((1r,4r)-4-(3-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)cyclohexyl)oxy]benzoic acid, ii. 4-[((1r,4r)-4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)cyclohexyl)oxy]benzoic acid, iii. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea, iv. 1-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea, v. 1-(9-fluoro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea, vi. 1-(9-chloro-2,3-dimethoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea, vii. 1-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(cyclopropanecarbonyl)piperidin-4-yl)urea, viii. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(cyclopropanecarbonyl)piperidin-4-yl)urea, ix. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)urea, x. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)urea, xi. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(isopropylsulfonyl)piperidin-4-yl)urea, xii. 1-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-propionylpiperidin-4-yl)urea, xiii. 4-(4-(3-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidin-1-yl)benzoic acid, xiv. 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)piperidin-1-yl)benzoic acid, xv. methyl 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annullen-7-yl)ureido)piperidine-1-carbonyl)benzoate, and xvi. The compound according to any one of claims 1 to 7, selected from the group consisting of 4-(4-(3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annullen-7-yl)ureido)piperidine-1-carbonyl)benzoic acid.

11. A pharmaceutical or veterinary composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7.

12. The composition according to claim 11 for use as a medicine.

13. 12. The composition of claim 11 for use in the treatment or prevention of a disease or disorder amenable to amelioration by inhibition of soluble epoxide hydrolase in an animal, including a human.

14. The disease or disorder may be selected from the group consisting of pulmonary diseases such as hypertension, atherosclerosis, chronic obstructive pulmonary disorder, asthma, sarcoidosis and cystic fibrosis, renal diseases such as acute kidney injury, diabetic kidney disease, chronic kidney disease, kidney damage due to hypertension and kidney damage due to high fat diet, stroke, pain, neuropathic pain, inflammation, pancreatitis, particularly acute pancreatitis, immune disorders, neurodevelopmental disorders such as schizophrenia and autism spectrum disorders, eye diseases, particularly diabetic keratopathy, exudative age-related macular degeneration, and retinopathies such as retinopathy of prematurity and diabetic retinopathy, cancer, obesity including obesity-induced colon inflammation, diabetes, metabolic syndrome, pre-eclampsia, anorexia nervosa, depression, male sexual dysfunction such as erectile dysfunction, wound healing, NSAID-induced ulcers, emphysema, scrapie, Parkinson's disease, arthritis, arrhythmias.

14. The compound or composition for use according to claim 13, wherein the compound or composition is selected from the group consisting of: inflammatory bowel disease, cardiac fibrosis, Alzheimer's disease, Raynaud's syndrome, Niemann-Pick disease type C, cardiomyopathy, vascular cognitive impairment, mild cognitive impairment, inflammatory bowel disease, liver cirrhosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, osteoporosis, chronic periodontitis, sepsis, seizure disorders such as epilepsy, dementia, edema such as cerebral edema, attention deficit hyperactivity disorder, schizophrenia, drug addiction, social anxiety disorder, colitis, amyotrophic lateral sclerosis, chemotherapy induced side effects, laminitis, inflammatory joint pain and synovitis, endothelial dysfunction, subarachnoid hemorrhage including aneurysmal subarachnoid hemorrhage, traumatic brain injury, cerebral ischemia, diabetes induced learning and memory impairment, cytokine storm, multiple sclerosis, and idiopathic pulmonary fibrosis.

15. 12. Use of a composition according to claim 11 in the manufacture of a medicament for the treatment or prevention of a disease or disorder amenable to amelioration by inhibition of soluble epoxide hydrolase in an animal, including a human.

16. The disease or disorder may be selected from the group consisting of pulmonary diseases such as hypertension, atherosclerosis, chronic obstructive pulmonary disorder, asthma, sarcoidosis and cystic fibrosis, renal diseases such as acute kidney injury, diabetic kidney disease, chronic kidney disease, kidney damage due to hypertension and kidney damage due to high fat diet, stroke, pain, neuropathic pain, inflammation, pancreatitis, particularly acute pancreatitis, immune disorders, neurodevelopmental disorders such as schizophrenia and autism spectrum disorders, eye diseases, particularly diabetic keratopathy, exudative age-related macular degeneration, and retinopathies such as retinopathy of prematurity and diabetic retinopathy, cancer, obesity including obesity-induced colon inflammation, diabetes, metabolic syndrome, pre-eclampsia, anorexia nervosa, depression, male sexual dysfunction such as erectile dysfunction, wound healing, NSAID-induced ulcers, emphysema, scrapie, Parkinson's disease, 16. The use according to claim 15, wherein the therapeutic agent is selected from the group consisting of arthritis, arrhythmias, cardiac fibrosis, Alzheimer's disease, Raynaud's syndrome, Niemann-Pick disease type C, cardiomyopathy, vascular cognitive impairment, mild cognitive impairment, inflammatory bowel disease, liver cirrhosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, osteoporosis, chronic periodontitis, sepsis, seizure disorders such as epilepsy, dementia, edema such as cerebral edema, attention deficit hyperactivity disorder, schizophrenia, drug addiction, social anxiety disorder, colitis, amyotrophic lateral sclerosis, chemotherapy induced side effects, laminitis, inflammatory joint pain and synovitis, endothelial dysfunction, subarachnoid hemorrhage including aneurysmal subarachnoid hemorrhage, traumatic brain injury, cerebral ischemia, diabetes induced learning and memory impairment, cytokine storm, multiple sclerosis, and idiopathic pulmonary fibrosis.

Images